Research Progress on the Mechanisms of Endogenous Neural Stem Cell Differentiation in Spinal Cord Injury Repair  Frontiers

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Research Progress on the Mechanisms of Endogenous Neural Stem Cell Differentiation in Spinal Cord Injury Repair - Frontiers

Bone marrow mesenchymal stem cells (BM-MSCs) are a vital component of regenerative medicine due to their ability to differentiate into various cell types and modulate immune responses. Their therapeutic potential has led to extensive research on their biological properties, mechanisms of action, and clinical applications.

Understanding BM-MSCs requires examining their microenvironment, distinguishing characteristics, isolation techniques, differentiation pathways, and how they compare to other stem cell types.

BM-MSCs originate from the mesodermal germ layer during embryonic development and persist into adulthood for tissue maintenance and repair. Within the bone marrow, they coexist with hematopoietic stem cells (HSCs) and other stromal components, contributing to the marrow niches structure and function. Their distribution is not uniform, with higher concentrations in trabecular-rich regions such as the iliac crest, femur, and sternum. These sites provide a supportive environment where BM-MSCs interact with the extracellular matrix, soluble factors, and neighboring cells to regulate proliferation and differentiation.

The bone marrow microenvironment is a specialized niche that governs BM-MSC behavior through biochemical and mechanical cues. It consists of an extracellular matrix composed of collagen, fibronectin, and laminin, which provides structural support and modulates adhesion. Oxygen tension in the marrow is lower than in peripheral tissues, with hypoxic conditions (1% to 7% oxygen) helping maintain BM-MSC quiescence and stemness. Hypoxia-inducible factors (HIFs) mediate responses to low oxygen levels, promoting genes involved in self-renewal and metabolic adaptation.

Cellular interactions further shape BM-MSC function. Crosstalk with endothelial cells, osteoblasts, and pericytes influences their role in supporting hematopoiesis and tissue homeostasis. Endothelial cells secrete vascular endothelial growth factor (VEGF), enhancing BM-MSC survival and migration. Osteoblasts provide osteogenic signals that prime BM-MSCs for differentiation into bone-forming cells. Pericytes, which share similarities with BM-MSCs, contribute to vascular stability and regulate stem cell fate.

BM-MSCs are defined by a unique set of surface markers that distinguish them from other stromal and hematopoietic populations. Unlike HSCs, BM-MSCs lack CD34, CD45, and CD14, which are associated with blood cell lineages. Instead, they express CD73, CD90, and CD105, as established by the International Society for Cell and Gene Therapy (ISCT). These markers facilitate identification, isolation, and functional characterization.

CD73, also known as ecto-5-nucleotidase, catalyzes the conversion of extracellular AMP into adenosine, modulating microenvironmental signals. CD90, or Thy-1, is a glycoprotein involved in cell-cell and cell-matrix interactions, influencing BM-MSC proliferation and differentiation. CD105, or endoglin, serves as a co-receptor for transforming growth factor-beta (TGF-), maintaining BM-MSC multipotency and guiding lineage commitment.

Additional markers refine BM-MSC characterization. CD146, a pericyte-associated marker, is linked to heightened clonogenic potential. STRO-1, an early mesenchymal progenitor marker, correlates with enhanced osteogenic differentiation but diminishes with cell expansion. CD271, or low-affinity nerve growth factor receptor (LNGFR), has been proposed for isolating highly pure BM-MSC populations with superior regenerative properties.

Isolating and expanding BM-MSCs are critical for research and clinical applications. Various techniques selectively extract BM-MSCs while minimizing contamination from hematopoietic and other stromal cells.

Density gradient centrifugation separates mononuclear cells from other bone marrow components based on cell density. Ficoll-Paque and Percoll are commonly used media that enrich BM-MSCs by allowing lower-density mononuclear cells to form a distinct layer after centrifugation. This method is simple and cost-effective but does not exclusively isolate BM-MSCs, as the mononuclear fraction contains hematopoietic cells. To improve purity, plastic adherence-based selection is often employed, where BM-MSCs attach to tissue culture plastic while non-adherent cells are removed. However, this approach has limitations, including variability in yield and potential contamination.

Fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) isolate BM-MSCs based on surface marker expression. FACS uses fluorescently labeled antibodies targeting BM-MSC markers such as CD73, CD90, and CD105, allowing high-purity selection through laser-based detection. MACS employs magnetic beads conjugated to antibodies, enabling rapid and scalable cell separation. While FACS provides greater resolution, it requires specialized equipment and is time-intensive. MACS, though less precise, is more accessible and suitable for large-scale cell enrichment.

Enzymatic digestion methods use proteolytic enzymes such as collagenase and trypsin to break down the extracellular matrix and release BM-MSCs. Collagenase digestion is commonly used to degrade collagen-rich structures while preserving viability. Trypsin, often combined with other enzymes, aids in cell detachment. While enzymatic dissociation enhances cell recovery, excessive enzyme exposure can compromise viability and surface marker integrity. This method is often combined with culture-based selection for further enrichment.

BM-MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes. This process is governed by transcription factors and environmental cues that guide lineage commitment. The surrounding microenvironment, including mechanical forces and biochemical signals, influences differentiation outcomes.

Osteogenic differentiation is driven by RUNX2, which activates genes responsible for bone matrix deposition. Calcium, phosphate, and bone morphogenetic proteins (BMPs) reinforce osteogenesis by enhancing mineralization. Chondrogenic differentiation is regulated by SOX9, which promotes cartilage-specific proteins such as aggrecan and type II collagen. Hypoxic conditions sustain chondrocyte-like characteristics. Adipogenic differentiation is controlled by PPAR and C/EBP, which drive lipid accumulation and adipocyte-specific gene expression.

BM-MSC differentiation is regulated by signaling pathways that govern self-renewal, proliferation, and lineage commitment. The Notch, Wnt, and BMP pathways play key roles in directing fate decisions.

The Notch pathway influences BM-MSC proliferation and differentiation through cell-to-cell communication. Activation occurs when Notch ligands bind to receptors, triggering cleavage and release of the Notch intracellular domain (NICD). NICD translocates to the nucleus and modulates gene expression. Notch signaling maintains BM-MSCs in an undifferentiated state by suppressing osteogenic and adipogenic differentiation while promoting chondrogenesis. Sustained Notch activation enhances cartilage formation by upregulating SOX9, while inhibition facilitates osteogenesis by relieving suppression on RUNX2.

The Wnt signaling cascade affects BM-MSC fate through canonical and non-canonical pathways. In the canonical pathway, Wnt ligands bind to Frizzled receptors, stabilizing -catenin, which activates osteogenic genes. This pathway promotes bone formation by enhancing RUNX2 expression and matrix mineralization. The non-canonical pathway, independent of -catenin, regulates cytoskeletal organization and migration. Canonical Wnt signaling favors osteogenesis while inhibiting adipogenesis by suppressing PPAR, maintaining a balance in BM-MSC differentiation.

Bone morphogenetic proteins (BMPs) regulate BM-MSC differentiation, particularly in bone and cartilage formation. BMP ligands bind to receptors, triggering SMAD phosphorylation and transcriptional regulation. BMP2 and BMP7 induce osteogenesis by upregulating RUNX2 and enhancing extracellular matrix deposition. BMP signaling also synergizes with SOX9 to promote chondrogenesis. While BMPs favor skeletal differentiation, excessive signaling can lead to aberrant ossification.

BM-MSCs differ from other stem cell populations in differentiation potential, immunomodulatory effects, and tissue origin. Unlike HSCs, which primarily generate blood cells, BM-MSCs contribute to mesodermal-derived tissues such as bone, cartilage, and adipose. Their ability to differentiate into multiple skeletal and connective tissue types makes them valuable for regenerative applications.

Compared to embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), BM-MSCs have a more restricted differentiation capacity, as they do not generate cells from all three germ layers. However, this reduces the risk of teratoma formation, a concern with pluripotent stem cell-based therapies. BM-MSCs are also more accessible and ethically uncontroversial, as they can be harvested from adult bone marrow. Their immunomodulatory properties further distinguish them, as they modulate immune responses through cytokine secretion and direct interactions, making them useful in inflammatory and autoimmune conditions.

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Bone Marrow Mesenchymal Stem Cells: Key Insights and Functions

Newborn Mice May Hold the Key to Simpler Gene Therapy  the-scientist.com

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Newborn Mice May Hold the Key to Simpler Gene Therapy - the-scientist.com

New Gene Therapy Reverses Three Diseases With Shots to the Bloodstream  SingularityHub

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New Gene Therapy Reverses Three Diseases With Shots to the Bloodstream - SingularityHub

In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking  Nature

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In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking - Nature

Parkinson's disease (PD) develops from the gradual loss of neurons that produce dopamine, which is critical to your movement, mood and motivation. The quest for effective treatments that address dopamine loss has included stem cell research using tissue that can be transformed into dopamine neurons. However, previous stem cell studies showed mixed results for Parkinsons and attempts at transplanting stem cells into the brain have fallen short.

A new avenue of possibilities has emerged with induced pluripotent stem (iPS) and human embryonic stem (hES) cells. These types of stem cells have the unique ability to develop into any cell type in the body, offering a potentially limitless source for generating the dopamine neurons lost in Parkinson's.

Scientists have been exploring the potential of these cells to create safe and effective therapies that could one day alleviate Parkinsons symptoms. Interestingly, the development of iPS cells earned Shinya Yamanaka the Nobel Prize in Physiology or Medicine in 2012. This type of stem cell is derived directly from adult tissue and is not associated with embryonic stem cells.

Two new clinical trials (Phase I and II), both published in Nature, evaluated the safety and potential benefits of transplanting early-stage dopamine-producing cells derived from specific types of stem cells.

One study, conducted in Japan, explored iPS cells, which were derived from the blood of a healthy adult.

The other study, conducted in the U.S. and Canada, used a human embryonic stem (hES) cell line developed in 1998.

These trials involved a total of 19 people living with Parkinson's, with seven enrolled in the iPS study and 12 in the hES study.

Each participant received a transplantation of cells on the path to becoming dopaminergic neurons, derived from either iPS or hES cells, directly into a part of the brain involved in movement (called the putamen). Both studies randomly divided participants in half, with half receiving a higher dose of cells, and half receiving a lower dose of cells. All participants received immunosuppressive medication, which reduces the activity of the body's immune system to prevent it from attacking the new dopamine-producing cells.

The primary focus of these trials was to monitor the safety of the approach and to carefully track any problems that occurred 18-24 months after transplantation.

Encouragingly, the results showed no serious adverse events in either study directly linked to the cell transplantation. Magnetic resonance imaging (MRI) scans showed no signs of tumors forming from the transplanted cells. Additionally, there were no issues in either study with involuntary movements (dyskinesias) induced by the transplanted cells, which has been a concern with previous cell studies.

Beyond safety, the researchers also observed any changes in the participants' symptoms and their brain's ability to produce dopamine. Most participants continued their PD medications.

For the participants receiving cells from iPS cells, among the six participants who underwent a thorough evaluation (one dropped out due to a COVID-19 infection), most showed notable improvements in their movement symptoms.

Four participants showed improvement on a standard scale used to assess Parkinson's movement symptoms when they were off their medication and five participants had improvements in the PD measurement scale when they were on medication.

Furthermore, brain scans using a specialized tracer that detects dopamine production revealed an average increase of 44.7% in dopamine activity in a key brain region called the putamen, with even greater increases seen in those who received a higher dose of the transplanted cells.

While other measures showed more subtle changes, the overall findings are promising.

For the participants receiving cells from hES cells, the researchers also saw signs that the therapy might be working. Brain scans taken 18 months after the transplant showed:

Increased activity in the putamen, suggesting that the transplanted cells had survived and were potentially functioning.

Furthermore, those who received the higher dose of the cell therapy showed an average improvement of 23 points on their PD measurement scale scores when they were off their regular medication.

While these are early results that need to be replicated, they offer a glimpse into a potential new way to treat Parkinson's and pave the way for larger studies to confirm these findings.

Two studies enrolled 19 people with Parkinsons and transplanted stem cell-derived progenitor cells on the path to becoming dopaminergic neurons directly into a part of their brain called the putamen.

Both studies used established stem cell lines, meaning no new tissue donation was involved.

Both studies observed an improvement in Parkinson's movement symptoms in most participants.

Brain scans showed increased activity in the area of the brain after the cells were transplanted, suggesting that the cells survived and were potentially functioning.

There were no tumors formed or other issues linked to the cells 18 months after transplantation.

Overall, the main takeaway from these studies is that it appears stem cell research can be conducted safely without major adverse effects. Additionally, the studies also suggest the possibility that stem cell treatments may be able to help people with PD manage symptoms. However, more research is needed to confirm that this treatment is safe and effective, particularly in larger and longer-term studies.

In addition, while these studies may have just re-opened the door for more PD-related stem cell research, it is important to know that potential stem cell treatments are linked to PD movement symptoms relief, not non-movement symptoms. In summary, these studies will most likely kick-start new research surrounding stem cell therapy as a promising treatment for Parkinsons.

This breakthrough offers a new line of research hope for people living with Parkinsons today. It has been a long time since stem cell-based therapies have been seen as a safe treatment option with promise for symptom management. However, stem cell therapies are not yet a proven treatment for PD.

Given the promising results of these iPS cell or hES cell studies, similar studies will most likely be on the horizon. If you find a stem cell study of interest, talk to your PD doctor about the study, and share the study protocol and informed consent for him/her to review. It is a red flag if a study does not provide either one of these documents. Importantly, there should never be a fee or cost to participate in a clinical trial, including stem cell trials and studies.

This article is part of our Science News series. The studies mentioned in this article are conducted by a third party and are not funded by the Parkinson's Foundation.

The Parkinsons Foundation believes in empowering the Parkinsons community through education. Learn more about PD and the topics in this article through our below resources, or by calling our free Helpline at 1-800-4PD-INFO (1-800-473-4636) for answers to your Parkinsons questions.

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Two New Trials Explore Stem-Cell Therapy for Parkinson's

World's first therapy to reverse spinal cord injury enters human trial  New Atlas

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World's first therapy to reverse spinal cord injury enters human trial - New Atlas

Phase 2a trial of RAP-219 in refractory focal epilepsy fully enrolled and on track for topline results in September 2025 Phase 2a trial of RAP-219 in refractory focal epilepsy fully enrolled and on track for topline results in September 2025

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Rapport Therapeutics Hosts Investor and Analyst Day; Provides Corporate Updates

TORONTO, June 02, 2025 (GLOBE NEWSWIRE) -- Cronos Group Inc. (NASDAQ: CRON) (TSX: CRON) (“Cronos” or the “Company”), an innovative global cannabinoid company, today announced that Mike Gorenstein, Chairman, President and CEO, will speak at the TD Cowen 9th Annual Future of the Consumer Conference on Wednesday, June 4, 2025, at 3:30 p.m. EST.

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Cronos Group Inc. to Speak at the TD Cowen 9th Annual Future of the Consumer Conference

Abivax Presents First Quarter 2025 Financial Results

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Abivax Presents First Quarter 2025 Financial Results

– Results from Phase 1b clinical trial evaluating onvansertib + paclitaxel for metastatic triple negative breast cancer demonstrated 40% objective response rate –

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Cardiff Oncology Announces Positive Data from Investigator-Initiated Trial of Onvansertib in Combination with Paclitaxel in Metastatic Triple-Negative...

WALTHAM, Mass., June 02, 2025 (GLOBE NEWSWIRE) -- Ardelyx, Inc. (Nasdaq: ARDX), a biopharmaceutical company founded with a mission to discover, develop and commercialize innovative, first-in-class medicines that meet significant unmet medical needs, today announced that Mike Kelliher, formerly Executive Vice President, Corporate Development and Strategy, has been promoted to Chief Business Officer, and James P. Brady has joined the company as Chief Human Resources Officer.

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Ardelyx Appoints Mike Kelliher Chief Business Officer and James P. Brady Chief Human Resources Officer

LONDON, Ontario and BOSTON, June 02, 2025 (GLOBE NEWSWIRE) -- Sernova Biotherapeutics, (TSX: SVA) (OTCQB: SEOVF) (FSE/XETRA: PSH), a leading regenerative medicine company focused on developing its Cell Pouch Bio-hybrid Organ as a functional cure for type 1 diabetes (T1D), today announced the appointment of Sernova’s Chief Executive Officer Jonathan Rigby as Interim Chair of the board of directors. Mr. Rigby will assume the Chair role, effective immediately, until a new independent director is appointed to serve as the next Chair of the Board.

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Sernova Appoints Jonathan Rigby as Interim Chair

Meeting adjourned to June 13, 2025 at 8:30 a.m. Pacific Time

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Vaxart Announces Adjournment of Annual Meeting of Stockholders

MALVERN, Pa., June 02, 2025 (GLOBE NEWSWIRE) --  Neuronetics, Inc. (NASDAQ: STIM), a vertically integrated, commercial stage, medical technology and healthcare company with a strategic vision of transforming the lives of patients whenever and wherever they need help, with the leading neurohealth therapies in the world, today announced that it is set to join the broad-market Russell 3000® Index and the small-cap Russell 2000® Index at the conclusion of the Russell indexes annual reconstitution, effective after the US market opens on June 30, 2025.

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Neuronetics Set to Join Russell 2000® and Russell 3000® Indexes

BOSTON, June 02, 2025 (GLOBE NEWSWIRE) -- Entrada Therapeutics, Inc. (Nasdaq: TRDA) today announced that the Company granted an aggregate of 23,820 restricted stock units (“RSUs”) to six newly-hired non-executive employees under the Company’s 2025 Inducement Equity Plan (the “Inducement Plan”), effective as of June 1, 2025. The inducement grants were previously approved by the Compensation Committee of the Company’s Board of Directors, as a material inducement to the new employees’ entry into employment with the Company in accordance with Nasdaq Listing Rule 5635(c)(4).

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Entrada Therapeutics Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)

HOLLISTON, Mass., June 02, 2025 (GLOBE NEWSWIRE) -- Harvard Bioscience, Inc. (Nasdaq: HBIO) (the “Company”) today announced the appointment of John Duke to its board of directors, effective June 2, 2025. Mr. Duke will also serve on the audit and nominating and governance committees. The Company also announced that Katherine Eade has been named Lead Independent Director of the Company’s board of directors.

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Harvard Bioscience Appoints John Duke to Board of Directors

EDMONTON, Alberta, June 02, 2025 (GLOBE NEWSWIRE) -- Quest PharmaTech Inc. (TSX-V: QPT) (“Quest” or the “Company”), a Canadian based pharmaceutical company developing products to improve the quality of life through investee companies and proprietary technologies, today provided a corporate update and announced that it has filed its annual audited financial statements for the year ended January 31, 2025, Management’s Discussion and Analysis and related filings on SEDAR+ (www.sedarplus.ca). The Company reported a net loss of $1.8 million, total liabilities of $1.2 million and total assets of $22.6 million, including the Company’s bonds of OQP Bio Inc. (“OQP Bio”) that were valued at $17 million as at January 31, 2025.

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Quest PharmaTech Provides Corporate Update

– CR/CRh rate of 23% in pivotal Ph 2 cohort of R/R NPM1-m AML patients –

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Kura Oncology and Kyowa Kirin Report Positive Pivotal Ziftomenib Monotherapy Data at 2025 ASCO Annual Meeting

VICTORIA, British Columbia, June 02, 2025 (GLOBE NEWSWIRE) -- Eupraxia Pharmaceuticals Inc. (“Eupraxia” or the “Company”) (TSX: EPRX) (NASDAQ: EPRX), a clinical-stage biotechnology company leveraging its proprietary DiffuSphere™ technology designed to optimize drug delivery for applications with significant unmet need, is pleased to announce the results from its Annual General and Special Meeting of Shareholders (the “Meeting”) held on June 2, 2025.

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Eupraxia Pharmaceuticals Announces Voting Results from Annual General and Special Meeting of Shareholders