As the second wave of the pandemic engulfs us and the world works at warp speed to develop vaccines and therapies to respond, the importance of regenerative medicine has never been higher. Since 2017, Goldman Sachs has touted the sector as one of the most compelling areas for venture capital investment. With billions of dollars of global government spending being poured into the search for vaccines and therapies to respond to the novel coronavirus, and with the FDA having now granted approval to the first vaccines based on CRISPR mRNA gene-editing technologies, business models based on regenerative medicines are commanding record values. Despite the flood of cash into regenerative medicine, legal and ethical considerations will continue to cause much controversy.

Regenerative medicine ultimately accelerates the human bodys healing process. It is an area of biomedical sciences that involves medical treatments to repair or replace damaged cells, tissues, or organs. Instead of merely focusing on the symptoms, regenerative medicine uses cellular therapies, tissue engineering, medical devices, and artificial organs to improve peoples health. For example, stem cell therapies, tissue grafts, and organ transplants are all part of regenerative medicine.

Today, cellular and acellular regenerative medicines are often used in clinical procedures such as cell, immunomodulation, and tissue engineering therapies. They have the potential to effectively treat many chronic diseases, including Alzheimers, Parkinsons and cardiovascular disorders, osteoporosis, and spinal cord injuries.

A small number of unscrupulous actors, according to the FDA, however, have seized on the clinical promise of regenerative medicine to offer patients unproven treatments. The FDA and other regulators are challenged to provide assurances of safety for these therapies without stifling development, as well as to approve treatments based on manipulation of stem cells derived from human and animal embryos given the ethical issues involved.

In the future, stem cell research will play an increasingly outsized role in regenerative medicine techniques. In November 2020, voters in California narrowly passed Proposition 14, a referendum to approve $5.5 billion in new government funding for stem cell research. Other governments around the world are doing the same.

Today, the growing prevalence of chronic medical ailments and genetic disorders across the globe is a primary factor driving the regenerative medicine industrys growth, according to the Regenerative Medicine Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2020-2025. The increasing aging population, prone to various musculoskeletal, oncological, dermatological, and cardiological disorders, is a key growth driver. Widespread adoption of organ transplantation is another contributing factor to this growth in market share. The current pandemic that began in January 2020, however, has changed the paradigm for regenerative medicine.

Market applications are burgeoning. Regenerative medicine can prevent and cure disease through effective vaccines and efficacious therapies. It can minimize the risk of organ rejection post-transplant and speed recovery. Technological advancements in cell-based therapies, such as the development of 3-D bioprinting techniques and the adoption of artificial intelligence in the production of regenerative medicines, are also stimulating growth. These advancements also facilitate dermatological grafting procedures to treat burns, bone defects, and skin wounds. Other factors, including extensive research and development activities in medical sciences and improving healthcare infrastructure, are also predicted to drive the market even further.

According to the Alliance for Regenerative Medicine, there are approaching approximately 1,000 companies focusing on this evolving area worldwide. These new companies are focusing on gene therapy, cell therapy and tissue engineering therapeutic developers. More than half of these companies are in North America, followed by almost a quarter in Europe and Israel and approximately 20% in Asia. More than 50% of these companies are focusing on cell therapy and gene therapy.

From 2014 to 2019, the global regenerative medicine market experienced a nearly 16% CAGR. Companies involved in gene and cell therapies as well as other regenerative medicine areas raised $4.8 billion during the first half of 2019, including $2.6 billion in the second quarter. Meanwhile, companies in Europe and Israel saw an acceleration of fundraising, with $1.3 billion amassed in just the first half of 2019, representing a 17% increase over the same period in 2018. Project Warp Speed has attracted billions of dollars of U.S. government spending, and similar efforts are ongoing in China, Russia, the European Union and among other major powers. Consequently, regenerative medicine has never before benefited from such a combination of public and private investment.

Whenever the viability and quality of human life are at stake, ethical and legal considerations always arise.

The modern ethical controversy surrounding regenerative medicine began in 1998 when research scientists at the University of Wisconsin succeeded in deriving and growing stem cells from early-stage human embryos. Ethicists and right-to-life activists protested that scientists were taking away human life (embryos) to conduct scientific experiments. Left unchecked, so the argument went, doctors could usurp nature and play God by developing the power to create and terminate life. A society where human life could be fundamentally perverted by medicine conjured up comparisons to Nazi Germany and Frankenstein. In 2001, then-U.S. President George W. Bush cut off federal funding for any research involving newly created embryonic stem cell lines, but agreed to continue funding research on 60 existing stem cell lines, where the life and death decision ha[d] already been made. The State of California responded in 2004 and again in 2020 with voter-approved programs directing billions of funding into stem cell research, making the region the global hub of regenerative medicine.

The use of human-derived embryonic stem cells, or animal-derived stem cells, continues to cause much controversy among ethicists and society at large. Some fear the risks of enrolling humans in experimental stem cell studies. Others fear the use of organs from human-animal chimeras in transplantation.

While these techniques have the potential to cure disease and save lives, they also have the potential to forever alter the nature of life as we know it and fundamental aspects of our society.

In the United States, legal jurisdiction for regulating regenerative medicine on a federal level lies with the FDA and in a patchwork of state laws, R&D funding programs and non-binding, NGO-promulgated statements of policy. The main responsibility of the FDA is to protect the public from dangerous products and ensure its safety, including overseeing medications for humans and animals, vaccines, and more.

During the Trump Administration, the FDA has largely focused on enabling developers to gain product approvals through a less burdensome and costly process. In numerous policy statements, the FDA under President Trump has deferred questions about the efficacy of new regenerative health products to the free markets, so long as they posed no serious safety or toxicity concerns.

The U.S. federal government is now transitioning to an administration led by President-elect Biden. The president-elect has spent many years advocating for increased R&D funding and going for moonshots. With a new mandate from the U.S. electorate to address the coronavirus, more money will be earmarked for regenerative medicines and stem cell research. How this will affect the release of new products into the market remains to be seen.

Regenerative medicine is poised to change the way we live, work and interact like never before. The fourth industrial revolution is upon us. CRISPR gene-editing technologies, facilitated by quantum-computing capabilities at the edge of a computer network powered by 5G telecommunications bandwidths, artificial intelligence and machine learning, have changed the game for regenerative medicine. We can foresee a day when those suffering from paralysis regain movement, when a damaged heart reverses course through regeneration, and when a diagnosis of Alzheimers Disease no longer means neurodegeneration. What a wonderful day that will be.

Changing the traditional healthcare model and moving from cure to prevention will take time.

The rise in chronic disease and the effort to reduce healthcare costs presents a large opportunity for the field of regenerative medicine.

As the continent becomes a bigger player, western companies should explore the potential prospects.

Topics from regenerative medicine to artificial intelligence to cannabis will be discussed.

The rest is here:
Regenerative Medicine: Market Trends and Legal Developments on the Horizon for 2021 - MedTech Intelligence

Spinal Cord Stem Cells Comments Off on Regenerative Medicine: Market Trends and Legal Developments on the Horizon for 2021 – MedTech Intelligence | December 13th, 2020

Abstract

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cellderived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.

Remyelination occurs in multiple sclerosis (MS) lesions but its capacity decreases over time (13). Failed remyelination in MS leads to altered conduction followed by axon degeneration, which, in the long run, results in severe and permanent neurological deficits (4). MS lesions may or may not harbor immature oligodendroglia (oligodendrocyte progenitors and pre-oligodendrocytes), with these cells failing to differentiate into myelin-forming cells, suggesting that oligodendrocyte differentiation is blocked (57). So far, the mechanism underlying this block is poorly understood. It may result from adverse environmental conditions or the failed capacity of oligodendrocyte progenitors/pre-oligodendrocytes to migrate or mature efficiently into myelin-forming cells or even a combination of these conditions, all of which may worsen with aging. It has been shown that increasing remyelination either through manipulating the endogenous pool (8, 9) or by grafting competent myelin forming oligodendroglia (10, 11) or both (12) can restore the lost axonal functions, improve the clinical scores, and protect from subsequent axonal degeneration in experimental (13, 14) or clinical (3) settings.

There are multiple ways to investigate the oligodendroglial lineage in disease. Cells can be studied in postmortem tissue sections or purified from postmortem adult human brain for in vitro and transcriptomic/proteomic analysis. In this respect, in vitro experiments highlighted the heterogeneity of the adult human oligodendrocyte progenitor population in terms of antigen and microRNA expression, suggesting that remyelination in the adult human brain involves multiple progenitor populations (15). Moreover, single-cell transcriptomics characterized in detail the heterogeneity of human oligodendroglial cells, emphasizing changes in MS, with some subpopulations expressing disease-specific markers that could play a role in disease onset and/or aggravation (16, 17).

Yet, this MS signature could preexist or be acquired early at disease onset. Moreover, most of these MS postmortem analyses or experimental models cannot overlook the involvement of extrinsic factors such as immune factors that might add more complexity toward understanding the behavior of MS oligodenroglial cells.

Little is known about the biology of the MS oligodendroglial lineage, primarily due to the impossibility, for ethical reasons, to harvest oligodendroglial populations from patients and study the diseased cells and their matching controls in vitro or in vivo after cell transplantation. While cell-cell interactions and cell heterogeneity in diseased conditions generate more complexity when comparing control and pathological samples, the induced pluripotent stem cell (iPSC) technology provides a unique opportunity to study homogeneous populations of human oligodendroglial cells and gain further insights into monogenetic diseases and multifactorial diseases, such as MS. The iPSC technology has unraveled differences in oligodendroglia biology, in Huntingtons disease (18), and schizophrenia (19, 20), indicating that these cells can contribute autonomously to multifactorial diseases outcome. However, so far, little is known about the potential contribution of MS oligodendroglia to failed remyelination. While senescence affects iPSCneural precursor cells (NPCs) derived from patients with primary progressive MS (PPMS) (21), only few preliminary reports alluded to the fate of PPMS (22, 23) or relapsing-remitting (RRMS) (24) iPSC-derived oligodendroglia after experimental transplantation and did not study per se their capacity to differentiate into functional myelin-forming cells. We exploited a robust approach (25) to generate large quantities of iPSCs-derived O4+ oligodendroglial cells from skin fibroblasts (hiOLs) of three RRMS and three healthy subjects, including two monozygous twin pairs discordant for the disease. As a critical feature of the pluripotent-derived cells should be their ability to fully integrate and function in vivo, we compared the capacity of healthy and MS-hiOL derivatives to integrate and restore axo-glial and glial-glial functional interactions after engraftment in the developing dysmyelinated murine central nervous system (CNS). Our data show that in noninflammatory conditions, the intrinsic properties of iPSC-oligodendroglial cells to differentiate, myelinate, and establish functional cell-cell interactions in vivo are not altered in MS, making them candidates of interest for personalized drug/cell therapies as pluripotency maintains MS oligodendroglial cells in a genuine nonpathological state.

Fibroblasts were isolated from three control and three patients with MS and reprogrammed into iPSC. Pluripotent cells were differentiated into NPCs and further into O4+ hiOLs for 12 days in vitro under glial differentiation medium (GDM) conditions as previously described (25). hiOL cells were selected using flow cytometry for O4 before transplantation. Because our aim was to study the intrinsic properties of MS cells, we chose to engraft O4+ hiOLs in the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects.

We first questioned whether MS-hiOLs differed from control-hiOLs wild type (WT) in their capacity to survive and proliferate in vivo. To this aim, we grafted MS- and control-hiOLs in the forebrain of neonatal Shi/Shi:Rag2/ mice. MS cells engrafted (one injection per hemisphere) in the rostral forebrain, spread primarily through white matter, including the corpus callosum and fimbria, as previously observed using control human fetal (11, 26, 27) and iPSC (25, 28) progenitors. With time, cells also spread rostrally to the olfactory bulb and caudally to the brain stem and cerebellum (fig. S1). Examining engrafted brains at 8, 12, and 16 weeks postgraft (wpg), we found that MS-hiOLs expressing the human nuclear marker STEM101 and the oligodendroglial-specific transcription factor OLIG2 maintained a slow proliferation rate at all times (5 to 19% of STEM+ cells), with no difference in Ki67+ MS-hiOLs compared to control (Fig. 1, A and C). Moreover, immunostaining for cleaved Caspase3 at 8 wpg indicated that MS cells survived as well as control-hiOLs (Fig. 1, B and D). Evaluation of the cell density of human cells based on STEM positivity at each stage revealed no significant difference between grafted MS-hiOLs and control cells (fig. S2).

(A and C) Immunodetection of the human nuclei marker STEM101 (red) combined with OLIG2 (green) and the proliferation marker Ki67 (white) shows that a moderate proportion of MS-hiOLs sustains proliferation (empty arrowheads in the insets) following transplantation in their host developing brain, with no significant difference in the rate of proliferation between MS- and control-hiOLs over time. (B and D) Immunodetection of the apoptotic marker Caspase3 (green) indicates that MS-hiOLs survive as well as control-hiOLs 8 wpg. Two-way analysis of variance (ANOVA) followed by Tukeys multiple comparison or Mann-Whitney t tests were used for the statistical analysis (n = 3 to 4 mice per group). Error bars represent SEMs. H, Hoechst dye. Scale bars, 100 m.

Because MS-hiOLs and control cells proliferated and survived to the same extent, we next questioned whether their differentiation potential into mature oligodendrocytes could be affected. We used the human nuclei marker STEM101 to detect all human cells in combination with SOX10, a general marker for the oligodendroglial lineage, and CC1 as a marker of differentiated oligodendrocytes. We found that the number of MS oligodendroglial cells (SOX10+) increased slightly but significantly with time, most likely resulting from sustained proliferation (Fig. 2, A and B). Moreover, they timely differentiated into mature CC1+ oligodendrocytes with a fourfold increase at 12 wpg and a fivefold increase at 16 wpg when compared to 8 wpg and with no difference with control-hiOLs (Fig. 2, B and C).

(A) Combined immunodetection of human nuclei marker STEM101 (red) with CC1 (green) and SOX10 (white) for control (top) and MS-hiOLs (bottom) at 8, 12, and 16 wpg. (B and C) Quantification of SOX10+/STEM+ cells (B) and CC1+ SOX10+ over STEM+ cells (C). While the percentage of human oligodendroglial cells increased only slightly with time, the percentage of mature oligodendrocytes was significantly time regulated for both MS- and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 3 to 4 mice per group). Error bars represent SEMs. *P < 0.05 and ****P < 0.0001. Scale bar, 100 m.

The absence of abnormal MS-hiOL differentiation did not exclude a potential defect in myelination potential. We further investigated the capacity of MS-hiOLs to differentiate into myelin-forming cells. We focused our analysis on the core of the corpus callosum and fimbria. MS-hiOLs, identified by the human nuclear and cytoplasmic markers (STEM101 and STEM121), evolved from a bipolar to multibranched phenotype (Fig. 3A and fig. S3: compare 4 wpg to 8 and 12 wpg) and differentiated progressively into myelin basic proteinpositive (MBP+) cells associated, or not, with T-shaped MBP+ myelin-like profiles of increasing complexity (Fig. 3A and figs. S3 and S4B). Myelin-like profiles clearly overlapped with NF200+ axons (fig. S4A) and formed functional nodes of Ranvier expressing ankyrin G and flanked by paranodes enriched for CASPR (fig. S4B) or neurofascin (fig. S4C), as previously observed with control-hiOLs (25).

(A) Combined detection of human nuclei (STEM101) and human cytoplasm (STEM 121) (red) with MBP (green) in the Shi/Shi Rag2/ corpus callosum at 8, 12, and 16 wpg. General views of horizontal sections at the level of the corpus callosum showing the progressive increase of donor-derived myelin for control- (top) and MS- (bottom) hiOLs. (B) Evaluation of the MBP+ area over STEM+ cells. (C and D) Quantification of the percentage of (C) MBP+ cells and (D) MBP+ ensheathed cells. (E) Evaluation of the average sheath length (m) per MBP+ cells. No obvious difference was observed between MS and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 6 to 14 mice per group). Error bars represent SEMs. *P < 0.05, **P < 0.01, and ***P < 0.001. Scale bar, 200 m. See also figs. S3 and S5.

We further analyzed, in depth, the myelinating potential of MS-hiOLs, applying automated imaging and analysis, which provided multiparametric quantification of MBP as established in vitro (29) for each donor hiOL (three controls and three RRMS) at 4, 8, 12, 16, and 20 wpg in vivo (Fig. 3, B to D). We first examined the MBP+ surface area generated by the STEM+ cell population (Fig. 3B). While MS-hiOLs generated very low amount of myelin at 4 wpg, they generated significantly more myelin at 12, 16, and 20 wpg, with similar findings for control-hiOLs, highlighting the rapid progress in the percentage of myelin producing STEM+ cells in MS group over time. Detailed MBP+ surface area generated by the STEM+ cell population per donor is presented in fig. S5 and shows differences among hiOLs in the control and MS groups, respectively.

We also quantified the percentage of STEM+ cells expressing MBP and the percentage of MBP+ with processes associated with linear myelin-like features, which we called MBP+ ensheathed cells. Both parameters increased significantly with time for control-hiOLs, reaching a plateau at 16 wpg. The same tendency was achieved for MS-hiOLs with no significant differences between the control- and MS-hiOL groups (Fig. 3, C and D).

Myelin sheath length is considered to be an intrinsic property of oligodendrocytes (30). We analyzed this paradigm in our MS cohort at 12 and 16 wpg, time points at which sheaths were present at a density compatible with quantification. For those time points, we found that the average MS MBP+ sheath length was equivalent to that of control with 25.86 0.98 and 27.74 1.52 m for MS-hiOLs and 24.52 1.48 and 27.65 0.96 m for control-hiOLs at 12 and 16 wpg, respectively (Fig. 3F). In summary, our detailed analysis of immunohistochemically labeled sections indicates that MS-hiOLs did not generate abnormal amounts of myelin in vivo when compared to control-hiOLs.

Moreover, the myelinating potential of MS-hiOLs was further validated after engraftment in the developing spinal cord (4 weeks of age). Immunohistological analysis 12 wpg revealed that STEM+ cells not only populated the whole dorsal and ventral columns of the spinal cord with preferential colonization of white matter but also generated remarkable amounts of MBP+ myelin-like internodes that were found on multiple spinal cord coronal sections (fig. S6), thus indicating that their myelination potential was not restricted to only one CNS structure.

The presence of normal amounts of donor MBP+ myelin-like structures in the shiverer forebrain does not exclude potential structural anomalies. Therefore, we examined the quality of MS derived myelin at the ultrastructural level at 16 wpg in the Shi/Shi:Rag2/ forebrain. In the corpus callosum of both MS and control-hiOLs grafted mice, we detected numerous axons surrounded by electron dense myelin, which at higher magnification was fully compacted compared to the uncompacted shiverer myelin (Fig. 4, A to F) (25, 31). Moreover, MS myelin reached a mean g ratio of 0.76 1.15 comparable to that of control myelin (0.75 1.56) (Fig. 4G) and thus a similar myelin thickness. This argues in favor of (i) MS-hiOLs having the ability to produce normal compact myelin and thus its functional normality and (ii) a similar rate of myelination between the two groups and, consequently, an absence of delay in myelination for MS-hiOLs.

(A to F) Ultrastructure of myelin in sagittal sections of the core of the corpus callosum 16 wpg with control-hiOLs (A to C) and MS-hiOLs (D to F). (A and D) General views illustrating the presence of some electron dense myelin, which could be donor derived. (B, C, E, and F) Higher magnifications of control (B and C) and MS (E and F) grafted corpus callosum validate that host axons are surrounded by thick and compact donor derived myelin. Insets in (C) and (F) are enlargements of myelin and show the presence of the major dense line. No difference in compaction and structure is observed between the MS and control myelin. (G) Quantification of g-ratio revealed no significant difference between myelin thickness of axons myelinated by control- and MS-hiOLs. Mann-Whitney t tests were used for the statistical analysis of this experiment (n = 4 mice per group). Error bars represent SEMs. Scale bars, (A and D) 5 m , (B and E) 2 m, and (C and F) 500 nm [with 200 and 100 nm, respectively in (C) and (F) insets].

Myelin compaction has a direct impact on axonal conduction with slower conduction in shiverer mice compared to WT mice (10, 32). We therefore questioned whether newly formed MS-hiOLderived myelin has the ability to rescue the slow axon conduction velocity of shiverer mice in vivo (Fig. 5). As previously performed with fetal glial-restricted progenitors (11), transcallosal conduction was recorded in vivo at 16 wpg in mice grafted with MS- and control-hiOLs and compared with nongrafted shiverer and WT mice. As expected, conduction in nongrafted shiverer mice was significantly slower compared to WT mice. However, axon conduction velocity was rescued by MS-hiOLs and, to the same extent, by control-hiOLs.

(A) Scheme illustrating that intracallosal stimulation and recording are performed in the ipsi- and contralateral hemisphere, respectively. (B) N1 latency was measured following stimulation in different groups of Shi/Shi:Rag2/: intact or grafted with control or MS-hiOLs and WT mice at 16 wpg. MS-hiOLderived myelin significantly restored transcallosal conduction latency in Shi/Shi:Rag2/ mice to the same extent than control-derived myelin (P = 0.01) and close to that of WT levels. One-way ANOVA with Dunnetts multiple comparison test for each group against the group of intact Shi/Shi:Rag2/ was used. Error bars represent SEMs. *P < 0.05. (C) Representative response profiles for each group. Scales in Y axis is equal to 10 V and in the X axis is 0.4 ms.

Rodent oligodendrocyte progenitors and oligodendrocytes can be distinguished by cell stagespecific electrophysiological properties (33, 34). To assess the electrophysiological properties of oligodendroglial lineage cells derived from human grafted control- and MS-hiOLs, red fluorescent protein (RFP)hiOLs were engrafted in the Shi/Shi:Rag2/ forebrain and recorded with a K-gluconatebased intracellular solution in acute corpus callosum slices at 12 to 15 wpg (Fig. 6A). As previously described for rodent cells, hiOLs in both groups were identified by their characteristic voltage-dependent current profile recognized by the presence of inward Na+ currents and outwardly rectifying steady-state currents (Fig. 6B). We found that ~60 and ~44% of recorded cells were oligodendrocyte progenitors derived from MS and control progenies, respectively. No significant differences were observed in the amplitude of Na+ currents measured at 20 mV (Fig. 6D) or steady-state currents measured at +20 mV between MS- and control-derived oligodendrocyte progenitors (Isteady = 236.70 19.45 pA and 262.10 31.14 pA, respectively; P = 0.8148, Mann Whitney U test). We further confirmed the identity of these cells by the combined expression of SOX10 or OLIG2 with STEM101/121 and the absence of CC1 in biocytin-loaded cells (Fig. 6F, top). The remaining recorded cells (MS and control) did not show detectable Na+ currents after leak subtraction and were considered to be differentiated oligodendrocytes by their combined expression of SOX10, STEM101/121, and CC1 in biocytin-loaded cells (Fig. 6F, bottom). The I-V curve of these differentiated oligodendrocytes displayed a variable profile that gradually changed from voltage dependent to linear as described for young and mature oligodendroglial cells in the mouse (33). Figure 6C illustrates a typical linear I-V curve of fully mature MS-derived oligodendrocytes. No significant differences were observed in the amplitude of steady-state currents measured at +20 mV between MS- and control-derived oligodendrocytes (Fig. 6E). Overall, the electrophysiological profile of oligodendrocyte progenitors and oligodendrocytes derived from control and MS was equivalent and showed similar characteristics to murine cells (33, 34).

(A) Schematic representation of the concomitant Biocytin loading and recording of single RFP+ hiOL derivative in an acute coronal brain slice prepared from mice engrafted with hiOLs (control or MS) and analyzed at 12 to 14 wpg. (B and C) Currents elicited by voltage steps from 100 to +60 mV in a control-oligodendrocyte progenitor (B, left) and a MS-oligodendrocyte (C, left). Note that the presence of an inward Na+ current obtained after leak subtraction in the oligodendrocyte progenitor, but not in the oligodendrocyte (insets). The steady-state I-V curve of the oligodendrocyte progenitor displays an outward rectification (B, right) while the curve of the oligodendrocyte has a linear shape (C, right). (D) Mean amplitudes of Na+ currents measured at 20 mV in control and MS iPSCs-derived oligodendrocyte progenitors (n = 8 and n = 9, respectively, for four mice per condition; P = 0.743, Mann-Whitney U test). (E). Mean amplitudes of steady-state currents measured at +20 mV in control and patient differentiated iPSC-derived oligodendrocytes (n = 10 and n = 6 for 3 and four mice, respectively; P = 0.6058, Mann-Whitney U test). (F) A control iPSC-derived oligodendrocyte progenitor loaded with biocytin and expressing OLIG2, STEM101/121, and lacking CC1 (top) and an MS iPSCderived oligodendrocyte loaded with biocytin and expressing SOX10, CC1, and STEM101/121 (bottom). Scale bar, 20 m.

(A) Z-stack identifying a target and connected cell. One single grafted human RFP+ cell (per acute slice) was loaded with biocytin by a patch pipette and allowed to rest for 30 min. The white arrowheads and insets in (A) illustrate biocytin diffusion up to the donut-shaped tip of the human oligodendrocyte processes. Another biocytin-labeled cell (empty yellow arrowhead) was revealed at different morphological level indicating diffusion to a neighboring cell and communication between the two cells via gap junctions. (B and C) Split images of (A) showing the target (B) and connected (C) cell separately at different levels. Immunolabeling for the combined detection of the human markers STEM101/121 (red), OLIG2 (blue), and CC1 (white) indicated that the target cell is of human origin (STEM+) and strongly positive for OLIG2 and CC1, a mature oligodendrocyte, and that the connected cell is of murine origin (STEM-) and weakly positive for OLIG2 and CC1, most likely an immature oligodendrocyte. Scale bars, 30 m. See also fig. S7.

Studies with rodents have reported that oligodendrocytes exhibit extensive gap-junctional intercellular coupling between other oligodendrocytes and astrocytes (35). Whether oligodendrocytes derived from grafted human cells can be interconnected with cells in the adult host mouse brain was not known, and whether MS-hiOLs maintain this intrinsic property was also not addressed. Because biocytin can pass through gap junctions, we inspected biocytin-labeled cells for dye coupling (Figs. 6A and 7, A and B).

We found that two of seven MS-derived oligodendrocytes (~29%) and 5 of 21 control-derived oligodendrocytes (~24%) were connected with a single neighboring cell, which was either human or murine (Fig. 7), except in one case where three mouse cells were connected to the biocytin-loaded human cell. These findings reveal that gap junctional coupling can occur between cells from the same or different species, and MS-hiOLs can functionally connect to other glial cells to the same extent as their control counterparts.

To validate the presence of glial-glial interactions, we investigated whether the grafted hiOL-derived progeny had the machinery to be connected to one another via gap junctions. To this end, we focused on oligodendrocyte-specific Cx47 and astrocyte-specific Cx43 as Cx43/47 channels, which are important for astrocyte/oligodendrocyte cross talk during myelination and demyelination (36, 37). Combined immunolabeling for hNOGOA, CC1, OLIG2, and Cx47 revealed that MS-derived oligodendrocyte cell bodies and processes were decorated by Cx47+ gap junction plaques, which were often shared by exogenous MS-derived oligodendrocytes or by MS and endogenous murine oligodendrocytes (fig. S7A). In addition, colabeling exogenous myelin for MBP and Cx43 identified the presence of several astrocyte-specific Cx43 gap junction plaques between human myelin internodes, highlighting contact points between astrocyte processes and axons at the human-murine chimeric nodes of Ranvier (fig. S7B).

Last, colabeling of hNOGOA, with Cx47 and the astrocyte-specific Cx43, revealed coexpression of oligodendrocyte- and astrocyte-specific connexins at the surface of MS-derived oligodendrocyte cell bodies and at the level of T-shaped myelin-like structures (fig. S7C), thus implying connections between human oligodendrocytes and murine and/or human astrocytes, as a small proportion of the grafted hiOLs differentiated into astrocytes. Immunolabeling for human glial fibrillary acidic protein (GFAP), and Cx43 showed that these human astrocytes were decorated by Cx43+ aggregates, as observed in the host subventricular zone (fig. S8A).

Furthermore, immunolabeling for human GFAP, mouse GFAP, and Cx43 indicated that Cx43+ gap junctions were shared between human and mouse astrocytes as observed at the level of blood vessels (fig. S8B). These data validate interconnections between the grafted-derived human glia (MS and controls) with murine host glial cells and confirm their interconnection with the pan-glial network.

Two main hypotheses have been considered in understanding MS pathology and etiology: the outside-in hypothesis highlighting the role of immune regulators and environmental inhibitors as extrinsic key players in MS pathology and possibly its repair failure or the inside-out hypothesis pointing to the intrinsic characteristics of neuroglia including oligodendroglial cells as the main contributors in the MS scenario. Single-cell transcriptomic analysis revealed the presence of disease-specific oligodendroglia expressing susceptibility genes in MS brains (16) and altered oligodendroglia heterogeneity in MS (17). The question remains open as to whether these altered oligodendroglial phenotypes are acquired in response to the disease environment or whether they reflect intrinsic traits of the MS oligodendroglial population. On the other hand, the whole exome sequencing analysis in 132 patients from 34 multi-incident families identified 12 candidate genes of the innate immune system and provided the molecular and biological rational for the chronic inflammation, demyelination, and neurodegeneration observed in patients with MS (38) and revealed the presence of epigenetic variants in immune cells and in a subset of oligodendrocytes contributing to risk for MS (39).

While none of these hypotheses have been fully proven or rejected, research efforts for a better understanding of this multifactorial disease have continued. Impaired remyelination or oligodendrocyte differentiation block in MS is still considered a potentially disease-relevant phenotype (40, 41). Many histological and experimental studies suggest that impaired oligodendrocyte progenitor to oligodendrocyte differentiation may contribute to limited remyelination in MS, although some reports question the contribution of newly generated oligodendrocytes to remyelination (17, 42, 43). Understanding MS oligodendrocyte biology has been challenging mainly due to the following reasons: (i) oligodendroglial cells are not easily accessible to be studied in vivo; (ii) dynamic remyelination observed in patients with MS, which points to their individual remyelination potential, is inversely correlated with their clinical disability (3), highlighting even more complexity in oligodendrocyte heterogeneity between patients with MS; and (iii) exclusion of the role of immune system players in understanding MS oligodendrocyte biology being inevitable in most of clinical or experimental studies.

In such a complex multifactorial disease, one of the most accessible and applicable approaches to overcome these problems is the generation of large quantities of disease and control oligodendroglia using the iPSC technology, and to investigate their genuine behavior in vivo after engraftment in a B and T cellfree system. Using a very efficient reprogramming method (25), and the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects, we show that MS-hiOLs derivatives survive, proliferate, migrate, and timely differentiate into bona fide myelinating oligodendrocytes in vivo as efficiently as their control counterparts. Nicaise and colleagues reported that iPSC-NPCs from PPMS cases did not provide neuroprotection against active CNS demyelination compared to control iPSC-NPCs (44) and failed to promote oligodendrocyte progenitor genesis due to senescence without affecting their endogenous capacity to generate myelin-forming oligodendrocytes (21, 22). However, their myelinating potential was not evaluated against control cells. Generation of iPSC-oligodendrocyte progenitors from patients with PPMS or RRMS has also been reported by other groups, yet with no evidence for their capacity to become functional oligodendrocytes in vivo (23, 24). Thus, so far, no conclusion could be made regarding the potential impact of disease severity (PPMS verses RRMS) on the functionality of the iPSC-derived progeny.

We compared side by side, and at different time points after engraftment, hiOLs from patients with RRMS and controls including two pairs of homozygous twins discordant for disease. We found no significant difference in their capacity to timely differentiate (according to the human tempo of differentiation) and efficiently myelinate axons in the shiverer mouse in terms of the percentage of MBP+ cells generated, amount of myelin produced, length of MBP+ sheaths, and the ultrastructure and thickness of myelin sheaths. MS-hiOLs also reconstructed nodes of Ranvier expressing nodal components key to their function. We not only verified that the grafted MS-hiOLs derivatives were anatomically competent but also established their functionality at the electrophysiological level using (i) in vivo recordings of transcallosal evoked potentials and (ii) ex vivo recordings of the elicited current-voltage curves of the grafted MS-hiOLs verses controls. Our data show that the grafted MS-hiOLs were able to rescue the established delayed latency of shiverer mice to the same extent as control cells, as previously reported for human fetal glial progenitors grafted in the same model (11). Moreover, at the single-cell level, MS-hiOLderived oligodendrocyte progenitors and oligodendrocytes did not harbor aberrant characteristics in membrane currents compared to control cells ex vivo. Thus, iPSC-derived human oligodendroglial cells shift their membrane properties with maturation as previously observed in vitro (45) and these properties are not impaired in MS.

The absence of differences among control and MS-derivatives might be due to different causes. One might consider that pluripotency induction could by in vitro manipulation, erase cell epigenetic traits and/or reverse cells to an embryonic state, and as a result, modulate their intrinsic characteristics. Yet, several reports have highlighted differences in the behavior of diseased iPSC-derived oligodendrocytes in comparison to those from healthy controls using the same technology in multifactorial diseases such as schizophrenia (19, 20), Huntingtons disease (18), and others (46). In this regard, direct reprogramming of somatic cells into the desired cell type, bypassing the pluripotent stage, could be an attractive alternative. However, so far only mouse fibroblasts have been successfully directly converted into oligodendroglial cells, and with relatively low efficiency (47, 48).

iPSCs were transduced with three transcription factors to generate hiOLs in a fast and efficient way (25). While we cannot rule out that the use of these three transcription factors may have obscured differences between MS and controls, results for controls are quite comparable to our previously published data based on human fetal oligodendrocyte progenitor engraftment in the Shi/Shi:Rag2/ developing forebrain (49) or fetal NPC engrafted in the Shi/Shi:Rag2/ demyelinated spinal cord (50), suggesting that transduction with the three transcription factors does not overly modify the behavior of the grafted human cells. It could also be argued that the absence of differences between control and MS monozygous twins is not surprising given their equal genetic background. Yet, comparing controls with nonsibling MS hiOLS (compare C1 with RRMS2 and RRMS3; C2 with RRMS1, RRMS2, and RRMS3; and C3 with RRMS1 and RRMS2) revealed no defect in myelination for MS cells as well.

Analysis of hiOLs from each donor showed differences within each group. This could result from phenotypic instability, heterogeneity among donors, or disease subtype. Yet, the clinical history of each patient suggests a certain homogeneity among the MS disease phenotype, all being RRMS. In addition, the equal survival and proliferation rates between both groups argue in favor of cell stability. These confounding observations sustain that differences in terms of myelination are most likely due to heterogeneity among individuals rather than phenotypic instability or disease subtype.

While most preclinical transplantation studies have focused on myelination potential as the successful outcome of axo-glia interactions, less is known about the capacity of the grafted cells to fulfill glial-glial interactions in the pan-glial syncytium, which could ensure maintenance of newly generated myelin (51) and cell homeostasis (52). Oligodendrocytes are extensively coupled to other oligodendrocytes and oligodendrocyte progenitors through the homologous gap junctions Cx47 (35). These intercellular interactions between competing oligodendroglial cells influence the number and length of myelin internodes and the initiation of differentiation (53, 54). Oligodendrocytes are also coupled to astrocytes through heterologous gap junctions such as Cx32/Cx30 and Cx47/Cx43 (55). Disruption of oligodendrocytes from each other and from astrocytes, i.e., deconstruction of pan-glial network, has been observed in experimental models of demyelination (unpublished data) and frequently reported in MS and neuromyelitis optica (37, 56, 57). Mutations in Cx47 and Cx32 result in developmental CNS and PNS abnormalities in leukodystrophies (58, 59). Moreover, experimental ablation of Cx47 results in aberrant myelination (60) and significantly abolished coupling of oligodendrocytes to astrocytes (35).

In view of the major role of Cx-mediated gap junctions among oligodendrocytes and between oligodendrocytes and astrocytes during myelin formation (55), we asked whether the MS-hiOL progeny was capable of making functional gap junctions with other glial cells, and integrating into the host panglial network. We show that grafted MS-hiOLs, in common with rodent oligodendrocytes, express Cx47 that was frequently shared not only between the human and murine oligodendrocytes (through Cx47-Cx47) but also in conjunction with the astrocyte Cx43 (via Cx47/Cx43). The dye-coupling study highlighted that MS-hiOLs, similar to control cells, were capable of forming functional gap junctions with neighbor murine or human glial cells, indicating that MS-hiOLs retained the intrinsic property, not only to myelinate host axons but also to functionally integrate into the host pan-glial network. While our study focused mainly on oligodendroglial cells, a small proportion of the grafted hiOLs differentiated into astrocytes expressing Cx43. These human astrocytes were detected associated with blood vessels or the subventricular zone, where they were structurally gap-junction coupled to mouse astrocytes as observed after engraftment of human fetal glial restricted progenitors (61).

Together, our data highlight that human skinderived glia retain characteristics of embryonic/fetal brainderived glia as observed for rodent cells (10). In particular, we show that MS-hiOLs timely differentiate into mature oligodendrocytes, functionally myelinate host axons and contribute to the human-mouse chimeric pan-glial network as efficiently as control-hiOLs. These observations favor a role for extrinsic rather than intrinsic oligodendroglial factors in the failed remyelination of MS. The International Multiple Sclerosis Genetics Consortium after analyzing the genomic map of more than 47,000 MS cases and 63,000 control subjects, implicated microglia, and multiple different peripheral immune cell populations in disease onset (62). Moreover, neuroinflammation appears to block oligodendrocyte differentiation and to alter their properties and thereby aggravate the autoimmune process (63). Furthermore, MS lymphocytes are reported to exhibit intrinsic capacities that drive myelin repair in a mouse model of demyelination (64). On the other hand, a recent study highlighted the presence of disease-specific oligodendroglia in MS (16, 17). However, it should be considered that most of the data in the later were collected using single nuclei RNA sequencing of postmortem tissues from MS or control subjects of different ages that were suffering from other disorders ranging from cancer to sepsis and undergoing various treatment, and so died for different reasons, that may have influenced the type or level of RNA expression by the cells. In addition, the presence of genetic variants that alter oligodendrocyte function in addition to that of immune cells was also found (39). While this oligodendrocyte dysfunction contributes to MS risk factor, whether it is involved in other aspects of MS such as severity, relapse rate, and rate of progression is not yet known.

Numerous factors may cause the failure of oligodendrocyte progenitor maturation comprising factors such as axonal damage and/or altered cellular and extracellular signaling within the lesion environment (65) without neglecting aged-related environmental and cellular changes (40). Although the cells generated in this study are more of an embryonic nature, and did not experienced the kind of inhibitory environment that is present in MS, our data provide valuable findings in the scenario of MS pathology highlighting that RRMS-hiOLs, regardless of major manipulators of the immune system, do not lose their intrinsic capacity to functionally myelinate and interact with other neuroglial cells in the CNS under nonpathological conditions. Whether RRMS-hiOLs or oligodendroglial cells directly reprogrammed from MS fibroblasts would behave similarly well, if challenged with neuropathological inflammatory conditions as opposed to conditions wherein the immune system is intact (presence of T and B cells), or whether they would reflect intrinsic aging properties will require further investigation.

In summary, our findings provide valuable insights not only into the biology of MS oligodendroglia but also their application for cell-based therapy and should contribute to the establishment of improved preclinical models for in vivo drug screening of pharmacological compounds targeting the oligodendrocyte progenitors, oligodendrocytes, and their interactions with the neuronal and pan-glial networks.

We examined side by side the molecular, cellular, and functional behavior of MS hiOLs with their control counterparts after their engraftment in a dysmyelinating animal model to avoid the effect of major immune modulators. We used three MS and three control hiOLs including two monozygous twin pairs discordant for the disease. We performed in vivo studies in mouse with sample size between three to six animals per donor/time point/assay required to achieve significant differences. Numbers of replicates are listed in each figure legend. Animals were monitored carefully during all the study time, and animal welfare criteria for experimentation were fully respected. All experiments were randomized with regard to animal enrollment into treatment groups. The same experimenter handled the animals and performed the engraftment experiments to avoid errors. The data were analyzed by a group of authors.

Shiverer mice were crossed to Rag2 null immunodeficient mice to generate a line of Shi/Shi:Rag2/ dysmyelinating-immunodeficient mice to (i) prevent rejection of the grafted human cells and allow detection of donor-derived WT myelin and (ii) investigate the original behavior of MS-derived oligodendrocytes in a B cell/T cellfree environment. Mice were housed under standard conditions of 12-hour light/12-hour dark cycles with ad libitum access to dry food and water at the ICM animal facility. Experiments were performed according to European Community regulations and INSERM ethical committee (authorization 75-348; 20/04/2005) and were approved by the local Darwin ethical committee.

Fibroblasts were obtained under informed consent from three control and three RRMS subjects including two monozygous twin pairs discordant for the disease. They were reprogrammed into iPSCs using the replication incompetent Senda virus kit (Invitrogen) according to manufacturers instructions. Table S1 summarizes information about the human cell lines used in this study. The study was approved by the local ethical committees of Mnster and Milan (AZ 2018-040-f-S, and Banca INSpe).

Human iPSCs were differentiated into NPC by treatment with small molecules as described (66, 67). Differentiation of NPCs into O4+ oligodendroglial cells used a poly-cistronic lentiviral vector containing the coding regions of the human transcription factors Sox10, Olig2, and Nkx6.2 (SON) followed by an IRES-pac cassette, allowing puromycin selection for 16 hours (25). For single-cell electrophysiological recordings, the IRES-pac cassette was replaced by a sequence encoding RFP. Briefly, human NPCs were seeded at 1.5 105 cells per well in 12-well plates, allowed to attach overnight and transduced with SON lentiviral particles and protamine sulfate (5 g/ml) in fresh NPC medium. After extensive washing, viral medium was replaced with glial induction medium (GIM). After 4 days, GIM was replaced by differentiation medium (DM). After 12 days of differentiation, cells were dissociated by accutase treatment for 10 min at 37C, washed with phosphate-buffered saline (PBS) and resuspended in PBS/0.5% bovine serum albumin (BSA) buffer, and singularized cells were filtered through a 70-m cell strainer (BD Falcon). Cells were incubated with mouse immunoglobulin M (IgM) antiO4-APC antibody (Miltenyi Biotech) following the manufacturers protocol, washed, resuspended in PBS/0.5% BSA buffer (5 106 cells/ml), and immediately sorted using a FACS Aria cell sorter (BD Biosciences). Subsequently, human O4+ hiOLs were frozen and stored in liquid nitrogen. Media details were provided in (25). hiOLS from each donor was assayed individually (no cell mix) and studied as follows for forebrain engraftment: immunohistochemistry (all donors, three to seven mice per time point), electron microscopy (C1 and RRMS1, four mice per donor at 16 wpg), in vivo electrophysiology (C1 and RRMS1, six mice per donor and eight mice per medium at 16 wpg), dye coupling, and ex-vivo electrophysiology (C1-RFP and RRMS3-RFP, six to seven mice per donor at 16 wpg). For spinal cord engraftment: immuno-histochemistry (C1 and RRMS3, 3 and 4 mice respectively at 12 wpg).

RRMS1: Disease duration at biopsy was 11 years. Started on Rebif 22 and switched to Rebif 44 because of relapses. Relapse was treated with bolus of cortisone 20 to 30 days before biopsy and then switched to natalizumab.

RRMS2: Disease duration at biopsy was 16 months. Relapse at disease onset. On Rebif 22 from disease onset until biopsy with no episodes. A new lesion was identified 3 months after biopsy. At the time of biopsy, the patient reported cognitive difficulties, no motor dysfunctions.

RRMS3: Disease duration at biopsy was 15 months. Relapse 6 months before biopsy with dysesthesias and hypoesthesia right thigh and buttock. Active lesion identified by magnetic resonance imaging at day 10. On Rebif smart 44 mcg, 50 days later, and skin biopsy 4 months later. A new gadolinium negative temporal lesion identified 2 months after biopsy and the patient switched to Tecfidera.

To assay hiOL contribution to forebrain developmental myelination, newborn Shi/Shi:Rag2/ pups (n = 148) were cryo-anesthetized, and control and RRMS hiOLs were transplanted bilaterally, rostral to the corpus callosum. Injections (1 l in each hemisphere and 105 cells/l) were performed 1 mm caudally, 1 mm laterally from the bregma, and to a depth of 1 mm as previously described (49, 68). Animals were sacrificed at 4, 8, 12, 16, and, when indicated, 20 wpg for immunohistological studies and at one time point for electron microscopy (16 wpg), ex vivo (12 to 15 wpg), and in vivo (16 wpg) electrophysiology.

To assay the fate of hiOLs in the developing spinal cord, 4-week-old mice (n = 4) were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) (Alcyon) and xylazine (10 mg/kg) (Alcyon) and received a single injection at low speed (1 l/2 min) of hiOLs (1 l, 105 cells/l) at the spinal cord thoracic level using a stereotaxic frame equipped with a micromanipulator and a Hamilton syringe. Animals were sacrificed at 12 wpg for immunohistological studies.

Immunohistochemistry. Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 3 to 6 per group, donor and time point) were sacrificed by transcardiac perfusion-fixation with 4% paraformaldehyde in PBS. Tissues were postfixed in the same fixative for 1 hour and incubated in 20% sucrose in 1 PBS overnight before freezing at 80C. Serial horizontal brain and spinal cord cross sections of 12 m thickness were performed with a cryostat (CM3050S, Leica). Transplanted hiOLs were identified using anti-human cytoplasm [1:100; STEM121; Takara, Y40410, IgG1], anti-human nuclei (1:100; STEM101; Takara, Y40400, IgG1), and anti-human NOGOA (1:50; Santa Cruz Biotechnology, sc-11030, goat) antibodies. In vivo characterization was performed using a series of primary antibodies listed in tableS2. For MBP staining, sections were pretreated with ethanol (10 min, room temperature). For glial-glial interactions, oligodendrocyte-specific connexin was detected with anti-connexin 47 (1:200; Cx47; Invitrogen, 4A11A2, IgG1) and astrocyte-specific connexin, with anti-connexin 43 (1:50; Cx43; Sigma-Aldrich, C6219, rabbit), and sections were pretreated with methanol (10 min, 20C). Secondary antibodies conjugated with fluorescein isothiocyanate, tetramethyl rhodamine isothiocyanate (SouthernBiotech), or Alexa Fluor 647 (Life Technologies) were used, respectively, at 1:100 and 1:1000. Biotin-conjugated antibodies followed by AMCA AVIDIN D (1:20; Vector, A2006). Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI) (1 g/ml; Sigma-Aldrich) (1:1000). Tissue scanning, cell visualization, and imaging were performed with a Carl Zeiss microscope equipped with ApoTome 2.

Electron microscopy. For electron microscopy, Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 4 per group) were perfused with 1% PBS followed by a mixture of 4% paraformaldehyde/5% glutaraldehyde (Electron Microscopy Sciences) in 1% PBS. After 2-hour postfixation in the same solution, 100-m-thick sagittal sections were cut and fixed in 2% osmium tetroxide (Sigma-Aldrich) overnight. After dehydration, samples were flat-embedded in Epon. Ultra-thin sections (80 nm) of the median corpus callosum were examined and imaged with a HITACHI 120 kV HT-7700 electron microscope.

Electrophysiological recordings were performed in mice grafted with MS- and control-hiOLs, and compared with nongrafted intact or medium injected Shi/Shi:Rag2/ mice and WT mice 16 weeks after injection (n = 4 to 6 per group) as described (11). Briefly mice were anesthetized with 2 to 4% isoflurane performed under analgesia (0.1 mg/kg buprecare) and placed in a stereotaxic frame (D. Kopf, Tujunga, CA, USA). Body temperature was maintained at 37C by a feedback-controlled heating blanket (CMA Microdialysis). Electrical stimulation (0.1 ms at 0 to 0.1 mA) was applied using a bipolar electrode (FHC- CBBSE75) inserted to a depth of 200 m into the left cortex at 2 mm posterior to bregma and 3 mm from the midline. At the same coordinates in the contralateral hemisphere, homemade electrodes were positioned for recording local field potentials (LFPs) generated by transcallosal electric stimulation. Electrical stimulation and evoked LFPs were performed by the data acquisition system apparatus (Neurosoft, Russia), and signals were filtered at 0.01 to 1 000 Hz. Each response latency (in ms) was measured as the time between the onset of stimulus artifact to the first peak for each animal. A ground electrode was placed subcutaneously over the neck.

Slice preparation and recordings. Acute coronal slices (300 m) containing corpus callosum were made from Shi/Shi:Rag2/ mice grafted with control (n = 7) and RRMS (n = 6) RFP+ hiOLs. They were prepared from grafted mice between 12 and 15 wpg as previously described (69). Briefly, slices were performed in a chilled cutting solution containing 93 mM N-methyl-d-glucamine, 2.5 mM KCl, 1.2 mM NaH2PO4, 30 mM NaHCO3, 20 mM Hepes, 25 mM glucose, 2 mM urea, 5 mM Na-ascorbate, 3 mM Na-pyruvate, 0.5 mM CaCl2, and 10 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2) and kept in the same solution for 8 min at 34C. Then, they were transferred for 20 min to solution at 34C containing 126 mM NaCl, 2.5 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 20 mM glucose, 5 mM Na-pyruvate, 2 mM CaCl2, and 1 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2). Transplanted RFP+ hiOLs were visualized with a 40 fluorescent water-immersion objective on an Olympus BX51 microscope coupled to a CMOS digital camera (TH4-200 OptiMOS) and an light-emitting diode light source (CoolLed p-E2, Scientifica, UK) and recorded in voltage-clamp mode with an intracellular solution containing 130 mM K-gluconate, 0.1 mM EGTA, 2 mM MgCl2, 10 mM Hepes, 10 mM -aminobutyric acid, 2 mM Na2-adenosine 5-triphosphate, 0.5 mM Na-guanosine 5-triphosphate, 10 mM Na2-phosphocreatine, and 5.4 mM biocytin (pH 7.23). Holding potentials were corrected by a junction potential of 10 mV. Electrophysiological recordings were performed with Multiclamp 700B and Pclamp10.6 software (Molecular Devices). Signals were filtered at 3 kHz, digitized at 10 kHz, and analyzed off-line.

Immunostainings and imaging of recorded slices. For analysis of recorded cells, one single RFP+ cell per hemisphere was recorded in a slice and loaded with biocytin for 25 min in whole-cell configuration. After gently removing the patch pipette, biocytin was allowed to diffuse for at least 10 min before the slice was fixed 2 hours in 4% paraformaldehyde at 4C. Then, the slice was rinsed three times in PBS for 10 min and incubated with 1% Triton X-100 and 10% normal goat serum (NGS) for 2 hours. After washing in PBS, slices were immunostained for SOX10, CC1, and STEM101/121. Tissues were incubated with primary antibodies for 3 days at 4C. Secondary antibodies were diluted in 2% NGS and 0.2% Triton X-100. Tissues were incubated with secondary antibodies for 2 hours at room temperature. Biocytin was revealed with secondary antibodies using DyLight-488 streptavidin (Vector Laboratories, Burlingame, USA, 1:200). Images of biocytin-loaded cells were acquired either with a Carl Zeiss microscope equipped with ApoTome 2 or a LEICA SP8 confocal microscope (63 oil objective; numerical aperture, 1.4; 0.75-m Z-step) and processed with National Institutes of Health ImageJ software (70).

We adapted the heuristic algorithm from (29) to identify STEM+ MBP+ OLs in tissue sections. The foundations of the quantitative method remained the same. A ridge-filter extracted sheath-like objects based on intensity and segments associated to cell bodies using watershed segmentation. Two additional features adapted the workflow beyond its original in vitro application. First, we added functionality to allow colocalization of multiple fluorescent stains, as we needed to quantify triple positive STEM+/MBP+/DAPI+ cell objects. Second, because oligodendrocyte sheaths are not parallel and aligned in situ as they are in dissociated nanofiber cell cultures, we adapted the algorithm to report additional metrics about MBP production locally and globally that do not rely on the dissociation of sheaths in dense regions.

Cell nuclei were identified using watershed segmentation of DAPI+ regions and then colocalized pixel-wise with STEM+ objects. The DAPI+ nuclei were then used as local minima to seed a watershed segmentation of the STEM+ stain to separate nearby cell bodies. Last, the identified STEM+ cell bodies were colocalized with overlapping MBP+ sheath-like ridges to define ensheathed cells. We reported the area of MBP overlapping with STEM fluorescence in colocalized regions associated with individual cells, as well as the number of single, double, and triple fluorescently labeled cells. In addition, different cellular phenotypes were noted in situ that were then captured with the adapted algorithm. Qualitatively, we observed cells with expansive MBP production without extended linear sheath-like segments that were not observed in previous applications of the algorithm. These cells were denoted as tuft cells, and were quantitatively defined as STEM+/MBP+/DAPI+ cells without fluorescent ridges that could be identified as extended sheath-like objects.

The myelination potential of three control and 3 MS hiOLs was evaluated at 4, 8, 12, 16, and 20 wpg (n = 2 to 7 per line and per time point; n = 6 to 14 per time point). For each animal, six serial sections at 180-m intervals were analyzed. The percentage of MBP+ cells (composed of ensheathed or tuft cells) was evaluated. Total MBP+ area per STEM+ cells and the average length of MBP+ sheaths per MBP+ cells were analyzed.

Cell survival, proliferation, and differentiation in vivo. The number of STEM101+ grafted cells expressing Caspase3, or Ki67, or SOX10 and CC1 was quantified in the core of the corpus callosum at 8, 12, and 16 wpg. For each animal (n = 3 per group), six serial sections at 180-m intervals were analyzed. Cell counts were expressed as the percentage of total STEM101+ cells.

Myelination by electron microscopy. G ratio (diameter of axon/diameter of axon and myelin sheath) of donor-derived compact myelin was measured as previously described (10). Briefly, the maximum and minimum diameters of a given axon and the maximum and minimum axon plus myelin sheath diameter were measured with the ImageJ software at a magnification of 62,000 for a minimum of 70 myelinated axons per animal. Data were expressed as the mean of the maximal and minimal values for each axon for mice from each group (n = 4 mice per group). Myelin compaction was confirmed at a magnification of 220,000.

Data are presented as means + SEM. Statistical significance was determined by two-tailed Mann Whitney U test when comparing two statistical groups, and with one-way or two-way analysis of variance (ANOVA) followed by Tukeys or Dunnetts (in vivo electrophysiology) multiple comparison tests for multiple groups. Because electrophysiological data in brain slices do not follow a normal distribution after a DAgostino-Pearson normality test, we also performed two-tailed Mann-Whitney U test for comparison between groups. Statistics were done in GraphPad Prism 5.00 and GraphPad Prism 8.2.1 (GraphPad Software Inc., USA). See the figure captions for the test used in each experiment.

Acknowledgments: Funding: This work was supported by the Progressive MS Alliance [PMSA; collaborative research network PA-1604-08492 (BRAVEinMS)] to G.M., J.P.A., A.B.-V.E., and T.K., the National MS Society (NMSS RG-1801-30020 to T.K. and A.B.-V.E.), INSERM and ICM grants to A.B.-V.E., the German Research Foundation (DFG CRC-TR-128B07 to T.K.), and the Italian Multiple Sclerosis Foundation (FISM) (project no. Neural Stem Cells in MS to G.M.). M.C.A. was supported by grants from Fondation pour laide la recherche sur la Sclrose en Plaques (ARSEP) and a sub-award agreement from the University of Connecticut with funds provided by grant no. RG-1612-26501 from National Multiple Sclerosis Society. During this work, S.M. was funded by European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). B.G.-D. and M.J.F.L. were supported by the PMSA, PA-1604-08492 and the National MS Society (RG-1801-30020), respectively. B.M.-S. was supported by a Ph.D. fellowship from the French Ministry of Research (ED BioSPC). A.B. and M.C.A. thank respective imaging facilities, ICM Quant and IPNP NeurImag and their respective funding sources Institut des Neurosciences Translationnelles ANR-10-IAIHU-06 Fondation Leducq. Author contributions: Conceptualization: S.M. and A.B.-V.E. Methodology: S.M., L.S., B.M.-S., Y.K.T.X., B.G.-D., M.J.F.L., D.R., L.O., K.-P.K., H.R.S., J.P.A., T.K., G.M., T.E.K., M.C.A., and A.B.V.-E. Formal analysis: S.M., B.M-S., Y.K.T.X., M.C.A., and A.B.-V.E. Writing: S.M. and A.B.V.-E, with editing and discussion from all coauthors Funding acquisition: S.M. and A.B.V.-E. Supervision: A.B.V.-E. Competing interests: T.K. has a pending patent application for the generation of human oligodendrocytes. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo - Science Advances

Spinal Cord Stem Cells Comments Off on Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo – Science Advances | December 6th, 2020

By Pat Anson, PNN Editor

Scientists have developed an experimental drug that can lure stem cells to damaged tissues and help them heal -- a discovery being touted as a major advancement in the field of regenerative medicine.

The findings, recently published in the Proceedings of the National Academy of Sciences (PNAS), could improve the effectiveness of stem cell therapy in treating spinal cord injuries, stroke, amyotrophic lateral sclerosis(ALS), Parkinsons disease and other neurodegenerative disorders. It could also expand the use of stem cells to treat conditions such as heart disease and arthritis.

The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine, said lead authorEvan Snyder, MD, director of theCenter for Stem Cells & Regenerative Medicineat Sanford Burnham Prebys Medical Discovery Institute in La Jolla, CA. Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.

Over a decade ago, Snyder and his colleagues discovered that stem cells are drawn to inflammation -- a biological fire alarm that signals tissue damage has occurred. However, using inflammation as a therapeutic lure for stem cells wasnt advisable because they could further inflame diseased or damaged organs, joints and other tissue.

To get around that problem, scientists modified CXCL12 -- an inflammatory molecule that Snyders team discovered could guide stem cells to sites in need of repair to create a drug called SDV1a. The new drug works by enhancing stem cell binding, while minimizing inflammatory signals.

Since inflammation can be dangerous, we modified CXCL12 by stripping away the risky bit and maximizing the good bit, Snyder explained. Now we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation.

To demonstrate its effectiveness, Snyders team injected SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease. The experiment showed that the drug helped stem cells migrate and perform healing functions, which included extending lifespan, delaying symptom onset, and preserving motor function for much longer than mice that didnt receive the drug. Importantly, the stem cells also did not worsen the inflammation.

Researchers are now testing SDV1as ability to improve stem cell therapy in a mouse model of ALS, also known as Lou Gehrigs disease, which is caused by a progressive loss of motor neurons in the brain. Previous studies conducted by Snyders team found that broadening the spread of neural stem cells helps more motor neurons survive so they are hopeful that SDV1a will improve the effectiveness of neuroprotective stem cells and help slow the onset and progression of ALS.

We are optimistic that this drugs mechanism of action may potentially benefit a variety of neurodegenerative disorders, as well as non-neurological conditions such as heart disease, arthritis and even brain cancer, says Snyder. Interestingly, because CXCL12 and its receptor are implicated in the cytokine storm that characterizes severe COVID-19, some of our insights into how to selectively inhibit inflammation without suppressing other normal processes may be useful in that arena as well.

Snyders research is supported by the National Institutes of Health, U.S. Department of Defense, National Tay-Sachs & Allied Disease Foundation, Childrens Neurobiological Solutions Foundation, and the California Institute for Regenerative Medicine (CIRM).

Thanks to decades of investment in stem cell science, we are making tremendous progress in our understanding of how these cells work and how they can be harnessed to help reverse injury or disease, says Maria Millan, MD, president and CEO of CIRM. This drug could help speed the development of stem cell treatments for spinal cord injury, Alzheimers, heart disease and many other conditions for which no effective treatment exists.

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Share This Article:A stem cell research center at UC Davis. Courtesy California Institute for Regenerative MedicineBy Barbara Feder Ostrov | CalMatters

Californias stem cell research agency was supposed to be winding down its operations right about now, after a 16-year run and hundreds of millions in grants to scientists researching cutting-edge treatments for diabetes, cancer, Alzheimers and other diseases.

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Instead, the taxpayer-supported California Institute for Regenerative Medicine will get a $5.5 billion reboot after voters earlier this month narrowly passed the Proposition 14bond measure. The overall cost of the bonds with interest will total about $7.8 billion.

Were thrilled that California voters saw fit to continue the work weve done, said Jonathan Thomas, chair of the agencys governing board. California has always had a frontier mentality and a love for the cutting edge, and the work that CIRM has done has put it on the very forefront of regenerative medicine.

Even with Californias economy in a coronavirus-induced tailspin and somescientists arguingthat stem cell research no longer needs taxpayer support,Prop. 14passed with 51 percent of the vote after well-financed supporters pourednearly $21 millioninto the Yes on 14 campaign. The measure was essentially a rerun of Proposition 71, which California voters approved in 2004 after a since-revoked federal ban on embryonic stem cell research.

The cash infusion is expected to keep the institute running for another 10 to 15 years, although the agency will see some significant changes under Prop. 14.

The institute also must contend with longstanding concerns over conflicts of interest that have dogged it since its inception, observers say. About 80% of the money distributed has gone to universities and companies tied to agency board members, according to an analysisby longtime agency watchdog David Jensen, a former Sacramento Bee journalist who runs theCalifornia Stem Cell Reportblog and wrote abookon the institute.

Prop. 14 allows the agency to fund a wider array of research projects even some that dont involve stem cells, but instead are related to genetics, personalized medicine and aging.

Thats necessary because the field has evolved, said Paul Knoepfler, a UC Davis professor of cell biology who studies the role of stem cells in cancer and writes a stem cell blog. He received a 2009 grant from the institute.

Stem cells are interesting and important, but there are going to be a lot of new therapies in the next 10 years that are not stem-cell centric, Knoepfler said.

Other changes for the agency include:

Ysabel Duron, who joined the institutes board late last year, said she sees her role as promoting equity in opportunities for both researchers and patients and ensuring that treatments resulting from the research can benefit all Californians.

Researchers in particular need to boost the diversity of patients in their clinical trials and do a better job communicating the value of their work to the public, Duron said, noting that nearly 40% of Californians are Latino.

We need to keep researchers feet to the fire, said Duron, a former television journalist and founder of the Latino Cancer Institute. They need to show us a plan and we need to reward them.

To date, the agency has funded 64 clinical trials of treatments for many types of cancer, sickle cell disease, spinal cord injuries, diabetes, kidney disease and amyotrophic lateral sclerosis, commonlyknown as Lou Gehrigs disease.But the most advanced trials involve therapies for relatively rare conditions, such asSevere Combined Immunodeficiency known as the bubble baby disease, Jensen noted. That therapy is being reviewed by the FDA but has not yet been approved.

Cancer, heart disease these are the big killers. Thats what most people are interested in, Jensen said. You can fund something for a rare disease, but that doesnt affect the majority of Californians.

And, Jensen asks, what will happen after the agency runs out of money again? Will taxpayers once again be asked to refill its coffers? There was hope when the agency began that revenues from successful treatments would sustain its grant-making in the years to come, but the institute has only received a few hundred thousand dollars, not nearly enough to become self-sustaining without taxpayer support, according to theLegislative Analysts Office.

The sustainability issue is important and its hard to address, Jensen said. The money doesnt last forever.

Stem Cell Medical Research to Expand in California Following Passage of Prop. 14 was last modified: November 27th, 2020 by Editor

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Researchers at Stanford Burnham Prebys Medical Discovery Institute recently developed a drug that can lure stem cells to impaired tissue and enhance the efficacy of treatment.

This is considered a "scientific first," not to mention a major advance for the field of regenerative drugs. Such a discovery, which theProceedings of the National Academy of Sciences or PNASpublished could enhance the present stem cell treatments developed to cure such neurological disorders like stroke, spinal cord injury, ALS or other amyotrophic lateral sclerosis, as well as other neurodegenerative diseases -- and have their use expanded to new conditions such as arthritis or heart disease.

In the study, toxic or green cells disappeared when mice with a neurodegenerative condition were given both therapeutic or red cells and the drug SDV1a, which matched with delayed onset of symptoms and longer lives.

(Photo : Stem Cell Research via Getty Images)In this undated handout photo released by the Institute for Stem Cell Research in 2005, neurons (red) and astrocytes (green), which can be made from neural stem cells, are seen.

Results Suggesting Efficacy of the Drug

The study results proposed that SDV1a can be used to enhance the stem cell treatments' efficacy. According to Evan Snyder, MD, PhD, theCenter for Stem Cells & Regenerative Medicine at Stanford Burnham Prebysprofessor and director, "the ability to instruct a stem cell where to go in the body, or to a particular region of a given organ is the 'Holy Grail' for regenerative medicine.

Snyder, who's also the senior author of the study, added, now, for the first time, stem cells can be directed to a desired area and focus its therapeutic effect.

Almost a decade-and-a-half back, the senior author, together with his team, found that stem cells are drawn to infection, a biological 'fire alarm' indicating that damage has taken place.

Nevertheless, using inflammation as a healing appeal is not possible since an inflammation environment can be dangerous to the body. Hence, researchers have been searching for mechanisms to help in the migration of stem cells or 'home' to the body's desired areas.

Such a mechanism or tool, according to reports on this new finding, would be a great contributor for disorders in which preliminary inflammatory indicators disappear over time, like chronic spinal cord injury or stroke, and conditions where the inflammation's role is not clearly understood, like heart disease, for one.

Fortunately, after decades of investing in stem cell science, scientists are now making "tremendous progress," saidCalifornia Institute for Regenerative Medicine or CIRMpresident and CEO Maria Millan, MD said, in their understanding of the manner such cells work and the manner they can be attached to help reverse disease or an injury.

The CIRM partially funded this new study. Millan also said, Snyder's group has identified a medicine that could enhance "the ability of neural stem cells to home to sites of injury and initiate repair."

More so, the president and CEO also explained, the drug candidate could help fast-track the stem cell treatments' development, specifically for conditions including Alzheimer's disease and spinal cord injury.

In the research, study investigators modified an inflammatory molecule called CXCL12, which the Snyder's group discovered previously, could guide healing stem cells to areas that need repair to develop the SDV1a.

As such, this new medicine works by improving stem cell binding and minimizing inflammatory indicating and can be injected anywhere to attract stem cells to a particular site without causing any inflammation.

Since such inflammation can be dangerous, Snyder explained, they modified CXL12 by "tripping away the risky beat and maximizing the good bit."

Now, he added, they have a drug, drawing stem cells to an area of pathology, but not creating or worsening the unwanted infection.

"Now, we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation."

Furthermore, to present that the new medication can improve the effectiveness of stem cell therapy, the scientists implanted SDV1a and human neural stem cells into the brains of mice thatSandhoff disease, a neurodegenerative disease.

The scientists have already started testing the ability of SDV1a to enhance stem cell therapy in a mouse model of Lou Gehrig's disease, also known as ALS, which results from progressive loss of motor neurons in the brain.

Snyder said they are optimistic that the mechanism of action of this new drug may potentially benefit various neurodegenerative disorders and non-neurological conditions like arthritis, heart disease, and even brain cancer.

Interestingly, he also explained, since CXL12 and its receptor is said to be implicated in cytokine storm that exemplifies severeCOVID-19, some of their understandings of how to constrain infection without controlling other normal procedures selectively may be helpful in that field, as well.

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SEATTLE--(BUSINESS WIRE)--The cells of the body are made up of the same basic components, namely: Blood, Muscle, Nerve, Brain, Gut, Respiratory, Skin, Cardiovascular, Urine, and Stem Cells. Each of these cells is unique in its characteristics but all of them play an important role in how healthy your body is and how well it functions.

Blood cells are made up of red blood cells (erythrocytes), platelets (platelet-activating factor) and neutrophils (killer T cells). Unlike blood cells in other organs of the body, white blood cells (white blood cells) do not multiply: they only act as a defense mechanism for the body in the fight against infection and in keeping your immune system active. Blood cells can also be converted to other cells such as platelets and plasma by the action of the protein platelet-activating factor (PAF). When a platelet or plasma cell reproduces, it becomes another cell: a daughter cell. The daughter cell then either becomes a blood cell or goes on to differentiate into a different type of cell such as a red blood cell or a platelet.

The global stem cells market is expected to account for US$ 9941.2 Mn in 2020 in terms of value and is expected to grow at a CAGR of 9.1% during forecast 2020-2027.

Market Drivers:

High prevalence of cancer is expected to propel growth of the global stem cells market over the forecast period. For instance, according to the American Cancer Society, in 2019, there will be an estimated 1,762,450 new cancer cases diagnosed and 606,880 cancer deaths in the U.S.

Moreover, developments towards boosting the availability and use of induced pluripotent stem cell technology is also expected to aid in growth of the market. For instance, in November 2020, FUJIFILM Cellular Dynamics, Inc. partnered with Lonza Walkersville, Inc. to enable drug developers to leverage both companies expertise and technologies for the generation of human induced pluripotent stem cells through licensing agreements.

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Market Opportunities

Potential of stem cell therapy in the treatment of Covid-19 is expected to offer lucrative growth opportunities for players in the global stem cells market. For instance, in November 2020, the randomised, controlled Phase III trial of remestemcel-L in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 infection has been advised to continue by the independent Data Safety Monitoring Board (DSMB).

Moreover, increasing funding for R&D in stem cell therapy is also expected to aid in growth of the market. For instance, in November 2020, Californias stem cell agency will receive an infusion of US$ 5.5 billion in new research funding after voters approved Proposition 14. Similarly, in November 2020, California Institute for Regenerative Medicine awarded a US$ 9 million grant to Diana Farmer and Aijun Wang to help launch the worlds first human clinical trial using stem cells to treat spina bifida, a birth defect that occurs when the spine and spinal cord dont form properly.

Market Trends

Major players operating in the global stem cells market are focused on R&D to expand their product portfolio. For instance, in November 2020, IMAC Holdings, Inc. announced that the company is opening enrollment in its Phase 1 clinical trial for its investigational compound utilizing umbilical cord-derived allogenic mesenchymal stem cells for the treatment of bradykinesia, or the gradual slowing and loss of spontaneous body movement, due to Parkinsons disease.

Competitive Landscape:

Major players operating in the global stem cells market include, Advanced Cell Technology, Inc., FUJIFILM Cellular Dynamics, Inc., Angel Biotechnology Holdings PLC, Bioheart Inc., Lineage Cell Therapeutics., BrainStorm Cell Therapeutics, Inc., IMAC Holdings, Inc., California Stem Cell Inc., Celgene Corporation, Takara Bio Europe AB, Cellular Engineering Technologies, Cytori Therapeutics Inc., Osiris Therapeutics, and STEMCELL Technologies Inc.

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*Practice provides answer to challenges conventional medicine deemed unfixable, say expertsMore studies are validating the use of regenerative medicine to restore damaged organs, restore acute stroke patients, heal chronic pain and erectile dysfunction in male and female as well as prevent and treat viral infections such as COVID-19.

Indeed, several studies have shown that regenerative medicine is uniquely positioned to provide advanced organoid models to understand the infection mechanism of, identify patients at risk for, and develop ways to prevent COVID-19, as well as to introduce innovative treatments that have immune-modulatory and regenerative properties.

Organoids are tiny, self-organised three-dimensional tissue cultures that are derived from stem cells. Such cultures can be crafted to replicate much of the complexity of an organ, or to express selected aspects of it like producing only certain types of cells.

According to a recent study published in the journal Stem Cell Reviews and Reports and titled Regenerative Medicine in COVID-19 Treatment: Real Opportunities and Range of Promises, studies are increasing to find the best therapeutic approach for COVID-19 and its management.

The researchers said regenerative medicine offers various cell-tissue therapeutics and related products, such as stem cell therapy, natural killer (NK) cell therapy, Chimeric antigen receptor (CAR) T cell therapy, exosomes, and tissue products. Interestingly, mesenchymal stem cells (MSCs) can reduce inflammatory symptoms and protect against cytokine storm, which critically contributes to the COVID-19 progression, they said.

The researchers concluded: COVID-19 can involve multiple systems, including the central nervous system, the gastrointestinal system, and the respiratory system, and this will depend on its profound effects on the immune system. Regenerative medicine offers various cell-tissue therapeutics and related products that might help the reversal of COVID-19-related immune dysregulation. In particular, the promising features of MSCs, including their regenerative properties and ability to differentiate into diverse cell lineages, have generated considerable interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases.

The immune-modulatory effects of MSCs, which may assist in inhibiting cytokine storm and lung inflammation, are of particular interest for COVID-19 therapy. Finally, Induced pluripotent stem cells (iPSCs) can help the development of a personalised approach to COVID-19 therapy.

iPSCs are useful for researchers as they can provide an inexhaustible supply of cells that are identical to the patients.

A United States (U.S.) Board Certified Internist with a strong passion for regenerative aesthetic and cosmetic medicine, and Medical Director of Glory Wellness & Regenerative Centre, Ikeja, Lagos, Dr. David Ikudayisi, told The Guardian: One of the regenerative medicine protocols, which we also have available at our Centre, was approved for COVID-19 purposes; leveraging its immune modulatory effect to calm the potentially fatal cytokine storm of the disease. It also has the benefit of preventing or limiting lung scarring. Another protocol is in the early phase of clinical trial. While we are not a COVID-19 treating centre, it is important to note that regenerative medicine can play a role in the reduction of many of the adverse effects caused by COVID-19.

Ikudayisi said the future of regenerative medicine is very bright. We believe that the future of regenerative medicine is inevitable, and that conventional medicine will only have to catch up as it usually does to new discoveries in medicine. The more people get to hear about the merits and see the evidence; it will not be long before it becomes the norm. It starts with everyday people and medical professionals doing their due diligence and doing their research as I did. My team and I are always available to answer questions about it, and we welcome it on all our social platforms as well. We really hope it catches up soon enough to maximise these great benefits for many more patients in dire need of these amazing solutions.

Regenerative medicine has continued to generate excitement. What makes it significantly different from conventional medicine, and why would you recommend it for anyone in need of treatment? Ikudayisi said: It is great to see that Nigeria is catching up with the possibilities of regenerative medicine for our health. Conventional medicine uses anything from conservative management, the use of medication, or surgery at the other extreme to help maintain good health or get us as close to it as possible.

He said regenerative medicine on the other hand leverages the bodys natural healing mechanisms and attempts to accentuate their effects by increasing their availability to the specific organs needing regeneration. The ability to harness the bodys natural healing mechanisms using adult stem cell therapy (a subcategory of regenerative medicine) while minimising adverse effects confers on regenerative medicine a considerably greater safety profile than conventional medicine, Ikudayisi said.

He said regenerative medicine is not the secret sauce to fix all health problems, but is, however, a great tool provided by modern medicine to provide an answer to many health challenges that conventional medicine had deemed unfixable. Ikudayisi said conditions that have been considered incurable by conventional medicine due to their degenerative effects, are now made curable in the practical sense as regenerative medicine takes care of the organ degeneration.

The physician said the scientific/physiological base of the therapeutic effects of regenerative medicine, specifically adult stem cell therapy, creates endless opportunities for its application. Think about it this way, if the medical condition is of a degenerative nature, then regenerative medicine can be a viable option, he said.

Ikudayisi said he would continue to recommend regenerative medicine to anyone in need of treatment because where conventional medicine fails; it offers hope and delivers results beyond what conventional medicine can offer in most cases. The benefits are even more noticeable in acute phases of degeneration, he said.

Can regenerative medicine treat only select ailments or all manner of sicknesses? Ikudayisi said: The scope of application is broad and multi-systemic. This means it can be used for various systems and functions in the body. While the exceptions are diseases of a non-degenerative nature such as genetic or chromosome-related diseases; nonetheless, people with these challenges can see a reduction or improvement in symptoms even though it is not cured. Healthy people use it for anti-agEing, to feel stronger and healthier as well as look younger as they age.

As I mentioned earlier, regenerative medicine is not here to replace other branches of medicine. Like other new innovations in medicine, it can add value to other forms of medicine. For example, a patient with a displaced fracture needs the intervention of an orthopedic surgeon not regenerative medicine. However, it can be added during or after the orthopedic surgery to accelerate the healing process.

Here at Glory Wellness & Regenerative Centre in Lagos, Nigeria, we have seen so many success stories with this branch of medicine. We have treated patients with complex quadriplegia (two years old injury before our involvement due to partial transection of cervical spinal cord) and another with over nine years with cerebral palsy, both of whom have now gained the ability to move some of their extremities independently. We have also seen patients with uncontrolled diabetes with hypertension who now have blood pressures and hemoglobin A1c levels within the normal range as a result of these treatments.

We have also seen great results in patients treated for female/male sexual dysfunction, pain in their joints, neck, and back, and acute stroke (especially when the acute stroke is treated very early to prevent permanent residual symptoms). All patients with autoimmune disorders can also benefit from regenerative medicine; however, they will need continued treatments to maintain the symptoms relief.

Autistic patients in Nigeria are also benefiting from it, especially if the cause is autoimmune related (since up to 25 per cent of the autistic spectrum disorder could be caused by autoimmune diseases). Patients with chronic kidney disease in the early stages are not left out, but they will need more than one treatment session. This is just to mention a few medical conditions. One of the many joys we get is talking to people about their ailments and seeing how regenerative medicine can play a role in rejuvenating their health.

What feedback are you getting from those who have accessed this branch of medicine?Ikudayisi said many of the patients treated at Centre are delighted at their results, so much so that they are spreading the word person to person. We get a great number of them who are so pleasantly surprised of the outcome, as they also see improvements in areas they did not even think to mention to us. It is noteworthy that the therapeutic benefits they have received from regenerative medicine had been practically impossible with conventional medicine hence their satisfaction, joy, and excitement, he said.

The physician said an example is the case of a man with left testicular atrophy and low testosterone. After one session of autologous treatment, the left testicle grew back to normal size and the production of testosterone significantly increased. People who have infertility issues, both male and female, should not give up without considering one of the regenerative medicine protocols, especially those women that have tried In Vitro Fertilisation (IVF) without success, he said.

How affordable is this new branch of medicine? It is truly relatively expensive due to the demand on medical manpower and the present cost of required materials. However, the costs are gradually coming down which we hope is sustained and accelerated so that more people can benefit. Our goal is to get these treatments to as many people as possible. This involves finding ways to reduce cost without compromising on value. Whenever possible, we notify our patients of these price cuts. Furthermore, there are alternative options of treatment with varying costs: this makes these treatments ultimately accessible to more people. The latest biggest price reduction is for people with pain in their peripheral joints, female and male sexual dysfunction, female urinary incontinence, chronic non-healing wounds, facial acne, and uneven skin tone.

I would like to mention that middle class to low income patients in Nigeria have also benefited from some of our regenerative medicine protocols.

Regardless of the cost of the procedure, you cannot put a price tag on a human life. Human life is priceless. As the famous adage goes, Your health, your wealth.

What is the success rate of regenerative medicine for those who have accessed treatment? Ikudayisi said the United States of America (USA) Atlanta-based Emory Healthcare claims that 75 to 80 per cent of patients have had significant pain relief and improved function. The USA Mayo Clinic website says that 40 to 70 per cent of patients find some level of pain relief using some of the regenerative medicine protocols.

The physician said the success rate has been generally high both in the USA and Nigeria at all the centres where he worked. He insisted the results differ from one patient to another, and some other centers do have low success rates. I too have had a couple of patients with delayed onset of effectiveness of treatment or patients needing additional or second treatment sessions before they begin to see positive results. It is important to mention or remind ourselves that there is no guarantee in medicine despite the hype surrounding adult stem cell therapy or regenerative medicine as a whole. It does not work 100 percent of the time. Nonetheless, there is a very high success rate amongst the patients with non-bleeding acute stroke when treatment is done within a couple of days to few weeks, with the goal of preventing permanent residual symptoms post stroke. This was evident in all our non-haemorrhagic acute stroke patients that we treated directly at our facility or through consultation in other hospitals, ranging from a top government official to a low-income grandmother. The general rule of thumb is that the earlier the treatment is given in acute injuries, the higher the success rate, Ikudayisi said.

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Spinal Cord Trauma Treatment Market: Global Industry Analysis 2012 2016 and Forecast 2017 2025is the recent report of Persistence Market Research that throws light on the overall market scenario during the period of eight years, i.e. 2017-2025. According to this report, Globalspinal cord trauma treatment marketis expected to witness significant growth during the forecast period.

This growth is expected to be primarily driven by increasing incidence of spinal cord trauma, and increasing government support to reduce the burden of spinal cord injuries. Additionally, development of nerve cells growth therapy is expected to boost the market in near future.

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The global market for spinal cord trauma treatment is is estimated to be valued at US$ 2,276.3 Mn in terms of value by the end of 2017. The global spinal cord trauma treatment market is expected to expand at a CAGR of 3.7% over the forecast period to reach a value of US$ 3,036.2 Mn by 2025end.

Global Spinal Cord Trauma Treatment Market: Trends

Global Spinal Cord Trauma Treatment Market: Forecast by End User

On the basis of end user, the global spinal cord trauma treatment market is segmented into hospitals and trauma centers. Hospitals segment dominated the global spinal cord trauma treatment market in revenue terms in 2016 and is projected to continue to do so throughout the forecast period.

Hospitals and trauma centers segments are expected to approximately similar attractive index. Hospitals segment accounted for 53.2% value share in 2017 and is projected to account for 52.5% share by 2025 end.

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Global Spinal Cord Trauma Treatment Market: Forecast by Injury Type

On the basis of injury type, the global spinal cord trauma treatment market is segmented into complete spinal cord injuries and partial spinal cord injuries.

Partial spinal cord trauma treatment segment is expected to show better growth than the completed spinal cord treatment segment due to higher growth in the incidence rate of partial spinal cord trauma than the complete spinal cord trauma. With US$ 1,870.3 Mn market value in 2025, this segment is likely to expand at CAGR 3.8% throughout the projected period.

Global Spinal Cord Trauma Treatment Market: Forecast by Treatment Type

On the basis of treatment type, the global spinal cord trauma treatment market is segmented into corticosteroid, surgery, and spinal traction segments.

Surgery segment dominated the global spinal cord trauma treatment market in revenue terms in 2016 and is projected to continue to do so throughout the forecast period. Surgery segment is the most attractive segment, with attractiveness index of 2.6 over the forecast period.

Global Spinal Cord Trauma Treatment Market: Forecast by Region

This market is segmented into five regions such as North America, Latin America, Europe, APAC and MEA. Asia-Pacific account for the largest market share in the global spinal cord trauma treatment market.

Large patient population due to the high rate of road accidents and crime is making the Asia Pacific region most attractive market for spinal cord trauma treatment. On the other hand, MEA and Latin America is expected to be the least attractive market for spinal cord trauma treatment, with attractiveness index of 0.3 and 0.5 respectively over the forecast period.

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Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics and market research methodology to help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

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Ashish KoltePersistence Market ResearchAddress 305 Broadway, 7th FloorNew York City,NY 10007 United StatesU.S. Ph. +1-646-568-7751USA-Canada Toll-free +1 800-961-0353Sales[emailprotected]Website https://www.persistencemarketresearch.com

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The Spinal Cord Trauma Treatment Market To Walk The Path Of Double Digit CAGR Of 3.7% - KYT24

Spinal Cord Stem Cells Comments Off on The Spinal Cord Trauma Treatment Market To Walk The Path Of Double Digit CAGR Of 3.7% – KYT24 | November 18th, 2020

Market Report Summary

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Read Full Press Release Below

Spinal Cord Trauma Treatment Market: Global Industry Analysis 2012 2016 and Forecast 2017 2025is the recent report of Persistence Market Research that throws light on the overall market scenario during the period of eight years, i.e. 2017-2025. According to this report, Globalspinal cord trauma treatment marketis expected to witness significant growth during the forecast period.

This growth is expected to be primarily driven by increasing incidence of spinal cord trauma, and increasing government support to reduce the burden of spinal cord injuries. Additionally, development of nerve cells growth therapy is expected to boost the market in near future.

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Company Profiles

Get To Know Methodology of Report @ https://www.persistencemarketresearch.com/methodology/17353

The global market for spinal cord trauma treatment is is estimated to be valued at US$ 2,276.3 Mn in terms of value by the end of 2017. The global spinal cord trauma treatment market is expected to expand at a CAGR of 3.7% over the forecast period to reach a value of US$ 3,036.2 Mn by 2025end.

Global Spinal Cord Trauma Treatment Market: Trends

Global Spinal Cord Trauma Treatment Market: Forecast by End User

On the basis of end user, the global spinal cord trauma treatment market is segmented into hospitals and trauma centers. Hospitals segment dominated the global spinal cord trauma treatment market in revenue terms in 2016 and is projected to continue to do so throughout the forecast period.

Hospitals and trauma centers segments are expected to approximately similar attractive index. Hospitals segment accounted for 53.2% value share in 2017 and is projected to account for 52.5% share by 2025 end.

Access Full Report @ https://www.persistencemarketresearch.com/checkout/17353

Global Spinal Cord Trauma Treatment Market: Forecast by Injury Type

On the basis of injury type, the global spinal cord trauma treatment market is segmented into complete spinal cord injuries and partial spinal cord injuries.

Partial spinal cord trauma treatment segment is expected to show better growth than the completed spinal cord treatment segment due to higher growth in the incidence rate of partial spinal cord trauma than the complete spinal cord trauma. With US$ 1,870.3 Mn market value in 2025, this segment is likely to expand at CAGR 3.8% throughout the projected period.

Global Spinal Cord Trauma Treatment Market: Forecast by Treatment Type

On the basis of treatment type, the global spinal cord trauma treatment market is segmented into corticosteroid, surgery, and spinal traction segments.

Surgery segment dominated the global spinal cord trauma treatment market in revenue terms in 2016 and is projected to continue to do so throughout the forecast period. Surgery segment is the most attractive segment, with attractiveness index of 2.6 over the forecast period.

Global Spinal Cord Trauma Treatment Market: Forecast by Region

This market is segmented into five regions such as North America, Latin America, Europe, APAC and MEA. Asia-Pacific account for the largest market share in the global spinal cord trauma treatment market.

Large patient population due to the high rate of road accidents and crime is making the Asia Pacific region most attractive market for spinal cord trauma treatment. On the other hand, MEA and Latin America is expected to be the least attractive market for spinal cord trauma treatment, with attractiveness index of 0.3 and 0.5 respectively over the forecast period.

Explore Extensive Coverage of PMR`sLife Sciences & Transformational HealthLandscape

Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics and market research methodology to help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

Contact us:

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The Spinal Cord Trauma Treatment Market To Witness A Substantial Demand Amidst Covid-19, To Reach US$ 3000 Mn - The Think Curiouser

Spinal Cord Stem Cells Comments Off on The Spinal Cord Trauma Treatment Market To Witness A Substantial Demand Amidst Covid-19, To Reach US$ 3000 Mn – The Think Curiouser | November 10th, 2020

ANDOVER, Mass. The liquid that many hope could help end the Covid-19 pandemic is stored in a nondescript metal tank in a manufacturing complex owned by Pfizer, one of the worlds biggest drug companies. There is nothing remarkable about the container, which could fit in a walk-in closet, except that its contents could end up in the worlds first authorized Covid-19 vaccine.

Pfizer, a 171-year-old Fortune 500 powerhouse, has made a billion-dollar bet on that dream. So has a brash, young rival just 23 miles away in Cambridge, Mass. Moderna, a 10-year-old biotech company with billions in market valuation but no approved products, is racing forward with a vaccine of its own. Its new sprawling drug-making facility nearby is hiring workers at a fast clip in the hopes of making history and a lot of money.

In many ways, the companies and their leaders couldnt be more different. Pfizer, working with a little-known German biotech called BioNTech, has taken pains for much of the year to manage expectations. Moderna has made nearly as much news for its stream of upbeat press releases, executives stock sales, and spectacular rounds of funding as for its science.

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Each is well-aware of the other in the race to be first.

But what the companies share may be bigger than their differences: Both are banking on a genetic technology that has long held huge promise but has so far run into biological roadblocks. It is called synthetic messenger RNA, an ingenious variation on the natural substance that directs protein production in cells throughout the body. Its prospects have swung billions of dollars on the stock market, made and imperiled scientific careers, and fueled hopes that it could be a breakthrough that allows society to return to normalcy after months living in fear.

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Both companies have been frequently name-checked by President Trump. Pfizer reported strong, but preliminary, data on Monday, and Moderna is expected to follow suit soon with a glimpse of its data. Both firms hope these preliminary results will allow an emergency deployment of their vaccines millions of doses likely targeted to frontline medical workers and others most at risk of Covid-19.

There are about a dozen experimental vaccines in late-stage clinical trials globally, but the ones being tested by Pfizer and Moderna are the only two that rely on messenger RNA.

For decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA, or mRNA.

Researchers understood its role as a recipe book for the bodys trillions of cells, but their efforts to expand the menu have come in fits and starts. The concept: By making precise tweaks to synthetic mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory.

But turning scientific promise into medical reality has been more difficult than many assumed. Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval.

Even now, as Moderna and Pfizer test their vaccines on roughly 74,000 volunteers in pivotal vaccine studies, many experts question whether the technology is ready for prime time.

I worry about innovation at the expense of practicality, Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and an authority on vaccines, said recently. The U.S. governments Operation Warp Speed program, which has underwritten the development of Modernas vaccine and pledged to buy Pfizers vaccine if it works, is weighted toward technology platforms that have never made it to licensure before.

Whether mRNA vaccines succeed or not, their path from a gleam in a scientists eye to the brink of government approval has been a tale of personal perseverance, eureka moments in the lab, soaring expectations and an unprecedented flow of cash into the biotech industry.

It is a story that began three decades ago, with a little-known scientist who refused to quit.

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karik spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karik wanted to go further.

The problem, she knew, was that synthetic RNA was notoriously vulnerable to the bodys natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.

It was a real obstacle, and still may be, but Karik was convinced it was one she could work around. Few shared her confidence.

Every night I was working: grant, grant, grant, Karik remembered, referring to her efforts to obtain funding. And it came back always no, no, no.

By 1995, after six years on the faculty at the University of Pennsylvania, Karik got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

Usually, at that point, people just say goodbye and leave because its so horrible, Karik said.

Theres no opportune time for demotion, but 1995 had already been uncommonly difficult. Karik had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which shed devoted countless hours was slipping through her fingers.

I thought of going somewhere else, or doing something else, Karik said. I also thought maybe Im not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.

In time, those better experiments came together. After a decade of trial and error, Karik and her longtime collaborator at Penn Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University discovered a remedy for mRNAs Achilles heel.

The stumbling block, as Kariks many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karik and Weissman discovered, was the biological equivalent of swapping out a tire.

Every strand of mRNA is made up of five molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karikand Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the bodys defenses.

That was a key discovery, said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. Karik and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.

That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technologys lean years. And it was the starter pistol for the vaccine sprint to come.

And even though the studies by Karik and Weissman went unnoticed by some, they caught the attention of two key scientists one in the United States, another abroad who would later help found Moderna and Pfizers future partner, BioNTech.

Derrick Rossi, a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karik and Weissman deserve the Nobel Prize in chemistry.

If anyone asks me whom to vote for some day down the line, I would put them front and center, he said. That fundamental discovery is going to go into medicines that help the world.

But Rossi didnt have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.

He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells.

In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinsons disease to spinal cord injuries.

But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.

Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.

He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.

Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.

On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend and an ego-bruising squabble.

Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.

As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.

I think you can do a lot better than that, Langer recalled telling Rossi, referring to stem cells. I think you could make new drugs, new vaccines everything.

Langer could barely contain his excitement when he got home to his wife.

This could be the most successful company in history, he remembered telling her, even though no company existed yet.

Three days later Rossi made another presentation, to the leaders of Flagship Ventures. Founded and run by Noubar Afeyan, a swaggering entrepreneur, the Cambridge venture capital firm has created dozens of biotech startups. Afeyan had the same enthusiastic reaction as Langer, saying in a 2015 article in Nature that Rossis innovation was intriguing instantaneously.

Within several months, Rossi, Langer, Afeyan, and another physician-researcher at Harvard formed the firm Moderna a new word combining modified and RNA.

Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firms promise rivals that of the earliest biotechnology companies over 30 years ago adding an entirely new drug category to the pharmaceutical arsenal.

But although Moderna has made each of the founders hundreds of millions of dollars even before the company had produced a single product Rossis account is marked by bitterness. In interviews with the Globe in October, he accused Langer and Afeyan of propagating a condescending myth that he didnt understand his discoverys full potential until they pointed it out to him.

Its total malarkey, said Rossi, who ended his affiliation with Moderna in 2014. Im embarrassed for them. Everybody in the know actually just shakes their heads.

Rossi said that the slide decks he used in his presentation to Flagship noted that his discovery could lead to new medicines. Thats the thing Noubar has used to turn Flagship into a big company, and he says it was totally his idea, Rossi said.

Afeyan, the chair of Moderna, recently credited Rossi with advancing the work of the Penn scientists. But, he said, that only spurred Afeyan and Langer to ask the question, Could you think of a code molecule that helps you make anything you want within the body?

Langer, for his part, told STAT and the Globe that Rossi made an important finding but had focused almost entirely on the stem cell thing.

Despite the squabbling that followed the birth of Moderna, other scientists also saw messenger RNA as potentially revolutionary.

In Mainz, Germany, situated on the left bank of the Rhine, another new company was being formed by a married team of researchers who would also see the vast potential for the technology, though vaccines for infectious diseases werent on top of their list then.

A native of Turkey, Ugur Sahin moved to Germany after his father got a job at a Ford factory in Cologne. His wife, zlem Treci had, as a child, followed her father, a surgeon, on his rounds at a Catholic hospital. She and Sahin are physicians who met in 1990 working at a hospital in Saarland.

The couple have long been interested in immunotherapy, which harnesses the immune system to fight cancer and has become one of the most exciting innovations in medicine in recent decades. In particular, they were tantalized by the possibility of creating personalized vaccines that teach the immune system to eliminate cancer cells.

Both see themselves as scientists first and foremost. But they are also formidable entrepreneurs. After they co-founded another biotech, the couple persuaded twin brothers who had invested in that firm, Thomas and Andreas Strungmann, to spin out a new company that would develop cancer vaccines that relied on mRNA.

That became BioNTech, another blended name, derived from Biopharmaceutical New Technologies. Its U.S. headquarters is in Cambridge. Sahin is the CEO, Treci the chief medical officer.

We are one of the leaders in messenger RNA, but we dont consider ourselves a messenger RNA company, said Sahin, also a professor at the Mainz University Medical Center. We consider ourselves an immunotherapy company.

Like Moderna, BioNTech licensed technology developed by the Pennsylvania scientist whose work was long ignored, Karik, and her collaborator, Weissman. In fact, in 2013, the company hired Karik as senior vice president to help oversee its mRNA work.

But in their early years, the two biotechs operated in very different ways.

In 2011, Moderna hired the CEO who would personify its brash approach to the business of biotech.

Stphane Bancel was a rising star in the life sciences, a chemical engineer with a Harvard MBA who was known as a businessman, not a scientist. At just 34, he became CEO of the French diagnostics firm BioMrieux in 2007 but was wooed away to Moderna four years later by Afeyan.

Moderna made a splash in 2012 with the announcement that it had raised $40 million from venture capitalists despite being years away from testing its science in humans. Four months later, the British pharmaceutical giant AstraZeneca agreed to pay Moderna a staggering $240 million for the rights to dozens of mRNA drugs that did not yet exist.

The biotech had no scientific publications to its name and hadnt shared a shred of data publicly. Yet it somehow convinced investors and multinational drug makers that its scientific findings and expertise were destined to change the world. Under Bancels leadership, Moderna would raise more than $1 billion in investments and partnership funds over the next five years.

Modernas promise and the more than $2 billion it raised before going public in 2018 hinged on creating a fleet of mRNA medicines that could be safely dosed over and over. But behind the scenes the companys scientists were running into a familiar problem. In animal studies, the ideal dose of their leading mRNA therapy was triggering dangerous immune reactions the kind for which Karik had improvised a major workaround under some conditions but a lower dose had proved too weak to show any benefits.

Moderna had to pivot. If repeated doses of mRNA were too toxic to test in human beings, the company would have to rely on something that takes only one or two injections to show an effect. Gradually, biotechs self-proclaimed disruptor became a vaccines company, putting its experimental drugs on the back burner and talking up the potential of a field long considered a loss-leader by the drug industry.

Meanwhile BioNTech has often acted like the anti-Moderna, garnering far less attention.

In part, that was by design, said Sahin. For the first five years, the firm operated in what Sahin called submarine mode, issuing no news releases, and focusing on scientific research, much of it originating in his university lab. Unlike Moderna, the firm has published its research from the start, including about 150 scientific papers in just the past eight years.

In 2013, the firm began disclosing its ambitions to transform the treatment of cancer and soon announced a series of eight partnerships with major drug makers. BioNTech has 13 compounds in clinical trials for a variety of illnesses but, like Moderna, has yet to get a product approved.

When BioNTech went public last October, it raised $150 million, and closed with a market value of $3.4 billion less than half of Modernas when it went public in 2018.

Despite his role as CEO, Sahin has largely maintained the air of an academic. He still uses his university email address and rides a 20-year-old mountain bicycle from his home to the office because he doesnt have a drivers license.

Then, late last year, the world changed.

Shortly before midnight, on Dec. 30, the International Society for Infectious Diseases, a Massachusetts-based nonprofit, posted an alarming report online. A number of people in Wuhan, a city of more than 11 million people in central China, had been diagnosed with unexplained pneumonia.

Chinese researchers soon identified 41 hospitalized patients with the disease. Most had visited the Wuhan South China Seafood Market. Vendors sold live wild animals, from bamboo rats to ostriches, in crowded stalls. That raised concerns that the virus might have leaped from an animal, possibly a bat, to humans.

After isolating the virus from patients, Chinese scientists on Jan. 10 posted online its genetic sequence. Because companies that work with messenger RNA dont need the virus itself to create a vaccine, just a computer that tells scientists what chemicals to put together and in what order, researchers at Moderna, BioNTech, and other companies got to work.

A pandemic loomed. The companies focus on vaccines could not have been more fortuitous.

Moderna and BioNTech each designed a tiny snip of genetic code that could be deployed into cells to stimulate a coronavirus immune response. The two vaccines differ in their chemical structures, how the substances are made, and how they deliver mRNA into cells. Both vaccines require two shots a few weeks apart.

The biotechs were competing against dozens of other groups that employed varying vaccine-making approaches, including the traditional, more time-consuming method of using an inactivated virus to produce an immune response.

Moderna was especially well-positioned for this moment.

Forty-two days after the genetic code was released, Modernas CEO Bancel opened an email on Feb. 24 on his cellphone and smiled, as he recalled to the Globe. Up popped a photograph of a box placed inside a refrigerated truck at the Norwood plant and bound for the National Institute of Allergy and Infectious Diseases in Bethesda, Md. The package held a few hundred vials, each containing the experimental vaccine.

Moderna was the first drug maker to deliver a potential vaccine for clinical trials. Soon, its vaccine became the first to undergo testing on humans, in a small early-stage trial. And on July 28, it became the first to start getting tested in a late-stage trial in a scene that reflected the firms receptiveness to press coverage.

The first volunteer to get a shot in Modernas late-stage trial was a television anchor at the CNN affiliate in Savannah, Ga., a move that raised eyebrows at rival vaccine makers.

Along with those achievements, Moderna has repeatedly stirred controversy.

On May 18, Moderna issued a press release trumpeting positive interim clinical data. The firm said its vaccine had generated neutralizing antibodies in the first eight volunteers in the early-phase study, a tiny sample.

But Moderna didnt provide any backup data, making it hard to assess how encouraging the results were. Nonetheless, Modernas share price rose 20% that day.

Some top Moderna executives also drew criticism for selling shares worth millions, including Bancel and the firms chief medical officer, Tal Zaks.

In addition, some critics have said the government has given Moderna a sweetheart deal by bankrolling the costs for developing the vaccine and pledging to buy at least 100 million doses, all for $2.48 billion.

That works out to roughly $25 a dose, which Moderna acknowledges includes a profit.

In contrast, the government has pledged more than $1 billion to Johnson & Johnson to manufacture and provide at least 100 million doses of its vaccine, which uses different technology than mRNA. But J&J, which collaborated with Beth Israel Deaconess Medical Centers Center for Virology and Vaccine Research and is also in a late-stage trial, has promised not to profit off sales of the vaccine during the pandemic.

Over in Germany, Sahin, the head of BioNTech, said a Lancet article in January about the outbreak in Wuhan, an international hub, galvanized him.

We understood that this would become a pandemic, he said.

The next day, he met with his leadership team.

I told them that we have to deal with a pandemic which is coming to Germany, Sahin recalled.

He also realized he needed a strong partner to manufacture the vaccine and thought of Pfizer. The two companies had worked together before to try to develop mRNA influenza vaccines. In March, he called Pfizers top vaccine expert, Kathrin Jansen.

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The story of mRNA: From a loose idea to a tool that may help curb Covid - STAT

Spinal Cord Stem Cells Comments Off on The story of mRNA: From a loose idea to a tool that may help curb Covid – STAT | November 10th, 2020

DUBLIN, Nov. 9, 2020 /PRNewswire/ -- The "Regenerative Medicine Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2020-2025" report has been added to ResearchAndMarkets.com's offering.

The global regenerative medicine market grew at a CAGR of around 16% during 2014-2019. Regenerative medicine refers to a branch of biomedical sciences aimed at restoring the structure and function of damaged tissues and organs. It involves the utilization of stem cells that are developed in laboratories and further implanted safely into the body for the regeneration of damaged bones, cartilage, blood vessels and organs. Cellular and acellular regenerative medicines are commonly used in various clinical therapeutic procedures, including cell, immunomodulation and tissue engineering therapies. They hold potential for the effective treatment of various chronic diseases, such as Alzheimer's, Parkinson's and cardiovascular disorders (CVDs), osteoporosis and spinal cord injuries.

The increasing prevalence of chronic medical ailments and genetic disorders across the globe is one of the key factors driving the growth of the market. Furthermore, the rising geriatric population, which is prone to various musculoskeletal, phonological, dermatological and cardiological disorders, is stimulating the market growth. In line with this, widespread adoption of organ transplantation is also contributing to the market growth. Regenerative medicine minimizes the risk of organ rejection by the body post-transplant and enhances the recovery speed of the patient.

Additionally, various technological advancements in cell-based therapies, such as the development of 3D bioprinting techniques and the adoption of artificial intelligence (AI) in the production of regenerative medicines, are acting as other growth-inducing factors. These advancements also aid in conducting efficient dermatological grafting procedures to treat chronic burns, bone defects and wounds on the skin. Other factors, including extensive research and development (R&D) activities in the field of medical sciences, along with improving healthcare infrastructure, are anticipated to drive the market further. Looking forward, the publisher expects the global regenerative medicine market to continue its strong growth during the next five years.

Competitive Landscape:

The report has also analysed the competitive landscape of the market with some of the key players being Allergan PLC (AbbVie Inc.), Amgen Inc., Baxter International Inc., BD (Becton, Dickinson and Company), Integra Lifesciences Holdings Corporation, Medtronic plc, Mimedx Group Inc., Novartis AG, Osiris Therapeutics Inc. (Smith & Nephew plc) and Thermo Fisher Scientific Inc.

Key Questions Answered in This Report:

Key Topics Covered:

1 Preface

2 Scope and Methodology 2.1 Objectives of the Study2.2 Stakeholders2.3 Data Sources2.3.1 Primary Sources2.3.2 Secondary Sources2.4 Market Estimation2.4.1 Bottom-Up Approach2.4.2 Top-Down Approach2.5 Forecasting Methodology

3 Executive Summary

4 Introduction4.1 Overview4.2 Key Industry Trends

5 Global Regenerative Medicine Market5.1 Market Overview5.2 Market Performance5.3 Impact of COVID-195.4 Market Forecast

6 Market Breakup by Type6.1 Stem Cell Therapy6.1.1 Market Trends6.1.2 Market Forecast6.2 Biomaterial6.2.1 Market Trends6.2.2 Market Forecast6.3 Tissue Engineering6.3.1 Market Trends6.3.2 Market Forecast6.4 Others6.4.1 Market Trends6.4.2 Market Forecast

7 Market Breakup by Application7.1 Bone Graft Substitutes7.1.1 Market Trends7.1.2 Market Forecast7.2 Osteoarticular Diseases7.2.1 Market Trends7.2.2 Market Forecast7.3 Dermatology7.3.1 Market Trends7.3.2 Market Forecast7.4 Cardiovascular7.4.1 Market Trends7.4.2 Market Forecast7.5 Central Nervous System7.5.1 Market Trends7.5.2 Market Forecast7.6 Others7.6.1 Market Trends7.6.2 Market Forecast

8 Market Breakup by End User8.1 Hospitals8.1.1 Market Trends8.1.2 Market Forecast8.2 Specialty Clinics8.2.1 Market Trends8.2.2 Market Forecast8.3 Others8.3.1 Market Trends8.3.2 Market Forecast

9 Market Breakup by Region9.1 North America9.1.1 United States9.1.1.1 Market Trends9.1.1.2 Market Forecast9.1.2 Canada9.1.2.1 Market Trends9.1.2.2 Market Forecast9.2 Asia Pacific9.2.1 China9.2.1.1 Market Trends9.2.1.2 Market Forecast9.2.2 Japan9.2.2.1 Market Trends9.2.2.2 Market Forecast9.2.3 India9.2.3.1 Market Trends9.2.3.2 Market Forecast9.2.4 South Korea9.2.4.1 Market Trends9.2.4.2 Market Forecast9.2.5 Australia9.2.5.1 Market Trends9.2.5.2 Market Forecast9.2.6 Indonesia9.2.6.1 Market Trends9.2.6.2 Market Forecast9.2.7 Others9.2.7.1 Market Trends9.2.7.2 Market Forecast9.3 Europe9.3.1 Germany9.3.1.1 Market Trends9.3.1.2 Market Forecast9.3.2 France9.3.2.1 Market Trends9.3.2.2 Market Forecast9.3.3 United Kingdom9.3.3.1 Market Trends9.3.3.2 Market Forecast9.3.4 Italy9.3.4.1 Market Trends9.3.4.2 Market Forecast9.3.5 Spain9.3.5.1 Market Trends9.3.5.2 Market Forecast9.3.6 Russia9.3.6.1 Market Trends9.3.6.2 Market Forecast9.3.7 Others9.3.7.1 Market Trends9.3.7.2 Market Forecast9.4 Latin America9.4.1 Brazil9.4.1.1 Market Trends9.4.1.2 Market Forecast9.4.2 Mexico9.4.2.1 Market Trends9.4.2.2 Market Forecast9.4.3 Others9.4.3.1 Market Trends9.4.3.2 Market Forecast9.5 Middle East and Africa9.5.1 Market Trends9.5.2 Market Breakup by Country9.5.3 Market Forecast

10 SWOT Analysis10.1 Overview10.2 Strengths10.3 Weaknesses10.4 Opportunities10.5 Threats

11 Value Chain Analysis

12 Porters Five Forces Analysis12.1 Overview12.2 Bargaining Power of Buyers12.3 Bargaining Power of Suppliers12.4 Degree of Competition12.5 Threat of New Entrants12.6 Threat of Substitutes

13 Price Analysis

14 Competitive Landscape14.1 Market Structure14.2 Key Players14.3 Profiles of Key Players14.3.1 Allergan PLC (AbbVie Inc.)14.3.1.1 Company Overview14.3.1.2 Product Portfolio 14.3.1.3 Financials 14.3.1.4 SWOT Analysis14.3.2 Amgen Inc.14.3.2.1 Company Overview14.3.2.2 Product Portfolio14.3.2.3 Financials 14.3.2.4 SWOT Analysis14.3.3 Baxter International Inc.14.3.3.1 Company Overview14.3.3.2 Product Portfolio 14.3.3.3 Financials 14.3.3.4 SWOT Analysis14.3.4 BD (Becton, Dickinson and Company)14.3.4.1 Company Overview14.3.4.2 Product Portfolio 14.3.4.3 Financials 14.3.4.4 SWOT Analysis14.3.5 Integra Lifesciences Holdings Corporation14.3.5.1 Company Overview14.3.5.2 Product Portfolio 14.3.5.3 Financials 14.3.5.4 SWOT Analysis14.3.6 Medtronic Plc14.3.6.1 Company Overview14.3.6.2 Product Portfolio 14.3.6.3 Financials14.3.6.4 SWOT Analysis14.3.7 Mimedx Group Inc.14.3.7.1 Company Overview14.3.7.2 Product Portfolio14.3.7.3 Financials 14.3.8 Novartis AG14.3.8.1 Company Overview14.3.8.2 Product Portfolio 14.3.8.3 Financials14.3.8.4 SWOT Analysis14.3.9 Osiris Therapeutics Inc. (Smith & Nephew plc)14.3.9.1 Company Overview14.3.9.2 Product Portfolio14.3.10 Thermo Fisher Scientific Inc.14.3.10.1 Company Overview14.3.10.2 Product Portfolio 14.3.10.3 Financials14.3.10.4 SWOT Analysis

For more information about this report visit https://www.researchandmarkets.com/r/gcpeaa

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

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Worldwide Regenerative Medicine Industry to 2025 - Featuring Allergan, Amgen and Baxter International Among Others - PRNewswire

Spinal Cord Stem Cells Comments Off on Worldwide Regenerative Medicine Industry to 2025 – Featuring Allergan, Amgen and Baxter International Among Others – PRNewswire | November 10th, 2020

This article was originally published here

Cell Mol Neurobiol. 2020 Nov 5. doi: 10.1007/s10571-020-00989-x. Online ahead of print.

ABSTRACT

This article reviews the wealth of papers dealing with the different effects of epidermal growth factor (EGF) on oligodendrocytes, astrocytes, neurons, and neural stem cells (NSCs). EGF induces the in vitro and in vivo proliferation of NSCs, their migration, and their differentiation towards the neuroglial cell line. It interacts with extracellular matrix components. NSCs are distributed in different CNS areas, serve as a reservoir of multipotent cells, and may be increased during CNS demyelinating diseases. EGF has pleiotropic differentiative and proliferative effects on the main CNS cell types, particularly oligodendrocytes and their precursors, and astrocytes. EGF mediates the in vivo myelinotrophic effect of cobalamin on the CNS, and modulates the synthesis and levels of CNS normal prions (PrPCs), both of which are indispensable for myelinogenesis and myelin maintenance. EGF levels are significantly lower in the cerebrospinal fluid and spinal cord of patients with multiple sclerosis (MS), which probably explains remyelination failure, also because of the EGF marginal role in immunology. When repeatedly administered, EGF protects mouse spinal cord from demyelination in various experimental models of autoimmune encephalomyelitis. It would be worth further investigating the role of EGF in the pathogenesis of MS because of its multifarious effects.

PMID:33151415 | DOI:10.1007/s10571-020-00989-x

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Epidermal Growth Factor in the CNS: A Beguiling Journey from Integrated Cell Biology to Multiple Sclerosis. An Extensive Translational Overview -...

Spinal Cord Stem Cells Comments Off on Epidermal Growth Factor in the CNS: A Beguiling Journey from Integrated Cell Biology to Multiple Sclerosis. An Extensive Translational Overview -… | November 8th, 2020

According to IMARC Groups latest report, titled Regenerative Medicine Market: Industry Trends, Share, Size, Growth, Opportunity and Forecast 2020-2025,. Looking forward, IMARC Group expects the global regenerative medicine market to continue its strong growth during the next five years.

Regenerative medicine refers to a field of biomedical sciences involved in restoring the structure and function of damaged cells, organs, and tissues. It includes the study of stem cells that are developed in laboratories and then safely inserted into the human body to regenerate damaged bones, cartilage, blood vessels, and organs. Cellular and acellular regenerative medicines are widely adopted in various clinical therapeutic procedures, including cell therapies, immunomodulation, and tissue engineering. They have the potential to treat various chronic diseases, including Alzheimers, Parkinsons, cardiovascular disorders (CVDs), osteoporosis, spinal cord injuries, etc.

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Market Trends

The rising prevalence of chronic diseases and genetic disorders is primarily driving the demand for regenerative medicine across the globe. Moreover, the growing geriatric population who are more prone to musculoskeletal, dermatological, and cardiological disorders is also augmenting the need for regenerative medicines. Furthermore, several technological advancements in cell-based therapies have led to the adoption of 3D bioprinting techniques and artificial intelligence (AI), thereby further propelling the market for regenerative medicine. Moreover, regenerative medicine decreases the risk of organ rejection by the body post-transplant and increases the patients recovery speed, thereby gaining traction in numerous organ transplantation procedures. The increasing investments in extensive R&D activities in the field of medical sciences are expected to drive the market for regenerative medicine.

Regenerative Medicine Market 2020-2025 Analysis and Segmentation:

Competitive Landscape:

The competitive landscape of the market has been studied in the report with the detailed profiles of the key players operating in the market.

Some of these key players include:

The report has segmented the market on the basis of type, application, end user and region.

Breakup by Type:

Breakup by Application:

Breakup by End User:

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Breakup by Region:

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IMARC Group is a leading market research company that offers management strategy and market research worldwide. We partner with clients in all sectors and regions to identify their highest-value opportunities, address their most critical challenges, and transform their businesses.

IMARCs information products include major market, scientific, economic and technological developments for business leaders in pharmaceutical, industrial, and high technology organizations. Market forecasts and industry analysis for biotechnology, advanced materials, pharmaceuticals, food and beverage, travel and tourism, nanotechnology and novel processing methods are at the top of the companys expertise.

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Regenerative Medicine Market 2020: Analysis, Top Companies, Size, Share, Demand and Opportunity To 2025 - Eurowire

Spinal Cord Stem Cells Comments Off on Regenerative Medicine Market 2020: Analysis, Top Companies, Size, Share, Demand and Opportunity To 2025 – Eurowire | November 5th, 2020

Enhancer function, from sponges to humans

Identifying the function of enhancers, DNA regions that help to regulate gene expression and evolve rapidly, has been difficult. This area of research has been hampered by the difficultly in identifying functional conservation. Wong et al. now show that despite low sequence conservation, enhancer function is strongly conserved through the animal kingdom (see the Perspective by Harmston). Transgenic expression of sponge enhancers in zebrafish and mice demonstrates that these sequences can drive cell typespecific gene expression across species. These results suggest an unexpectedly deep level of conservation of gene regulation across the animal kingdom maintained over the course of metazoan evolution.

Science, this issue p. eaax8137; see also p. 657

In animals, gene regulatory networks specify cell identity in space and time. Transcription of genes in these networks is modulated by a class of cis-regulatory elements called enhancers that contain short (~10 base pairs) DNA sequence motifs recognized by transcription factors (TFs). In contrast to TFs, whose histories have been largely traced to the origin of the animal kingdom or earlier, the origin and evolution of enhancers have been relatively difficult to discern.

Although not a single enhancer has been shown to be conserved across the animal kingdom, enhancers may be as ancient and conserved as the TFs with which they interact. This inability to identify conserved enhancers is apparently because they evolve faster than both the TFs they interact with and the genes they regulate.

Putative enhancers in the sponge Amphimedon queenslandica had previously been identified on the basis of combinatorial patterns of histone modifications. Here, we sought to determine whether sponges share functionally conserved enhancers with bilaterians.

We primarily focused on deeply conserved metazoan microsyntenic gene pairs. These pairs are thought to be conserved because the cis-regulatory elements that regulate the developmental expression of one gene (the target gene) are located in the other gene (the bystander gene). This proposed regulatory linkage may underlie the maintenance of these microsyntenic gene pairs across 700 million years of independent evolution.

We found that enhancers present in Amphimedon microsyntenic regions drive consistent patterns of cell typespecific gene expression in zebrafish and mouse embryos. Although these sponge enhancers do not share significant sequence identity with vertebrates, they are in microsyntenic regions that are orthologous with microsyntenic regions in other metazoans and have strong histone H3 Lys4 methylation (H3K4me1) enhancer signals.

Focusing on an Islet enhancer in the Islet-Scaper microsyntenic region, we found that the sponge 709base pair enhancer, independent of its orientation, drives green fluorescent protein (GFP) expression in zebrafish cells in the hindbrain neuroepithelial region, the roof plate around the midline, the pectoral fin, and the otic vesicle; the activity overlaps with endogenous Isl2a expression. Systematic removal of sequences from the Amphimedon Islet enhancer revealed that both the 5 and 3 regions of this enhancer are required for consistent cell typespecific activity in zebrafish.

We then used the number and frequency of TF binding motifs in the Amphimedon Islet enhancer to identify putative enhancers in human, mouse, and fly Islet-Scaper regions. The candidate orthologous enhancers from humans and mice drove gene expression patterns similar to those in sponges and endogenous Islet enhancers in zebrafish.

We also demonstrated that a number of putative Amphimedon enhancers, which are outside conserved microsyntenic regions, can also drive unique expression patterns: Enhancers of sponge housekeeping genes drive broader expression patterns in zebrafish.

These results suggest the existence of an ancient and conserved, yet flexible, genomic regulatory syntax that (i) can be interpreted by the available TFs present in cells constituting disparate developmental systems and cell types, and (ii) has been repeatedly co-opted into cell typespecific networks across the animal kingdom.

This common regulatory code maintains a repertoire of conserved TF binding motifs that stabilize and preserve enhancer functionality over evolution. Once established, these enhancers may be maintained as part of conserved gene regulatory network modules over evolution. Although robust, these enhancers can evolve through the expansion and integration of new TF binding motifs and the loss of others. We posit that the expansion of TFs and enhancers may underlie the evolution of complex body plans.

Enhancers located within conserved microsyntenic units in the sponge Amphimedon queenslandica are tested in a zebrafish transgenic reporter system. In zebrafish, the sponge Islet enhancer drives a GFP reporter expression pattern similar to that of human, mouse, and zebrafish enhancers identified within the Islet-Scaper microsyntenic region. This suggests the conservation of regulatory syntax specified by flexible organizations of motifs.

Interactions of transcription factors (TFs) with DNA regulatory sequences, known as enhancers, specify cell identity during animal development. Unlike TFs, the origin and evolution of enhancers has been difficult to trace. We drove zebrafish and mouse developmental transcription using enhancers from an evolutionarily distant marine sponge. Some of these sponge enhancers are located in highly conserved microsyntenic regions, including an Islet enhancer in the Islet-Scaper region. We found that Islet enhancers in humans and mice share a suite of TF binding motifs with sponges, and that they drive gene expression patterns similar to those of sponge and endogenous Islet enhancers in zebrafish. Our results suggest the existence of an ancient and conserved, yet flexible, genomic regulatory syntax that has been repeatedly co-opted into cell typespecific gene regulatory networks across the animal kingdom.

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Deep conservation of the enhancer regulatory code in animals - Science Magazine

Spinal Cord Stem Cells Comments Off on Deep conservation of the enhancer regulatory code in animals – Science Magazine | November 5th, 2020

DUBLIN--(BUSINESS WIRE)--The "Regenerative Medicine Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2020-2025" report has been added to ResearchAndMarkets.com's offering.

The global regenerative medicine market grew at a CAGR of around 16% during 2014-2019. Looking forward, the publisher expects the global regenerative medicine market to continue its strong growth during the next five years.

Regenerative medicine refers to a branch of biomedical sciences aimed at restoring the structure and function of damaged tissues and organs. It involves the utilization of stem cells that are developed in laboratories and further implanted safely into the body for the regeneration of damaged bones, cartilage, blood vessels and organs. Cellular and acellular regenerative medicines are commonly used in various clinical therapeutic procedures, including cell, immunomodulation and tissue engineering therapies. They hold potential for the effective treatment of various chronic diseases, such as Alzheimer's, Parkinson's and cardiovascular disorders (CVDs), osteoporosis and spinal cord injuries.

The increasing prevalence of chronic medical ailments and genetic disorders across the globe is one of the key factors driving the growth of the market. Furthermore, the rising geriatric population, which is prone to various musculoskeletal, phonological, dermatological and cardiological disorders, is stimulating the market growth. In line with this, widespread adoption of organ transplantation is also contributing to the market growth. Regenerative medicine minimizes the risk of organ rejection by the body post-transplant and enhances the recovery speed of the patient.

Additionally, various technological advancements in cell-based therapies, such as the development of 3D bioprinting techniques and the adoption of artificial intelligence (AI) in the production of regenerative medicines, are acting as other growth-inducing factors. These advancements also aid in conducting efficient dermatological grafting procedures to treat chronic burns, bone defects and wounds on the skin. Other factors, including extensive research and development (R&D) activities in the field of medical sciences, along with improving healthcare infrastructure, are anticipated to drive the market further.

Companies Mentioned

Key Questions Answered in This Report:

Key Topics Covered:

1 Preface

2 Scope and Methodology

3 Executive Summary

4 Introduction

4.1 Overview

4.2 Key Industry Trends

5 Global Regenerative Medicine Market

5.1 Market Overview

5.2 Market Performance

5.3 Impact of COVID-19

5.4 Market Forecast

6 Market Breakup by Type

6.1 Stem Cell Therapy

6.1.1 Market Trends

6.1.2 Market Forecast

6.2 Biomaterial

6.2.1 Market Trends

6.2.2 Market Forecast

6.3 Tissue Engineering

6.3.1 Market Trends

6.3.2 Market Forecast

6.4 Others

6.4.1 Market Trends

6.4.2 Market Forecast

7 Market Breakup by Application

7.1 Bone Graft Substitutes

7.1.1 Market Trends

7.1.2 Market Forecast

7.2 Osteoarticular Diseases

7.2.1 Market Trends

7.2.2 Market Forecast

7.3 Dermatology

7.3.1 Market Trends

7.3.2 Market Forecast

7.4 Cardiovascular

7.4.1 Market Trends

7.4.2 Market Forecast

7.5 Central Nervous System

7.5.1 Market Trends

7.5.2 Market Forecast

7.6 Others

7.6.1 Market Trends

7.6.2 Market Forecast

8 Market Breakup by End User

8.1 Hospitals

8.1.1 Market Trends

8.1.2 Market Forecast

8.2 Specialty Clinics

8.2.1 Market Trends

8.2.2 Market Forecast

8.3 Others

8.3.1 Market Trends

8.3.2 Market Forecast

9 Market Breakup by Region

9.1 North America

9.2 Asia Pacific

9.3 Europe

9.4 Latin America

9.5 Middle East and Africa

10 SWOT Analysis

11 Value Chain Analysis

12 Porters Five Forces Analysis

13 Price Analysis

14 Competitive Landscape

14.1 Market Structure

14.2 Key Players

14.3 Profiles of Key Players

For more information about this report visit https://www.researchandmarkets.com/r/erd0e3

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Global Regenerative Medicine Market (2020 to 2025) - Industry Trends, Share, Size, Growth, Opportunity and Forecast - ResearchAndMarkets.com -...

Spinal Cord Stem Cells Comments Off on Global Regenerative Medicine Market (2020 to 2025) – Industry Trends, Share, Size, Growth, Opportunity and Forecast – ResearchAndMarkets.com -… | November 5th, 2020

Proposition 14 would authorize the sale of $5.5 billion in general obligation bonds for the California Institute for Regenerative Medicine, known as CIRM, for stem cell studies and trials.

Here is a rundown of the ballot measure:

In 2004, voters approved a bond measure to pay for stem cell research.

Now, with the money from that bond running out, supporters of the states stem cell agency are asking taxpayers for a new infusion of cash.

With interest, the bond could cost the state $260 million per year, or $7.8 billion over the next 30 years, according to the nonpartisan Legislative Analysts Office.

Proponents of Proposition 14 say the measure will help find new treatments and cures for chronic diseases and conditions, including cancers, spinal cord injuries, Alzheimers, Parkinsons and heart disease. They say the previous bond advanced research and treatments for more than 75 diseases, including two cancer treatments for fatal blood disorders that were approved by the U.S. Food and Drug Administration.

Without new funding to keep the program going, supporters of Proposition 14 say, groundbreaking medical discoveries and lifesaving research will be slowed or stopped.

Opponents say that the state shouldnt take on new debt while facing a pandemic-induced deficit and that medical advances attributed to the previous stem cell bond have been overstated. In addition, opponents say CIRM has been hampered by conflicts of interest and too little oversight, neither of which are remedied by the ballot measure.

The campaign to pass the 2004 ballot measure told voters that the bond would save millions of lives and cut healthcare costs by billions. Critics say thats not been the case to date, although supporters of this years measure note that they never intended those results within 16 years. While there is not much organized opposition, some newspaper editorial boards, including those at the Los Angeles Times and San Francisco Chronicle, have opposed it.

With Prop. 14, California voters will be asked for more borrowing to keep stem cell research going

Explaining Prop. 14

Times columnist George Skelton assesses Prop. 14

The California stem cell programs $5.5-billion funding request might be its downfall

Californias stem cell program faces an existential moment and a chance for reform

When it comes to disease, stem cells are a game-changer, scientists say. This is why

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California Prop. 14: What to know about the stem cell measure - Los Angeles Times

Spinal Cord Stem Cells Comments Off on California Prop. 14: What to know about the stem cell measure – Los Angeles Times | November 3rd, 2020

Professor Paul Glare at the Pain Management Research Institute.

Opioids are good for acute pain. With chronic pain they only work short to medium term, he says. But after about six months, you become tolerant and have to take bigger doses. Then theres the growing risk of accidental overdose, even accidental death.

For many people though, opioids seem like the only way to numb the pain that constantly attacks them. But do they in fact, numb the pain?

Most people who come off the long term use of opioids realise that the drugs werent doing that much, says Glare. Theyd already stopped working, so the pain without them is often no worse. In fact, the drugs were just messing with their heads. Still its a huge psychological step to let the drugs go.

Gently spoken and with a great sense of compassion for the people he works to help, Glare started his career in palliative care which took him into the area of cancer pain, then pain more generally. Because its difficult to tell people battling chronic pain that there is no satisfactory pharmaceutical answer at this time, the PMRI has a large and active pain education unit.

The Unit offers a Masters of Medicine Pain Management that is also conferred as a Masters of Science for non-medical graduates. It also runs cognitive behavioural therapy classes teaching strategies for rising above the pain.

The classes are challenging, says Glare. But many people who learn the self-management techniques can reduce or even stop their opioid use. Its about them not being afraid of their pain anymore.

Its the nature of chronic pain that the injury its warning you about, sometimes very loudly, isnt actually there. This can be seen in a persons posture as they sit and walk in a way that protects that non-injury. By gently confronting the pain, the person can eventually reclaim their normal posture and walk more confidently. Through that, they feel stronger within themselves and more in control of their pain.

The PMRI is now looking at digital support resources for people dealing with pain, Were developing an SMS based text messaging service and a more sophisticated chat-bot tool, to help people get over the hump of opioid tapering, says Glare. Its new in the pain world.

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How pain changes your brain - News - The University of Sydney

Spinal Cord Stem Cells Comments Off on How pain changes your brain – News – The University of Sydney | November 3rd, 2020

Central nervous system comprises brain and spinal cord, and is responsible for integration of sensory information. Brain is the largest and one of the most complex organs in the human body. It is made up of 100 billion nerves that communicate with 100 trillion synapses. It is responsible for the thought and movement produced by the body. Spinal cord is connected to a section of brain known as brain stem and runs through the spinal canal. The brain processes and interprets sensory information sent from the spinal cord. Brain and spinal cord serve as the primary processing centers for the entire nervous system, and control the working of the body. Neuroprosthetics improves or replaces the function of the central nervous system. Neuroprosthetics, also known as neural prosthetics, are devices implanted in the body that stimulate the function of an organ or organ system that has failed due to disease or injury. It is a brain-computer interface device used to detect and translate neural activity into command sequences for prostheses. Its primary aim is to restore functionality in patients suffering from loss of motor control such as spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, and stroke. The major types of neuroprosthetics include sensory implants, motor prosthetics, and cognitive prosthetics. Motor prosthetics support the autonomous system and assist in the regulation or stimulation of affected motor functions.

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Similarly, cognitive prosthetics restore the function of brain tissue loss in conditions such as paralysis, Parkinsons disease, traumatic brain injury, and speech deficit. Sensory implants pass information into the bodys sensory areas such as sight or hearing, and it is further classified as auditory (cochlear implant), visual, and spinal cord stimulator. Some key functions of neuroprosthetics include providing hearing, seeing, feeling abilities, pain relief, and restoring damaged brain cells. Cochlear implant is among the most popular neuroprosthetics. In addition, auditory brain stem implant is also a neuroprosthetic meant to improve hearing damage.

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North America dominates the global market for neuroprosthetics due to the rising incidence of neurological diseases and growth in geriatric population in the region. Asia is expected to display a high growth rate in the next five years in the global neuroprosthetics market, with China and India being the fastest growing markets in the Asia-Pacific region. Among the key driving forces for the neuroprosthetics market in developing countries are the large pool of patients, increasing awareness about the disease, improving healthcare infrastructure, and rising government funding in the region.

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Increasing prevalence of neurological diseases such as traumatic brain injury, stroke and Parkinsons disease, rise in geriatric population, increase in healthcare expenditure, growing awareness about healthcare, rapid progression of technology, and increasing number of initiatives by various governments and government associations are some key factors driving growth of the global neuroprosthetics market. However, factors such as high cost of devices, reimbursement issues, and adverse effects pose a major restraint to the growth of the global neuroprosthetics market.

Innovative self-charging neural implants that eliminate the need for high risk and costly surgery to replace the discharge battery and controlling machinery with thoughts would help to develop opportunities for the growth of the global neuroprosthetics market. The major companies operating in the global neuroprosthetics market are Boston Scientific Corporation, Cochlear Limited, Medtronic, Inc., Cyberonics, Inc., NDI Medical LLC, NeuroPace, Inc., Nervo Corp., Retina Implant AG, St. Jude Medical, and Sonova Group.

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The Neuroprosthetics market to stand in a good stead from 2015 to 2021 - KYT24

Spinal Cord Stem Cells Comments Off on The Neuroprosthetics market to stand in a good stead from 2015 to 2021 – KYT24 | November 3rd, 2020

Global Neuroprosthetics Market by Type (Output (Cognitive, Motor Prosthetics), Input (Cochlear, Retinal Implant)), Techniques (Deep Brain, Vagus Nerve, Spinal Cord stimulation), Application (Epilepsy, Paralysis, Alzheimers Disease). The neuroprosthetics market is projected to reach USD 10.48 billion by 2022 from USD 5.84 billion in 2017, at a CAGR of 12.4%.

Neuroprostheses uses electrodes to interface with the central or peripheral nervous system to restore lost motor or sensory capabilities. These devices can receive neural signals from the external environment & brain, and convert the signals to restore functions such as loss of hearing and vision.

They have applications in cognitive disorders, ophthalmic disorders, motor disorders, and auditory disorders.

Theneuroprosthetics marketis projected to reach USD 10.48 billion by 2022 from USD 5.84 billion in 2017, at a CAGR of 12.4%.

People suffering from diabetes may develop several foot problems, which cause damage to blood vessels and nerves. Diabetes can also damage the blood vessels in the retina, which can cause vision impairments or blindness.

As a result, the increasing incidence of diabetes is expected to support the growth of the retinal/bionic eye implants market. The top five countries with the highest diabetic population in 2013 (age group of 2079 years) were China, India, the US, Brazil, and the Russian Federation.

Dysvascular disorder- and diabetes-related amputations are expected to drive the demand for artificial limb replacements in the near future. The prevalence of diabetes has significant regional variation.

Since its burden is higher in the Asia Pacific region, this factor is expected to have a more substantial effect on the market in countries in Southeast Asia and the Indian subcontinent.

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Novel therapies, such as stem cell therapy, are showcasing a significant potential for the effective treatment of various neurological disorders. Stem cell therapy is an emerging branch of medicine that has the potential to restore organ and tissue function in patients suffering from serious injuries or chronic diseases.

These therapies offer advantages such as higher recovery rates and faster recovery periods for patients. Moreover, stem cells also have significant potential in the treatment of motor neuron disease, Parkinsons disease, and Alzheimers disease.

Furthermore, medicinal, physical, occupational, and speech therapies are available for the treatment of several neurological disorders. For instance, currently, the preference for drug therapies is higher among Parkinsons patients due to the lower cost and convenience of the treatment.

The availability of these alternative treatment options is one of the significant factors limiting the demand for and adoption of neuroprosthetic devices and implants among the target patient population.

Neuroprosthetic procedures involve minimally invasive techniques as opposed to alternate surgical procedures for treating tremors primarily associated with Parkinsons, which are invasive treatments. For instance, in a pallidotomy, the surgeon destroys a tiny part of the globus pallidus by creating a scar to reduce brain activity.

Doctors do not prefer this procedure and encourage the use of deep brain stimulation; instead, as it does not destroy brain tissue and has fewer risks as compared to pallidotomy.

The use of DBS in newer applications/indications, such as Alzheimers, epilepsy, and depression, is currently in clinical trials. Similarly, the treatment of heart failure, sleep apnea, obesity, and tinnitus through VNS (Vagus Nerve Stimulation); fecal incontinence by SNS (Sacral Nerve Stimulation); and tinnitus, migraine, and stroke by TMS (Transcranial Magnetic Stimulation) are also under clinical trials.

TMS is currently used to treat depression, SNS for urine incontinence, and VNS for epilepsy.

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North America is expected to command the largest share of the market during the forecast period.

Based on region, the neuroprosthetics market is segmented into North America, Europe, Asia Pacific, and the Rest of the World (RoW). In 2017, North America is expected to command the largest share of the neuroprosthetics market.

The large share of this market can primarily be attributed to the high incidence of vision and hearing loss, rising prevalence of neurological disorders, and the strong presence of industry players in this region.

Key Market Players

Medtronic plc (Medtronic) (US), Cochlear Ltd. (Cochlear) (Australia), Abbott Laboratories (Abbott) (US), Boston Scientific (US), LivaNova, PLC (LivaNova) (UK), and Second Sight Medical Products, Inc.(Second Sight) (US).MED-EL (Austria), Retina Implant AG (Germany), Sonova (Switzerland), Neuropace (US), NDIE Medical, LLC (Canada) Nevro (US).

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Neuroprosthetics Market: Increasing Prevalence of Diabetes in Neuroprosthetics investigated in the latest research - WhaTech

Spinal Cord Stem Cells Comments Off on Neuroprosthetics Market: Increasing Prevalence of Diabetes in Neuroprosthetics investigated in the latest research – WhaTech | November 3rd, 2020

Waking up the dead science fiction or a Halloween night horror movie? No, thats the goal of Bioquarks ReAnima project. The project aims to restore neuronal activity in brain dead people by combining several techniques: stem cell injection, nerve stimulation, and laser.

Stem Cells

Stem cells are increasingly becoming a serious treatment option for many nervous disorders: Alzheimers, Parkinsons, brain injuries, etc. So why not repair the brains of the dead to bring them back to life? This idea, worthy of a science fiction (or horror) film, is the crazy project of a company based in Philadelphia: Bioquark.

Read Also: Old Human Cells Successfully Rejuvenated Via Stem Cell Technology

This is not the first time that the company wants to participate in such an experiment. In 2016, the ReAnima study was launched in Bangalore, India, together with Himanshu Bansal, an orthopedic surgeon at Anupam Hospital. His plan was to combine several techniques to revive 20 brain dead people.

ReAnima consisted of injecting patients with mesenchymal stem cells and peptides that help regenerate brain cells; these peptides were to be supplied by Bioquark. In addition to these injections, transcranial laser stimulation and nerve stimulation were planned. This project was stopped by the Indian authorities in November last year, as revealed then by Science magazine.

But the company did not admit defeat. This time, according to the company, they are close to finding a new location for their clinical trials. Ira Pastor, CEO of Bioquark, told the Stat website that the company would announce the process in Latin America in the coming months.

Read Also: HGH Improves Memory In Stroke Victims Study Shows

If the experiment follows the same protocol as planned in India, it may involve 20 people. The clinical trial would again involve the injection of the patients stem cells, fat, blood Then a mixture of peptides would be injected into the spinal cord to stimulate the growth of new nerve cells. This compound, called BQ-A, was tested on animal models with head trauma. In addition, the nerves would be stimulated by nerve stimulation and 15 days of laser therapy to stimulate the neurons to make nerve connections. Researchers could then monitor the effects of this treatment using electroencephalograms.

But such a protocol raises many questions: How would a clinical trial be conducted on officially deceased people? If the person recovers some brain activity, in what state would he be? Will families be given false hope with a treatment that may take a long time?

Read Also: UC San Diego: Adult Brain Cells Revert to Younger State Following Injury, Study Shows

There is no indication that such a protocol will work. The company has not even tested the entire treatment on animal models! The mentioned treatments, such as injection of stem cells or transcranial stimulation, were tested in other situations, but not in cases of brain death. In an article published in 2016, neurologist Ariane Lewis and bioethicist Arthur Caplan stressed that the experiment had no scientific basis and that it gave families false and cruel hopes of a cure.

Experiment to raise the dead blocked in India

Response to a trial on reversal of Death by Neurologic Criteria

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Philadelphia Based Company Wants to Bring Back the Dead With Stem Cells - Gilmore Health News

Spinal Cord Stem Cells Comments Off on Philadelphia Based Company Wants to Bring Back the Dead With Stem Cells – Gilmore Health News | November 1st, 2020