A breakthrough study provides a blueprint for future investigation into pathological conditions associated with poor wound healing, such as in diabetic patients. A team of researchers from the University of California has published the first comprehensive overview of the major changes that occur in mammalian skin cells as they prepare to heal wounds.

The study, "Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics", was published this week in Cell Reports. According to Xing Dai, Ph.D., a professor of biological chemistry and dermatology in the UCI School of Medicine, and senior author, "This study is the first comprehensive dissection of the major changes in cellular heterogeneity from a normal state to wound healing in the skin."

This work also showcases the collaborative efforts between biologists, mathematicians and physicists at UCI, with support from the National Institute of Arthritis & Musculoskeletal & Skin Diseases-funded UCI Skin Biology Resource-based Center and the NSF-Simons Center for Multiscale Cell Fate Research. "Our research uncovered at least four distinct transcriptional states in the epidermal basal layer as part of a 'hierarchical-lineage' model of the epidermal homeostasis, or stable state of the skin, clarifying a long-term debate in the skin stem cell field," said Dai.

Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, the team identified three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization, which is the process by which the skin and mucous membranes replace superficial epithelial cells damaged or lost in a wound. Epithelial tissue maintenance is driven by resident stem cells, the proliferation and differentiation dynamics of which need to be tailored to the tissue's homeostatic and regenerative needs. However, our understanding of tissue-specific cellular dynamics in vivo at single-cell and tissue scales is often very limited.

"Our study lays a foundation for future investigation into the adult epidermis, specifically how the skin is maintained and how it can robustly regenerate itself upon injury," said Dai.

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

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Study reveals how skin cells prepare to heal wounds - Devdiscourse

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Dr. Gaines of Life Gaines Medical & Aesthetics Center sends out info about the COVID-19 virus for concerned patients and the general public in South Florida

Boca Raton, Florida--(Newsfile Corp. - March 20, 2020) - LifeGaines reaches out to its patients and community who are concerned about COVID-19, the novel coronavirus.

"Dear LifeGaines Medical & Aesthetics Family,

"The staff at LifeGaines takes your health and safety seriously and we won't compromise when it comes to protecting our patients. We are closely monitoring the World Health Organization and CDC with regard to ongoing developments of the coronavirus (COVID-19) and we are committed to providing you a safe and clean environment.

"In an effort to reassure our patients, we want to inform you that we are continuing our rigorous routines to keep our practice sanitized and clean and will continue to take every precaution to keep you safe. Our daily safety standards include disinfecting our treatment rooms and equipment after each treatment and thoroughly washing our hands. We also wear new, clean gloves when applying products to our patients' skin and discard after each use. Also, our office is cleaned daily including wiping down tabletops, doorknobs, and equipment using medical-grade disinfectants."

Dr. LifeGaines reaches out to patients and community in light of COVID-19

To view an enhanced version of this graphic, please visit:https://media.zenfs.com/en-us/newsfile_64/2f7e8700c7c06672c2bf9192647742d9

Please don't hesitate to contact us with any questions or concerns at (561) 931-2430. We look forward to seeing you soon.

https://www.facebook.com/LifeGaines/posts/1067452740282001 - Dr. Gaines gives a message on Facebook about how he is boosting his immune system as the COVID-19 virus spreads across the U.S.

Dr. Gaines talks about the benefits of IV ozone therapy. In addition to immunotherapy which helps boost someone's immune system, one should also drink plenty of water and get enough rest.

LifeGaines is mobile and visiting patients at their homes with the IV ozone therapy treatment. Inquire about this by calling LifeGaines.Learn about IV Vitamin Therapy here: https://lifegaines.com/wellness-therapies/iv-vitamin-therapy/

Don't hesitate to contact LifeGaines with any questions or concerns at (561) 931-2430.

About Dr. Gaines' LifeGaines team:

LifeGaines is one of the most highly respected age management medical teams anywhere. Age management medicine pioneer Dr. Richard Gaines has years of experience specializing in hormone replacement therapy, sexual wellness, platelet-rich plasma, stem cells, aesthetics, and advanced age management protocols.

About Dr. Gaines:

Dr. Richard Gaines graduated from Boston University School of Medicine in 1981. He completed his internship at Tufts University School of Medicine in 1981 and his residency at Harvard Medical School in 1985, where he was an anesthesiology fellow at Brigham and Women's Hospital. He served as a physician at Huntington General Hospital, as an anesthesiologist at Harvard Community Health Plan and at Sheridan Healthcorp. Dr. Gaines opened an age management and wellness practice after a 40-year career as a physician and health care executive. He has a Fellowship in Anti-Aging and Regenerative Medicine (FAARM) from the American Academy of Anti-Aging Medicine, he's board-certified from the American Board of Anti-Aging & Regenerative Medicine (ABAARM) and he's certified as a Functional Medicine Practitioner with advanced training at The Institute for Functional Medicine.

LifeGaines is responsible for this press release.

To view the source version of this press release, please visit https://www.newsfilecorp.com/release/53638

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Dr. Gaines Provides Insight Into How People Can Best Protect Themselves and Their Families From the COVID-19 Virus - Yahoo Finance

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The Sound of Science - 'Nina Tandon' (March 20, 2020)

Alexis: Welcome to the Sound of Science on WNIJ. Im Alexis from NIUSTEM Outreach.

Idalia: And Im Idalia. Todaywe will be discussing American biomedical engineer, Nina Tandon.

Alexis:Dr. Tandongrew upin New York City with two siblings with visual impairments. Its no wonder why she chose toinvestigatethe electrical currents that underline the nervous system.

Idalia:As a kid, she often took apart electronics to try to understand them from the inside out.

Alexis:Tandon went on to study Biomedical Engineering and earned her PhD from Columbia. She focused her research on studying electrical signals in engineered tissues, such as cardiac, skin, bone, and neural tissues.

Idalia:Her studies in both bioengineering and business came together as she and a colleague created EpiBone, the worlds first company to grow living human bones for skeletal reconstruction. EpiBoneuses stem cells from patients in need of new bones to produce skeletal structures based on each individual DNA profile.This decreases rejection, simplifies surgeries, and shortens recovery time.

Alexis:SinceDr. Tandon madesuch a giant leap for bioengineering innovation, its clear why she received awards such as "One of the 100 Most Creative People in Business" byFast Companyand "Global Thinker" byForeignPolicy.

Idalia:She is an inspirational woman who completed what was once thought to be impossible.Yet, sheis far from being done.Her companys bioengineered tissues are being used for testing pharmaceuticals without using rats or humans. She says Our process is essentially transforming biotechnology and pharmacology into information technology, helping us discover and evaluate drugs faster, more cheaply and more effectively.

Alexis: Tune in next week where wego into detail aboutmore women in STEM.This has been the Sound of Science on WNIJ.

Idalia: Where you learn something new every day.

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The Sound of Science - 'Nina Tandon' | WNIJ and WNIU - WNIJ and WNIU

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In this new business intelligence Stem Cell-Derived Cells market report, PMR serves a platter of market forecast, structure, potential, and socioeconomic impacts associated with the global Stem Cell-Derived Cells market. With Porters Five Forces and DROT analyses, the research study incorporates a comprehensive evaluation of the positive and negative factors, as well as the opportunities regarding the Stem Cell-Derived Cells market.

With having published myriads of Stem Cell-Derived Cells market reports, PMR imparts its stalwartness to clients existing all over the globe. Our dedicated team of experts deliver reports with accurate data extracted from trusted sources. We ride the wave of digitalization facilitate clients with the changing trends in various industries, regions and consumers. As customer satisfaction is our top priority, our analysts are available 24/7 to provide tailored business solutions to the clients.

Request Sample Report @ https://www.persistencemarketresearch.co/samples/28780

The Stem Cell-Derived Cells market report has been fragmented into important regions that showcase worthwhile growth to the vendors Region 1 (Country 1, Country 2), region 2 (Country 1, Country 2) and region 3 (Country 1, Country 2). Each geographic segment has been assessed based on supply-demand status, distribution, and pricing. Further, the study provides information about the local distributors with which the Stem Cell-Derived Cells market players could create collaborations in a bid to sustain production footprint.

key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

The report covers exhaustive analysis on:

Regional analysis includes

Report Highlights:

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Stem Cell-Derived Cells Value Projected to Expand by 2019-2025 - 3rd Watch News

IPS Cell Therapy Comments Off on Stem Cell-Derived Cells Value Projected to Expand by 2019-2025 – 3rd Watch News | March 20th, 2020

President Donald Trump has repeatedly said that the US is working to develop a vaccine for Covid-19, the disease caused by the novel coronavirus, as quickly as possible. But one of his own administrations policies appears to be standing in the way of at least one scientist.

According to a report by the Washington Posts Amy Goldstein, Kim Hasenkrug, an immunologist at the National Institutes of Healths Rocky Mountain Laboratories in Montana, wants to test potential treatments for Covid-19 in mice with humanized lungs. But as the Post first reported, the work is being held up by officials at the Department of Health and Human Services due to a 2019 ban on NIH scientists using donated fetal tissue from abortions in their research.

While fetal tissue isnt typically used to develop actual therapies or treatments, it has one particularly key use for researchers: the ability to create mice with human tissue suitable for medical testing. Mice, generally, have similar immune systems to humans, making them particularly useful for early medical testing.

Humanized mice have been key to developing several important medical treatments for diseases like the Zika virus or HIV/AIDS, which was Hasenkrugs previous research focus. The calculation is simple. You cant test certain treatments without humanized mice, and you cant get humanized mice without fetal tissue.

There are, of course, many avenues of research using other kinds of tissue, but fetal cells can rapidly divide, grow, and adapt to new environments in ways that make them the gold standard for some disease research. And in other research areas, we dont yet know if there is anything that could substitute, R. Alta Charo, professor of law and bioethics at the University of Wisconsin at Madison, wrote in the New England Journal of Medicine in 2015.

And as the Posts Goldstein noted, scientists have already shown that humanized mice could make good test subjects for coronavirus treatments specifically:

Just months ago, before the new coronavirus began to infect people around the world, other U.S. scientists made two highly relevant discoveries. They found that specialized mice could be transplanted with human fetal tissue that develops into lungs the part of the body the new coronavirus invades. These humanized mice, they also found, could then be infected with coronaviruses to which ordinary mice are not susceptible closely related to the one that causes the new disease, Covid-19.

Outside researchers have offered the mice to Hasenkrug for coronavirus research. But so far, Hasenkrug and other government researchers havent been allowed to obtain the mice they need to perform testing, the Post reported, thanks to a June 2019 HHS directive banning fetal tissue research for those employed by the government.

Caitlin Oakley, a HHS spokesperson, told the Post that no decision has been made about Hasenkrugs request. A separate HHS spokesperson confirmed that in a statement to Vox.

The spokesperson also pointed to an HHS statement from last June detailing the administrations policy on fetal tissue research. Promoting the dignity of human life from conception to natural death is one of the very top priorities of President Trumps administration, reads the statement.

Hasenkrug, and the potentially millions of Americans who may benefit from his research, now find themselves caught in a deeply divisive political issue thats been years in the making.

The US government had funded fetal tissue research efforts since the 1950s and for nearly as long, anti-abortion activists have opposed the practice.

In the Trump era, they finally found an administration ready to listen.

In 2018, the US government spent $115 million on about 173 research projects utilizing fetal tissue, a third of which were devoted to developing therapies for HIV/AIDS.

Research using fetal tissue has led to the development of vaccines such as those for polio, rubella, and measles, the International Society for Stem Cell Research (ISSCR) said in a statement last September. Fetal tissue is still helping advance science, with research underway using cells from fetal tissue to evaluate conditions including Parkinsons disease, ALS, and spinal cord injury. Fetal tissue is also necessary for the development of potential treatments for Zika virus and HIV/AIDS.

But anti-abortion activists argue it incentivizes abortion providers to perform more abortions in order to procure more tissue they could sell to third-party companies, which then provide the tissue directly to researchers. Fetal tissue procurement has been heavily regulated since enactment of the NIH Revitalization Act of 1993, which states that profits cannot be made in the transfer or acceptance of fetal tissue for research purposes.

That hasnt stopped anti-abortion activists from continuing to call into question the ethics of abortion providers or procurement companies. In 2000, the anti-abortion rights group Life Dynamics seemingly began the practice of releasing false or deceptively edited videos targeting the fetal tissue sales process. The main source in their videos was found to be not credible.

The George W. Bush administration did not take action against fetal tissue research, instead enacting restrictions on stem cell research derived from embryos in an August 2001 executive order. Those restrictions were later rolled back by an executive order from President Barack Obama in 2009.

More recently, the anti-abortion rights group Center for Medical Progress, run by activist David Daleiden, infamously released heavily edited videos appearing to show a Planned Parenthood employee negotiating prices for fetal tissue, and CMP accused the abortion care provider of illegally profiting from sales.

The videos caught the attention of Republican lawmakers. Investigations by the House Energy and Commerce, House Judiciary, and Oversight and Government Reform committees found no wrongdoing. Further investigations into Planned Parenthood and fetal tissue transfer proceeded with the creation of the Select Investigative Panel on Infant Lives in October 2015, chaired by Rep. Marsha Blackburn (R-TN), leading to $1.59 million in spending and a 471-page final report making numerable anti-abortion recommendations.

Among those requests was a call for the government to ban fetal tissue research by government scientists, which Barack Obamas administration, which favored the practice, ultimately ignored.

Democrats on the committee released their own report, disputing the conclusions of their Republican colleagues. At the end of their crusade, the conclusion was undeniable: There was no wrongdoing on behalf of fetal tissue researchers, including Advanced Bioscience Resources, or anyone else in the fetal tissue research space, said Rep. Jan Schakowksy (D-IL), who served as the ranking Democrat on the select committee, in a statement to Rewire.News in October 2018.

Anti-abortion activists saw an opportunity to advance their agenda on fetal tissue research when President Donald Trump won election in 2016, but it took a conservative media freakout in 2018 to enact new restrictions.

Over the summer of 2018, conservative media focused on several transactions by Advanced Bioscience Resources, a company that procured fetal tissue from abortion providers and shipped it to researchers for use. ABR was also one of the subjects of the 2015 select committee investigation.

HHS decided to cancel the governments contract with ABR in late September 2018 and began a review of the agencys rules and processes for procuring fetal tissue for research. That review concluded last summer, with HHS announcing in June that it would ban any fetal tissue studies by in-house NIH scientists, like Hasenkrug. It also introduced strict paperwork requirements for any outside scientists conducting research funded by the government.

The decision came as welcome news to anti-abortion activists. The language is trying to hold an ethical standard for the research proposals and the research that might be done. The policy is not just about science. Its also about ethics, David Prentice, vice president and research director at the anti-abortion Charlotte Lozier Institute, told Science magazine last July.

For his part, Hasenkrug has reportedly asked the Trump administration several times for permission to begin working with UNCs humanized mice for a coronavirus cure, but is still waiting on permission. Per the Post:

On Feb. 19, two people said, Hasenkrug wrote to a senior NIH official, asking for permission to use those mice and run experiments related to covid-19. He eventually was told that his request had been passed on to senior HHS officials.

Since then, he has written repeatedly to NIH, laying out in greater detail the experiments he wants to undertake and why several alternatives to the fetal tissue-implanted mice would not be as useful. In one appeal to NIH, Hasenkrug wrote that the mice he was offered are more than a year old and have a relatively short time remaining to live, so they should be used quickly, according to Kerry Lavender, a Canadian researcher familiar with the correspondence.

Hasenkrugs request has reportedly been forwarded to the White House Domestic Policy Council, which is chaired by Trump himself, but the government has not made a decision on the research as of yet.

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Coronavirus treatment research is delayed by Trumps ban on the use of fetal tissue - Vox.com

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Study in mouse, human cells suggests unique anti-cancer properties of such a therapy

Pictured is a natural killer (NK) cell that researchers developed in the lab from human pluripotent stem cells. These NK cells mimic the properties of those found in the yolk sac during the earliest stages of development. Such NK cells may be more effective as immunotherapy for cancer treatment than adult NK cells that come from bone marrow, according to a new study from Washington University School of Medicine in St. Louis. White arrows point out granules that contain potent anti-cancer enzymes. Adult NK cells have very few of these granules.

Immunotherapy that involves treating cancer with the bodys own immune cells, or those of a matched donor, shows promise in clinical trials for some patients, but not all.

A new study from Washington University School of Medicine in St. Louis suggests that the age of certain immune cells used in such therapy plays a role in how effective the immunotherapy is. These cells natural killer (NK) cells appear to be more effective the earlier they are in development, opening the door to the possibility of an immunotherapy that would not utilize cells from the patient or a matched donor. Instead, they could be developed from existing supplies of what are called human pluripotent stem cells.

We are trying to improve the effectiveness of immunotherapy for more patients, said senior author Christopher M. Sturgeon, PhD, an assistant professor of medicine. This special source of natural killer cells has the potential to fill some of the gaps remaining with adult NK cell therapy. There is early evidence that they are more consistent in their effectiveness, and we would not need to process cells from a donor or the patient. They could be manufactured from existing cell supplies following the strict federal guidelines for good manufacturing practices. The characteristics of these cells let us envision a supply of them ready to pull off the shelf whenever a patient needs them.

Unlike the adult versions of NK cells used in most investigational therapies, earlier versions of such cells do not originate from bone marrow. Rather, these NK cells are a special type of short-lived immune cell that forms in the yolk sac of the early mammalian embryo. But for therapeutic purposes, such cells do not need to originate from embryos they can be developed from human pluripotent stem cells, which have the ability to give rise to many different cell types, including these specialized natural killer cells. Manufacturing such cells which many academic medical centers already have the ability to do would make them available quickly, eliminating the time needed to process the patients or donors cells, which can take weeks.

The study appears March 19 in the journal Developmental Cell.

Before a certain time point in early development, there is no such thing as bone marrow, but there is still blood being made in the embryo, Sturgeon said. Its a transient wave of blood that the yolk sac makes to keep the embryo going until bone marrow starts to form. And thats the blood cell generation thats making these unique natural killer cells. This early blood appears to be capable of things that adult blood simply cant do.

Studying mouse and human induced pluripotent stem cells that have been coaxed into forming these unique NK cells, the researchers showed that the NK cells are better at releasing specific anti-tumor chemicals a process called degranulation than their adult counterparts. Even NK cells derived from umbilical cord blood do not respond as robustly. NK cells of adult origin also release different chemicals that trigger harmful inflammation, but this response is not necessarily effective against cancer.

Past work by other groups suggested NK cells from earlier development might be more effective, but how and why this was the case remained unknown. The specific origin of these cells was also a mystery.

Now we know where these special natural killer cells come from and that we can never get them from an adult donor, only a pluripotent stem cell, Sturgeon said. Based on their unique behavior alone, there is one small clinical trial of these cells that is ongoing. Now that we know how to manufacture them and how they work, it opens the door for more trials and for improving upon their function.

According to Sturgeon, such cells could be produced from existing lines of pluripotent stem cells that would not need to come from a matched donor because, in general, NK cells do not heavily attack the bodys healthy tissues, as many T cell therapies can. T cells are another type of immune cell often used to treat blood cancer as part of a stem cell transplant, commonly called a bone marrow transplant. Even when NK cells do cause harm, they do not stay in the body for long periods of time.

From a basic science standpoint, Sturgeon also is interested in understanding why these cells are present in the early embryo in the first place and where they go in later development and after birth.

We can only speculate at this point, but its possible that during early embryonic development, when there is so much rapid cell division, these cells are there as a surveillance mechanism to protect against pediatric cancers or infection, he said.

This work was supported by the National Institutes of Health (NIH), grant numbers HL007088-41, R01DK09361, R01CA205239, P50CA171963, 5K12CA167540, and UL1TR002345; an American Society of Hematology Scholar Award; the University of Rochester; the American Cancer Society, grant number IRG-58-010-59-2; the Washington University Center of Regenerative Medicine; the technical expertise of Leah Vit; and the M. Napoleon Memorial Foundation. Electron microscopy was performed at the Washington University Center for Cellular Imaging (WUCCI). Transcriptome analyses were performed at the Genome Technology Access Center (GTAC).

Dege C, Fegan KH, Creamer JP, Berrien-Elliott MM, Luff SA, Kim D, Wagner JA, Kingsley PD, McGrath KE, Fehniger TA, Palis J, Sturgeon CM. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Developmental Cell. March 19, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Immunotherapy using 'young cells' offers promising option against cancer - Washington University School of Medicine in St. Louis

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Abstract

Biomaterials composed of extracellular matrix (ECM) provide both mechanical support and a reservoir of constructive signaling molecules that promote functional tissue repair. Recently, matrix-bound nanovesicles (MBVs) have been reported as an integral component of ECM bioscaffolds. Although liquid-phase extracellular vesicles (EVs) have been the subject of intense investigation, their similarity to MBV is limited to size and shape. Liquid chromatographymass spectrometry (LC-MS)based lipidomics and redox lipidomics were used to conduct a detailed comparison of liquid-phase EV and MBV phospholipids. Combined with comprehensive RNA sequencing and bioinformatic analysis of the intravesicular cargo, we show that MBVs are a distinct and unique subpopulation of EV and a distinguishing feature of ECM-based biomaterials. The results begin to identify the differential biologic activities mediated by EV that are secreted by tissue-resident cells and deposited within the ECM.

The development of extracellular matrix (ECM)based biomaterials as surgical meshes, topical powders, and injectable hydrogels is a relatively recent pursuit compared to similar efforts with synthetic biomaterials (1). The evolutionarily conserved composition of the ECM, and its critical role in development, cell, tissue, and organ homeostasis, and the response to tissue injury provide a compelling rationale for its use as an inductive biomaterial to promote the repair of damaged tissues and organs (2). However, gaps in our understanding of the dynamic biophysical properties and composition of ECM limit our ability to design and fabricate ECM-based biomaterials that fully capitalize upon their therapeutic potential. Although advanced proteomic techniques have begun to provide an accurate profile of ECM fibrillar and soluble protein components (2), the effects of constitutive (phospho)lipids and incorporated (extracellular) RNA on matrix biology and the host tissue response following injury are largely unknown.

Extracellular vesicles (EVs) are nanometer-sized vesicles encapsulated by a membrane, which transport cell signaling molecules including microRNA (miRNA), (phospho)lipids, and proteins (3). As a potent mediator of cell signaling, EVs have been the subject of intense investigation and thought to be secreted exclusively into a liquid phase where they can be relocated freely between cells and to distant sites using biologic fluids as a mobile medium. Recently, the presence of EV firmly embedded within the ECM, termed matrix-bound nanovesicles (MBVs), was described (4). In contrast to liquid-phase EV, MBVs are secreted by tissue-resident cells and integrated into the fibrillar matrix, a feature that may define their biological purpose and mechanism of action. The nature and biologic significance of the MBV cargo and lipid membrane has not been characterized. Given that MBVs are integrated within the matrix, it is plausible that the molecular speciation of their constituent phospholipids may facilitate this interaction.

The objective of the present study is to identify similarities and differences between liquid-phase (i.e., exosomes) and matrix-bound forms (i.e., MBV) of EV. However, given that EV present in biological fluids, MBV present in native tissue ECM, and ECM-based biomaterials represent heterologous populations secreted from multiple cell sources, a direct comparative in vivo analysis between these putative EV populations is problematic. As an alternative to using body fluid or tissue-derived vesicles, ECM and conditioned medium produced in vitro by cultured cells can be isolated (5). This approach offers several advantages such as the use of a single cell type source, thereby obviating any doubts regarding vesicle origin, the ability to selectively harvest vesicles from either liquid- or solid-phase compartments, and the ability to control the cell culture environment and thus also control vesicle composition and cargo.

Here, we use a fibroblast cell culture model that allows selective harvesting of liquid-phase EV and MBV integrated into the matrix. We conduct RNA sequencing and bioinformatic analysis to characterize the differential miRNA signature and use liquid chromatographymass spectrometry (LC-MS)based lipidomics and redox lipidomics protocols to perform detailed analysis of molecular speciation of liquid-phase EV and MBV phospholipids. Results from these comparative material analyses show that MBVs represent a subpopulation of nanovesicle distinct from EV found in a liquid phase and significantly expand our understanding of EV and matrix biology. Separately, the use of ECM-based therapies can now be examined by new perspectives, and MBV can assist in the design of next-generation ECM-based materials. For example, given their nanometer size, MBV can be used in minimally invasive applications that are otherwise untenable for decellularized ECM scaffolds from which MBVs are derived, such as intravitreal injections to prevent ischemia-induced retinal ganglion cell axon degeneration (6), or incorporated into existing ECM-based devices for sustainable release of vesicles (7, 8). Furthermore, results of the present study may aid in the future development of EV-based theranostic biomaterials such as artificial EV for clinical use (9).

We used scanning electron microscopy (SEM) to provide high-resolution, high-magnification imaging of MBV embedded within an ECM bioscaffold derived from porcine urinary bladder matrix (UBM). SEM images revealed discrete spheres approximately 100 nm in diameter dispersed throughout the collagen fibers (Fig. 1A). Given their compartmentalization within ECM scaffolds, we hypothesized that MBVs deposited into a solid ECM substrate are a unique class of EV separate from EV secreted into a liquid phase. To test this hypothesis, we used an in vitro 3T3 fibroblast cell culture model that allows selective harvesting of vesicles from a liquid-phase or solid-phase extracellular compartment (Fig. 1B). Representative images from phase-contrast microscopy, and hematoxylin and eosin (H&E) and 4,6-diamidino-2-phenylindolestained sections showed that no residual cells or intact nuclei were visible after decellularization of the cell culture plate (Fig. 1C). Transmission electron microscopy (TEM) imaging of liquid-phase EV harvested from the cell culture supernatant (Fig. 1D) and MBV isolated from decellularized ECM (Fig. 1E) showed that these two populations of vesicles shared a similar morphology. Moreover, nanoparticle tracking analysis (NTA) distribution plots showed similar vesicle size of both liquid-phase EV and MBV, with the majority of vesicles having a diameter of <200 nm (Fig. 1F). To determine whether MBV contained markers commonly attributed to exosomes, immunoblot analysis was performed for CD63, CD81, CD9, and Hsp70 (10). Results showed that, in contrast to liquid-phase EV, the MBV showed a marked decrease in CD63, CD81, and CD9 (Fig. 1G). Furthermore, silver staining of electrophoretically separated proteins showed that MBV contained a protein cargo that was distinctly different than the liquid-phase EV (Fig. 1H), suggesting that MBV may be a unique subpopulation of nanovesicle.

(A) SEM images of an ECM scaffold derived from urinary bladder matrix (UBM) showing discrete spherical bodies approximately 100 nm in diameter dispersed throughout the matrix. Scale bars, 1 m. (B) Illustration of the 3T3 fibroblast cell culture model used to selectively harvest vesicles from a liquid-phase or solid-phase extracellular compartment. (C) Phase-contrast microscopy, hematoxylin and eosin (H&E) staining, and 4,6-diamidino-2-phenylindole (DAPI) staining showing the absence of cells and intact cell nuclei after decellularization. (D and E) TEM of liquid-phase EV (D) and MBV (E) isolated from the 3T3 fibroblast cell culture model. Scale bars, 100 nm. (F) Size distribution plots from nanoparticle tracking analysis (NTA) of liquid-phase EV (top) and MBV (bottom) isolates from the 3T3 fibroblast cell culture. (G) Immunoblot analysis of CD9, CD63, CD81, and Hsp70 expression levels in liquid-phase EV and MBV. (H) Silverstain analysis of electrophoretically separated proteins in liquid-phase EV and MBV. M.W., molecular weight.

We used comprehensive next-generation RNA-sequencing (RNA-seq) to catalog differentially expressed miRNA in MBV and liquid-phase EV relative to the 3T3 fibroblast parent cell from which these vesicles were derived. Bioanalyzer analysis revealed the absence of 18S and 28S ribosomal RNA, and an enrichment of small RNA molecules [<200 nucleotides (nt)] in total RNA isolated from liquid-phase EV and MBV. However, the small RNA size distribution from liquid-phase EV was much broader than MBV with a marked enrichment of small RNA molecules between 100 and 200 nt in liquid-phase EV (Fig. 2A). We focused the analysis on differential miRNA signatures by conducting next-generation sequencing of miRNA libraries generated from the parental cellular RNA, the liquid-phase EV, and the MBV isolates (n = 3 per group). Principal components analysis (PCA) showed that within respective groups, the replicate miRNA profiles clustered close to one another (Fig. 2B). However, extensive differences in miRNA content were observed between the parental cell and the liquid-phase EV and MBV isolates. Overall, 28 (50.91%) miRNAs were found to be differentially expressed in MBV compared to liquid-phase EV by at least twofold (Fig. 2C). In addition, respective liquid-phase EV or MBV and the parental cellular miRNA profiles were clearly distinct (Fig. 2, B and C). To validate the results of miRNA sequencing, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to detect three up-regulated miRNAs (miR-163-5p, miR-27a-5p, and miR-92a-1-5p) and three down-regulated miRNAs (miR-451a, miR-93b-5p, miR-99b-5p) in MBV compared to liquid-phase EV isolated from 3T3 fibroblasts (Fig. 2D). As anticipated, the results showed that the level of miR-163-5p, miR-27a-5p, and miR-92a-1-5p was up-regulated, and miR-451a, miR-93b-5p, and miR-99b-5p was down-regulated in MBV compared to liquid-phase EV, thereby corroborating the results from the miRNA sequencing data. Ingenuity Pathway Analysis (IPA) of differentially enriched miRNAs in MBV compared to liquid-phase EV showed a strong association with organ and system development and function. In contrast, miRNAs differentially enriched in liquid-phase EV compared to MBV were associated with pathways involved in cellular growth, development, proliferation, and morphology (Fig. 2E).

(A) Bioanalyzer analysis of total RNA isolated from 3T3 parental cells and their secreted liquid-phase EV and MBV. (B) Principal components analysis (PCA) comparing liquid-phase EV (green), MBV (blue), and cellular (red) RNA-seq datasets. (C) Volcano plot showing the differential expression of miRNAs in liquid-phase EV, MBV, and the parental cells. The inclusion criteria were a twofold difference of log2 (fold change) in either direction with a P value of <0.05. Each dot represents a specific miRNA transcript; green dots to the right of the vertical dashed line correspond to a relative increase in expression level, and red dots to the left correspond to a relative decrease in expression level. Blue dots indicate miRNA with no significant change in expression level. (D) RT-qPCR validation of the results of miRNA sequencing. *P < 0.05, n = 4. (E) IPA functional analysis. Significantly enriched molecular functions identified by IPA functional analysis considering differentially expressed miRNA in MBV (red) and liquid-phase EV (blue).

Results with the 3T3 fibroblast cell model showed selective packaging of miRNA within MBV deposited in the ECM compared to liquid-phase EV secreted into the cell culture supernatant. We next sought to determine whether MBV miRNA cargo is unique to the cellular origin. We characterized and compared the miRNA composition of MBV isolated from ECM produced in vitro by bone marrowderived stem cells (BMSCs), adipose stem cells (ASCs), and umbilical cord stem cells (UCSCs) isolated from different human donors using next-generation sequencing methods. A representative phase-contrast microscopy image of a decellularized BMSC cell culture plate showed the absence of cells and the presence of branched fibrillar structures (Fig. 3A). TEM imaging of isolated MBV from a decellularized BMSC cell culture plate showed the characteristic morphology attributed to EV (Fig. 3B). Furthermore, NTA showed similar distribution plots between BMSC-, ASC-, and UCSC-derived MBV, with the majority of vesicles having a diameter of <200 nm (Fig. 3, C to E). After isolation of total RNA from these samples, bioanalyzer analysis showed the absence of ribosomal RNA and an enrichment of small RNA molecules (<200 nt) (Fig. 3F). miRNA libraries were generated from the samples (BMSC, n = 3 human donors; ASC, n = 3 human donors; UCSC, n = 3 human donors) and subjected to miRNA sequencing. A PCA showed that samples clustered primarily by the cell type from which they were derived (Fig. 3G). Of note, despite the use of three separate human donors for each cell type used to generate the MBV samples, the PCA showed a high degree of homogeneity in the miRNA profile within the respective groups (Fig. 3G). In addition, volcano plots showed that fewer miRNAs were found differentially expressed between BMSC- and UCSC-derived MBV than between BMSC-ASC and UCSC-ASC.

(A) Phase-contrast microscopy image of a decellularized BMSC cell culture plate showing the absence of cells. (B) TEM of MBV isolated from the decellularized BMSC culture plate. Scale bars, 100 nm. (C to E) Size distribution plots from NTA of MBV isolated from BMSC (C), ASC (D), and UCSC (D) decellularized culture plates. (F) Bioanalyzer analysis of total RNA isolated from BMSC-, ASC-, and UCSC-derived MBV. (G) PCA comparing BMSC MBV (green), UCSC MBV (blue), and ASC MBV (red) RNA-seq datasets. (H) Volcano plot showing the differential expression of miRNAs in BMSC-, ASC-, and UCSC-derived MBV. The inclusion criterion was a twofold difference of log2 (fold change) in either direction with a P value of <0.05. Each dot represents a specific miRNA transcript; green dots to the right of the vertical dashed line correspond to a relative increase in expression level, and red dots to the left correspond to a relative decrease in expression level. Blue dots indicate miRNA with no significant change in expression level.

Several studies have characterized the lipid composition of EV (11). However, there are no data on phospholipid composition of MBV. Therefore, we performed LC-MSbased global lipidomics and redox lipidomics analyses to comparatively evaluate the phospholipid composition of MBV and liquid-phase EV compared to their 3T3 fibroblast parent cells (Fig. 4, A and D). Nine major phospholipid classes were detected in all three types of samples, with the total number of detected molecular species of 536 distributed between the following major classes: bis-monoacylglycerophosphate (BMP), 59 species; phosphatidylglycerol (PG), 37 species; cardiolipin (CL), 117 species; phosphatidylinositol (PI), 33 species; phosphatidylethanolamine (PE), 102 species; phosphatidylserine (PS), 45 species; phosphatidic acid (PA), 26 species; phosphatidylcholine (PC), 107 species; and sphingomyelin (SM), 10 species (Fig. 4D). In terms of their content of polyunsaturated fatty acid (PUFA) residues, PE, PI, PC, and PS represented the major reservoir of these polyunsaturated phospholipid species containing four to seven double bonds (Fig. 4B). These PUFA phospholipids represent the likely precursors of the signaling lipid mediators. The formation of the mediators occurs via the catalytic oxygenation of PUFA phospholipids by 5-lipoxygenase or 15-lipoxygenase to yield oxygenated phospholipids that are subsequently hydrolyzed by one of specialized phospholipases A2 to release oxygenated fatty acids, i.e., lipid mediators (12, 13). In addition, oxidized PUFA phospholipids act as signaling molecules coordinating many intracellular processes and cell responses, including apoptosis, ferroptosis, and inflammation (14). We found significant differences in molecular speciation of these phospholipids and their relative contents between liquid-phase EV and MBV (Fig. 4E). With a notable exception of SM, arachidonic acid (AA) and docosahexaenoic acid (DHA) residues were detected in all phospholipids (Fig. 4E). For many of the phospholipids, the amounts were significantly higher in MBV versus liquid-phase EV and parent cells (Fig. 4E), which identify MBV as a rich reservoir of PUFA phospholipids. PUFA phospholipids can be hydrolyzed by phospholipase A2 (PLA2), resulting in the release of free PUFA and lysophospholipids (LPLs) (15). The former can be further used by two major oxygenases, cyclooxygenase (COX) and lipoxygenase (LOX), to produce lipid mediators with pro- or anti-inflammatory capacities (13, 16, 17). This finding qualifies MBV as potential precursors for synthesis of these lipid mediators dependently on the cell/tissue context (13). Quantitatively, MBVs were enriched in PI, PS, PG, and BMP (Fig. 4C and table S1). In contrast, the content of PE, PA, and SM was higher in liquid-phase EV. PC was a predominant phospholipid in cells and liquid-phase EV. The content of a unique mitochondrial phospholipid, CL, was significantly lower in liquid-phase EV compared to MBV and parent cells (Fig. 4F). Because CL is a unique mitochondria-specific phospholipid localized predominantly in the inner mitochondrial membrane (18), this finding represents a possible link of the MBV biogenesis with the mitochondrial compartment of cells. Plasmalogen phospholipids (or ether phospholipids) are structurally different from diacyl phospholipids (or ester phospholipids) (19). In plasmalogens, vinyl ether bond is linking the sn-1 saturated or monounsaturated chain to the glycerol backbone of phospholipids (19). It has been shown that ether lipids, PE, and PC plasmalogens can facilitate membrane fusion (20) and increase membrane thickness of EV (21, 22) and therefore may play a role in nanovesicle uptake by cells. Detailed MS/MS analysis showed a high level of ether PE and PC species (plasmalogens) in both liquid-phase EV and MBV. These species were identified as PE-16:0p/20:4, PE-16:1p/20:4, PE-18:1p/20:4, PE-18:1p/22:6 and PC-16:0p/20:4, PC-18:0p/20:4, PC-20:0p/20:4, PC-18:0p/22:6, respectively (Fig. 4E).

(A) Typical total ion chromatogram of phospholipids obtained from MBV. (B) Mass spectra of the major phospholipid classes in MBV. Quantitative assessment of saturated (double bond number = 0), monounsaturated (double bond number = 1), and polyunsaturated (double bond number = 2 to 10) species of phospholipids. (C) Pie plots showing the total content of major phospholipids. Data are presented as percentage of total phospholipids. (D to F) Contents of different phospholipid molecular species. Data are presented as heat maps, autoscaled to z scores, and coded blue (low values) to red (high values). EV, exosomal vesicles; MBV, matrix-bound vesicles; PC, phosphatidylcholine; PCd, PC diacyl species; PCp, PC plasmalogens; PE, phosphatidylethanolamine; PEd, PE diacyl species; PEp, PE plasmalogens; PI, phosphatidylinositol; PS, phosphatidylserine; BMP, bis-monoacylglycerophosphate; PA, phosphatidic acid; PG, phosphatidylglycerol; SM, sphingomyelin.

LPLs, hydrolytic metabolites of phospholipids created by phospholipases A, are bioactive signaling molecules that modulate a variety of physiological responses, including macrophage activation (23), inflammation and fibrosis (24), tissue repair and remodeling (25), and wound healing (26). LC-MS analysis showed that LPLs were present in all three types of samples, albeit with their total content in MBV and liquid-phase EV being 1.7 to 1.8 times greater compared to the parent cells. More specifically, seven classes of LPL have been identified: lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), lysophosphoinositol (LPI), lysophosphatidic acid (LPA), lysophosphatidylglycerol (LPG), and monolysocardiolipin (mCL) (Fig. 5A). MBVs were enriched in LPE, LPA, and LPG compared to parent cells (Fig. 5B). The content of LPI and mCL was significantly lower in MBV and liquid-phase EV versus cells. We found that the contents of LPA and LPG were significantly higher in MBV compared to EV. The levels of mCL and LPI in MBV were 3 and 6.3 times higher than in EV but 3.3 and 1.9 times lower compared to cells (Fig. 5, C and D). No significant changes in the contents of LPE, LPC, and LPS between MBV and EV were found. The non-oxidizable molecular species containing 16:0, 16:1, 18:0, and 18:1 were the major types found in all LPL species detected (Fig. 5C). As LPL may act as fusogenic lipids facilitating the transfer of the vesicular contents into cellular targets, this important role of LPL found in MBV should be further explored.

(A) Typical mass spectra of major LPL obtained from MBV. (B) Pie plots showing the total content of major LPL. Data are presented as percentage of total LPL. (C and D) Contents of LPL molecular species. Data are presented as heat maps, autoscaled to z scores, and coded blue (low values) to red (high values). N = 3. LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPI, lysophosphatidylinositol; LPS, lysophosphatidylserine; LPA, lysophosphatidic acid; LPG, lysophosphatidylglycerol; mCL, monolysocardiolipin.

Given that exposure of murine bone marrowderived macrophages to MBV results in expression of M2-like markers, Fizz1 and Arg1, which are associated with a constructive macrophage phenotype (4), we performed LC-MS analysis of PUFA and their oxygenated products in MBV versus liquid-phase EV and parent cells. MBVs were strongly enriched in AA (20:4), DHA (22:6), and docosapentaenoic fatty acids (DPA; 22:5) (Fig. 6A). In other words, MBVs represent a reservoir of substrates for the biosynthesis of signaling lipid mediators by the respective enzymatic mechanisms, COXs and LOXs. In liquid-phase EV, the major PUFAs were linoleic (18:2) and linolenic (18:3) acids (Fig. 6A).

(A and B) Content of free PUFA (A) and their oxygenated metabolites (B) in parent cell, liquid-phase EV, and MBV. Data are means SD. *P < 0.05 versus cells or MBV. N = 3. (C) Contents of singly, doubly, and triply oxygenated phospholipid species in parent cells, liquid-phase EV, and MBV. Data are presented as heat maps, autoscaled to z scores, and coded blue (low values) to red (high values). PL, phospholipids; CL, cardiolipin.

As EVs contain enzymatic machinery for biosynthesis of AA-derived lipid mediators (27), redox lipidomics analysis of oxygenated fatty acids was performed. Higher levels of AA metabolites such as 12-HETE (12-hydroxy-eicosatetraenoic acid), 15-HETE (15-hydroxy-eicosatetraenoic acid), and lipoxin A4 (LXA4) were found in liquid-phase EV versus MBV (Fig. 6B). In the context of tissue repair, LXA4 and D-series resolvin D1 (RvD1), produced by 12/15-LOX from AA (20:4) and DHA (22:6), stimulate macrophage activation to the M2-like phenotype (28). Last, we characterized oxidized phospholipids containing oxygenated AA and DHA in MBV and liquid-phase EV. The levels of oxygenated species were higher in MBV than in liquid-phase EV, where PS, PI, and PC were represented by mono-oxygenated species. BMP, PG, and CL contained singly and doubly oxygenated AA and DHA residues; triply oxygenated PUFAs were found only in PE (Fig. 6C). Overall, lipidomics and oxidative lipidomics results show that the levels of free AA, DHA, and DPA and PUFA-containing phospholipids as well as their oxidatively modified molecular species are higher in MBV than those in liquid-phase EV.

To date, research regarding EV has been largely focused on their presence in biological fluids and their potential as biomarkers of disease, with lesser emphasis upon their therapeutic potential. These liquid-phase EVs are broadly categorized based on their biogenesis, morphology, density, or cargo (29). Although it has been shown that liquid-phase EVs contain surface proteins that can mediate binding with cells and ECM molecules (30), the integration of MBV within the fibrillar network of the ECM and trafficking of MBV across all cell membranes is largely unexplored. Traditional in vitro cell culture models neglect to differentiate the liquid-phase EV secreted into the cell culture supernatant from the MBV embedded within the ECM. Here, we fractionated vesicle populations based on their compartmentalization into either the liquid-phase cell culture medium or the solid-phase ECM substrate. In terms of composition, we found that MBV isolated from the ECM of 3T3 fibroblasts contained a differential miRNA and lipid signature compared with liquid-phase EV and with the parent cell. These data are suggestive of a scenario in which molecular sorting occurs during vesicle biogenesis to specifically distribute miRNA and lipids to vesicles destined for different extracellular locations. Moreover, the cells capacity to differentiate between a liquid interface and a solid substrate and to selectively deposit tailored subpopulations of vesicles with distinct lipid signatures into these disparate compartments provides evidence for a different and independent membrane biogenesis of MBV from the biogenesis of EV secreted into a liquid phase. Considering that MBVs were shown to be integrated within the dense fibrillar network of the ECM, it is plausible that MBVs are secreted by cells in concert with ECM components during matrix deposition, tissue development and homeostasis, and dynamic matrix remodeling following injury. Furthermore, given that the ECM is a complex mixture of proteins, proteoglycans, and glycosaminoglycans arranged in a tissue-specific three-dimensional architecture (2), it is logical that MBV cargo and lipid content are also unique to the tissue and cellular origin. We have previously shown that MBVs isolated from ECM bioscaffolds derived from anatomically distinct source tissue have differential miRNA signatures (4). Results from the present study further support this hypothesis in that MBV isolated from ECM produced in vitro by BMSC, ASC, and UCSC derived from different human donors contained a distinctive miRNA signature specific to the cell source. In addition, fewer miRNAs were found differentially expressed between BMSC- and UCSC-derived MBV than between BMSC-ASC and UCSC-ASC, a finding that may be attributed to tissue-specific differentiation potentials of ASC (31). These findings further underline the cell-specific features of MBV miRNA profiles, which were not significantly affected by the intrinsic variability of donors. However, given that the three human donors were all male, further studies to determine sex-related variations in the miRNA cargo of MBV from the stem cell samples are warranted. Gender-specific differential expression of exosomal miRNA has been observed in human subjects (32). Gender variation is just one aspect for further investigation since other variables including age (33) and disease state (34) have been shown to affect EV miRNA cargo. PCA showed a high degree of batch-to-batch consistency of the miRNA cargo from MBV deposited by specific cell types isolated from different human donors, a finding that has important implications for MBV and ECM biomaterial manufacturing for use as research tools or clinical therapeutics. For example, a major challenge in the production of EV or ECM biomaterials for preclinical or clinical use is the standardization of product characterization to meet regulatory requirements for batch consistency and for reproducibility of the manufacturing process (35, 36). Stated differently, the observed batch-to-batch consistency in miRNA cargo from MBV deposited by specific cell types may lend itself to the development of markers to verify identity and purity of MBV intended for clinical testing. Although the present study establishes that MBV integrated into the matrix are a unique subpopulation of EV, we cannot rule out the possibility of heterogeneity within the MBV subset. A similar heterogeneity has recently been described for EV secreted into cell culture medium by mesenchymal stem cells, which were shown to secrete at least three types of liquid-phase EV that could be differentially isolated based on their affinities for membrane lipidbinding ligands (37). In addition, although MBV showed a marked decrease in proteins commonly attributed to exosomes (e.g., CD63, CD81, and CD9), future proteomics studies will be required to identify the differential expression of surface and luminal proteins associated with liquid-phase EV compared to MBV.

As the composition and compartmentalization are different for liquid-phase EV and MBV integrated into the matrix, these subpopulations of vesicles are likely to have different biological functions. IPA network analysis of differentially enriched miRNAs in MBV compared to liquid-phase EV isolated from the 3T3 fibroblast model showed that miRNAs in MBV are associated with significant network-associated functions in organ and system development compared to miRNA enriched from liquid-phase EV. MBVs have previously been shown to recapitulate functional and phenotypical properties attributed to the ECM bioscaffolds from which they are derived, including stem cell differentiation and activation of an anti-inflammatory and pro-resolving macrophage phenotype, both of which are hallmarks of constructive tissue remodeling (2).

In contrast to EV that are secreted into body fluids and readily available for cell-cell communication, MBVs embedded within tissue ECM are stably associated with the matrix and can only be isolated following degradation of the ECM material (4). The requirement for matrix degradation to release MBV may partially define their mechanism of action, including those related to their capacity to generate pro-resolving lipid mediators. Because MBVs remain intact and attached to ECM even after decellularization, the molecular speciation of their constituent phospholipids likely plays a role in facilitating such MBV-ECM interactions. Using LC-MSbased lipidomics and redox lipidomics approaches, we performed detailed characterization of the molecular speciation of MBV phospholipids, LPL, and the oxygenated and non-oxygenated PUFA and can speculate upon the relationship of these various molecular species with their utilization as metabolic lipid signaling platforms. We report that high levels of LPL, bioactive molecules that are important for macrophage differentiation, tissue repair, remodeling, and wound healing, are a characteristic feature of MBV. In addition, as fusogenic lipids, LPL can facilitate the transfer of the vesicular contents to intracellular targets. MBVs, but not liquid-phase EVs, were enriched in PUFA non-oxygenated and oxygenated phospholipids and therefore represent a potential reservoir of oxidized and oxidizable esterified phospholipid species, the role of which has not yet been elucidated. Notably, PUFA-enriched MBV can be viewed as an important source of lipid mediators activated by different phospholipases dependent on the pro-/anti-inflammatory context of the extracellular environment.

A limitation of the present study is the use of a single cell line to evaluate differences in liquid-phase EV and MBV cargo. The 3T3 fibroblast cell line used in this study was chosen because it is a well-characterized and widely used cell line in biologic research. Furthermore, results from the RNA-seq and lipidomic analyses showed that multiple replicates of MBV derived from the 3T3 fibroblast model showed a high level of consistency in terms of miRNA and lipid cargo and that this cargo is significantly different from the cargo of the corresponding liquid-phase EV, which supports the fidelity of our results. However, further studies are required with other cell types, including primary cells, before one can derive a more definitive understanding of the biologic purpose of MBV versus liquid-phase EV. In addition, additional studies are warranted to identify and determine the biologic relevance of MBV in native (nondecellularized) tissues.

The findings of the present study may have significant clinical implications. EVs harvested from biological fluids have been used for diagnostic purposes (38), and EVs isolated from cell culture supernatant are being explored as therapeutic agents in early-phase clinical trials (39, 40). However, delineation of the MBV subpopulation may now allow new perspectives on EV-based therapeutics, especially in the design and manufacture of novel biomaterials and artificial EV for clinical use. Given the selective loading of specific miRNA and lipid cargo within MBV, further studies on MBV biogenesis may prove to be instrumental in guiding new strategies for cargo loading of EV (9) or for the incorporation of EV into ECM-based biomaterials to be used as an inductive substrate for tissue repair (7, 8).

The objective of the present study was to conduct a comparative material analysis of EV secreted into a liquid medium versus MBV integrated into the ECM using an in vitro 3T3 fibroblast cell culture model that allows selective harvesting of vesicles from liquid-phase or solid-phase extracellular compartments. 3T3 fibroblasts were seeded on polystyrene plates in the presence of ascorbic acid to induce deposition of ECM (41, 42). After 7 days, the cell culture medium containing liquid-phase EV was harvested, and the culture plates were decellularized to remove cells while maintaining the molecular composition and ultrastructure of the ECM. Following decellularization, MBVs were isolated from decellularized ECM by enzymatic digestion. We used LC-MSbased lipidomics and redox lipidomics to perform detailed analysis of liquid-phase EV and MBV phospholipids and conducted comprehensive RNA-seq and bioinformatic analysis of the intravesicular miRNA cargo.

Human BMSC, human ASC, and human UCSC ECM plates were provided by StemBioSys (San Antonio, TX) and prepared according to a published protocol (43). Briefly, human BMSCs, human ASCs, or human UCSCs were seeded onto a 75-cm2 cell culture flask coated with human fibronectin (1 hour at 37C) at a cell density of 3500 cells/cm2 and cultured in -minimum essential medium (-MEM) supplemented with 20% fetal bovine serum (FBS) and 1% penicillin-streptomycin for 14 days. The medium was refreshed the day after initial seeding and then every 3 days. At day 7, ascorbic acid 2-phosphate (Sigma-Aldrich) was added to the medium at a final concentration of 50 M. At day 14, plates were decellularized using 0.5% Triton in 20 mM ammonium hydroxide for 5 min and rinsed two times with Hanks balanced salt solution containing both calcium and magnesium (HBSS +/+) and once with ultrapure H2O. Murine NIH 3T3 fibroblast cells were seeded onto a 75-cm2 cell culture flask at a cell density of 3500 cells/cm2 and cultured in Dulbeccos modified Eagles medium (DMEM) supplemented with exosome-depleted FBS (44), 1% penicillin-streptomycin, and ascorbic acid 2-phosphate (Sigma-Aldrich) at a final concentration of 50 M for 7 days. At day 7, the supernatant from cultured 3T3 fibroblast cells was collected, and the culture plates were washed three times with phosphate-buffered saline (PBS), decellularized using 0.5% Triton in 20 mM ammonium hydroxide for 5 min, and then rinsed three times with ultrapure H2O.

MBVs were isolated as previously described with minor modifications (4) . Briefly, the decellularized ECM was enzymatically digested with Liberase DL (100 ng/ml; Roche) in buffer [50 mM tris (pH 7.5), 5 mM CaCl2, and 150 mM NaCl] for 1 hour at 37C. The cell culture supernatant containing the liquid-phase EV and the digested ECM containing the MBV were subjected to differential centrifugation at 500g (10 min), 2500g (20 min), and 10,000g (30 min), and the supernatant was passed through a 0.22-m filter (Millipore). The clarified supernatant containing the liberated MBV or liquid-phase EV was then centrifuged at 100,000g (Beckman Coulter Optima L-90K Ultracentrifuge) at 4C for 70 min to pellet the vesicles. The vesicle pellets were then washed and resuspended in 1 PBS and stored at 20C until further use.

UBM was prepared from market-weight pigs (Tissue Source LLC, Lafayette, IN) as previously described (4). Briefly, the tunica serosa, muscularis externa, submucosa, and muscularis mucosa were removed by mechanical delamination, and the urothelial cells of the tunica mucosa were dissociated from the basement membrane by washing with deionized water. The remaining basement membrane and the lamina propria (collectively referred to as UBM) were decellularized by agitation in 0.1% peracetic acid with 4% ethanol for 2 hours at 300 rpm followed by PBS and type 1 water washes. UBM was then lyophilized and milled using a Wiley Mill with a #60 mesh screen.

UBM was fixed in cold 2.5% glutaraldehyde for 24 hours followed by three 30-min washes in 1 PBS. Samples were then dehydrated in a graded series of alcohol (30, 50, 70, 90, and 100% ethanol) for 30 min per wash and then placed in 100% ethanol overnight at 4C. Samples were washed three additional times in 100% ethanol for 30 min each and critical pointdried using a Leica EM CPD030 critical point dryer (Leica Microsystems, Buffalo Grove, IL, USA) with carbon dioxide as the transitional medium. Samples were then sputter-coated with a 4.5-nm-thick gold/palladium alloy coating using a 108 Auto sputter coater (Cressington Scientific Instruments, UK) and imaged with a JEOL JSM6330F scanning electron microscope (JEOL, Peabody, MA, USA).

TEM imaging was conducted on MBV or liquid-phase EV loaded on carbon-coated grids and fixed in 4% paraformaldehyde as previously described (4). Grids were imaged at 80 kV with a JEOL 1210 TEM with a high-resolution Advanced Microscopy Techniques digital camera. The size of MBV was determined from representative images using JEOL TEM software.

Particle size and concentration of the liquid-phase EV and the MBV were calculated using a NanoSight (NS300) instrument equipped with fast video capture and particle-tracking software. Samples were diluted 1:500 to a final volume of 1000 l using particle-free water. A syringe pump was used to dispense the sample into the system. Measurements were performed from three captures of 45 s each sample. For the video processing and particle calculation, the detection threshold was adjusted to 4. Data are presented as concentration versus particle size for each of the evaluated samples.

Total RNA was isolated from 3T3 cells, liquid-phase EV, and MBV using the RNeasy Mini Kit (Qiagen) according to the manufacturers instructions. Before RNA isolation, liquid-phase EV and MBV samples were treated with ribonuclease A (10 g/ml) at 37C for 30 min to degrade any contaminating RNA. RNA quantity was determined using a NanoDrop spectrophotometer, and its quality was determined by Agilent Bioanalyzer 2100 (Agilent Technologies).

The miRNA library preparation was initiated with 100 ng of each sample and the QIAseq miRNA Library Kit (Qiagen) following the manufacturers instructions. Briefly, mature miRNAs were ligated to adapters on their 3 and 5 ends. The ligated miRNAs were then reverse-transcribed to complementary DNA (cDNA) using a RT primer with unique molecular indices. The cDNA was then cleaned up to remove adapter primers, followed by amplification of the library with a universal forward primer and one of 48 reverse primers that assign a sample index. A presequencing quality control was performed using the Agilent RNA ScreenTape System. Next-generation sequencing was performed on a NextSeq 500 instrument with a loading concentration of 2.5 pM. Bioinformatic analysis was conducted by Genevia Technologies (Tampere, Finland). The quality of the sequencing reads was inspected using FastQC software. TrimGalore! (version 0.4.5) was used to remove the adapter sequences, with default settings, on all the samples. All reads were shortened to 21 bases, the typical size of miRNAs, using the fastx_trimmer software (FASTX-Toolkit by Hannon Lab, version 0.0.14). The reads of each sample were then aligned against the corresponding reference genome (hg38, GRCm38). Tables of miRNA counts across samples were created using the softwares bowtie (version 1.2.2) and miRDeep2 (version 0.0.8). In this process, precursor miRNA and mature miRNA sequences for each species involved in the study were taken from miRbase. Counts of mature miRNAs were obtained by taking the median of all precursor miRNAs associated with them. The counts of mature miRNAs of all samples were normalized using DESeq2. To ensure data quality before further analyses, PCA was performed and the results were visualized using ggplot2, separately for murine and human samples. Normalization of mature miRNA data and statistical testing between sample groups were performed with DESeq2. P values were corrected for multiple testing using the Benjamini-Hochberg method. miRNAs with adjusted P value of <0.05 and absolute log2 fold change >1 were considered as significantly differentially expressed. Tables of differentially expressed miRNAs were annotated with their targets and their confidences using the mirTARbase database of experimentally tested miRNA target interactions. Differentially expressed miRNAs were also annotated with predicted targets using the R package miRNAtap. miRNAtap aggregates the miRNA target predictions from five different databases (PicTar, DIANA, TargetScan, miRanda, and miRDB) and calculates an overall miRNA target score. The minimum amount of database sources required for a potential miRNAtarget interaction to be included into the annotations was 3.

IPA software (version 01-14) was used for functional analysis of differentially expressed miRNAs. miRNA targets were identified using the IPA Core Analysis. The filter was set to Experimentally Observed findings to obtain information about significantly enriched molecular and cellular functions and physiological system development functions that were affected by the miRNAs.

RT and qPCR were performed using the TaqMan Advanced miRNA Assays Protocol (Applied Biosystems). Briefly, 10 ng of total RNA was used with the TaqMan Advanced miRNA cDNA Synthesis Kit (Applied Biosystems, catalog no. A28007) to synthesize and adapt a 3-poly(A) tail to the miRNAs. Universal RT primers recognizing the poly(A) tail were used to synthesize the cDNA in the RT reaction, followed by a miR-AMP step, using miR-AMP forward and reverse universal primers, to increase the number of cDNA molecules. The qPCR was made on a QuantStudio system machine using the TaqMan Fast Advanced Master Mix (Applied Biosystems, catalog no. 4444556) and specific TaqMan Advanced miRNA Assays (Applied Biosystems, catalog no. A25576) recognizing mmu-miR-163-5p, mmu-miR-27a-5p, mmu-miR-92a-1-5p, mmu-miR-451a, mmu-miR-93-5p, and mmu-miR-99b-5p. Fold change expression on the MBV sample was calculated for each of the specific targets using liquid-phase EV as a reference.

Liquid-phase EV and MBV, derived from three separate cultures of 3T3 fibroblasts, were respectively pooled and quantified by nanotracking particle analysis. For both immunoblot and silverstain analysis, an equal number of vesicles for both the liquid-phase EV and MBV samples were loaded onto the gel. MBV or liquid-phase EV (21 1011) was mixed with 2 Laemmli buffer (R&D Systems) containing 5% mercaptoethanol (Sigma-Aldrich), resolved on a 4 to 20% gradient SDSpolyacrylamide gel electrophoresis (Bio-Rad), and then transferred onto a polyvinylidene difluoride membrane. Membranes were incubated overnight with the following primary antibodies: rabbit anti-CD63, rabbit anti-CD81, rabbit anti-CD9, and rabbit anti-Hsp70, at 1:1000 dilution (System Biosciences). Membranes were washed three times for 15 min each before and after they were incubated with goat anti-rabbit secondary antibody, at 1:5000 dilution (System Biosciences). The washed membranes were exposed to chemiluminescent substrate (Bio-Rad) and then visualized using a ChemiDoc Touch instrument (Bio-Rad). Silver staining of gels was performed using the Silver Stain Plus Kit (Bio-Rad) according to the manufacturers instruction and visualized using a ChemiDoc Touch instrument (Bio-Rad).

Lipids were extracted from 3T3 cells, exosomes, and MBV by Folch procedure (45). MS analysis of phospholipids and their oxygenated products was performed on an Orbitrap Fusion Lumos mass spectrometer (Thermo Fisher Scientific), as previously described (46). Briefly, phospholipids were separated on a normal-phase column [Luna 3 m Silica (2) 100 , 150 2.0 mm (Phenomenex)] at a flow rate of 0.2 ml/min on a Dionex Ultimate 3000 HPLC system. The column was maintained at 35C. The analysis was performed using gradient solvents (A and B) containing 10 mM ammonium acetate. Solvent A contained propanol:hexane:water (285:215:5, v/v/v), and solvent B contained propanol:hexane:water (285:215:40, v/v/v). All solvents were LC-MS grade. The column was eluted for 0 to 23 min with a linear gradient from 10 to 32% B, 23 to 32 min using a linear gradient of 32 to 65% B, 32 to 35 min with a linear gradient of 65 to 100% B, 35 to 62 min held at 100% B, and 62 to 64 min with a linear gradient from 100 to 10% B followed by an equilibration from 64 to 80 min at 10% B. Spectra were acquired in negative ion mode. Deuterated phospholipids were used as internal standards (Avanti Polar Lipids). Three technical replicates for each sample were run to evaluate reproducibility. Analysis of LC-MS data was performed using the software package Compound Discoverer (Thermo Fisher Scientific) with an in-house generated analysis workflow and nonoxidized/oxidized phospholipid database. Lipids were further filtered by retention time and confirmed by fragmentation mass spectrum.

Free fatty acids were analyzed by LC-MS using a Dionex Ultimate 3000 HPLC system coupled online to a Q Exactive hybrid quadrupole-orbitrap mass spectrometer (Thermo Fisher Scientific, San Jose, CA), as previously described (47). Briefly, fatty acids and their oxidative derivatives were separated by a C18 column (Acclaim PepMap RSLC, 300 m 15 cm, Thermo Fisher Scientific) using gradient solvents A [methanol (20%)/water (80%) (v/v)] and B [methanol (90%)/water (10%) (v/v)], both containing 5 mM ammonium acetate. The column was eluted at a flow rate of 12 l/min using a linear gradient from 30% solvent B to 95% solvent B over 70 min, held at 95% B from 70 to 80 min, followed by a return to initial conditions by 83 min and re-equilibration for an additional 7 min. Spectra were acquired in negative ion mode. Analytical data were acquired and analyzed using Xcalibur software. A minimum of three technical replicates for each sample was run to increase the reproducibility.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: We gratefully acknowledge T. Block and S. Griffey from StemBioSys for providing the ECM plates and K.-L. Aho from Genevia for the bioinformatic analysis. This project used the University of Pittsburgh HSCRF Genomics Research Core. We thank H. Deborah for conducting the small RNA-seq assay. Funding: This work was supported by NIH (HL114453-06, U19AI068021) and by Russian academic excellence program 5-100. S.F.B. and G.S.H. were supported, in part, by NIH R01AR073527, Mechanisms of functional skeletal muscle repair: Critical role of matrix associated IL-33. Author contributions: G.S.H., V.E.K., and S.F.B. conceptualized and designed the research. G.S.H., C.P.M., M.C.C., Y.Y.T., V.A.T., Y.C.L., S.O.E.-M., M.H.M., and P.S.T. performed the experiments. G.S.H., C.P.M., Y.Y.T., V.A.T., Y.C.L., P.S.T., V.E.K., and S.F.B. analyzed the data and interpreted the results of experiments. G.S.H., C.P.M., Y.Y.T., and V.E.K. prepared the figures. G.S.H., V.E.K., and S.F.B. drafted the manuscript. Competing interests: S.F.B. is the chief scientific officer and equity holder in ECM Therapeutics Inc., which has license rights to MBV technology from the University of Pittsburgh. S.F.B. and G.S.H. are inventors on several patents related to this work filed by the University of Pittsburgh. 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 are available from the authors upon request.

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Lipidomics and RNA sequencing reveal a novel subpopulation of nanovesicle within extracellular matrix biomaterials - Science Advances

Bone Marrow Stem Cells Comments Off on Lipidomics and RNA sequencing reveal a novel subpopulation of nanovesicle within extracellular matrix biomaterials – Science Advances | March 20th, 2020

With coronavirus dominating the headlines, its easy to forget what else is going on in the world.

And it can be even harder to see any good news as most of the globe tackles the pandemic.

But in recent weeks there has been plenty of positive news to help with the coronavirus worries.

These are eight good news stories from across the world since the coronavirus outbreak began:

A million seagrass seeds were planted off the Welsh coast to help tackle climate change.

The seagrass seeds are being planted in a new 20,000sqm meadow off Pembrokeshire.

Seagrass can absorb carbon dioxide faster than trees, and scientists hope it can boost fish numbers and life in the sea.

In the summer of 2019, one million seeds were collected from areas like Porthdinllaen in the Lln Peninsula by a group of volunteers.

The seagrass, which is found in shallow, sheltered areas along the coast, was reached by snorkelling, diving and wading.

After being taken to Swansea University, the seeds were placed in hessian bags ready to be planted again at Dale Bay.

In more good news for the planet, carbon emissions from the power sector across the world have seen their biggest drop since 1990.

Research from environmental think tank Ember, emissions dropped 2% in 2019.

They said the historic decline was largely caused by the US and Europe moving away from coal power which saw a global drop of 3% - the largest decrease in three decades.

The budget doesnt normally bring much good news. But this year it was announced VAT on all sanitary products will be abolished from 2021.

Although small, it could mean women could save around 40 in a lifetime.

Scientists said a former chef living in the UK has become the second person in the world to be 'cured' of HIV.

Adam Castillejo has remained free of HIV for two-and-a-half years since he was given ground-breaking therapy at Hammersmith Hospital in west London.

The 40-year-old, who was born in Venezuela but lives in England, received a transplant of bone marrow stem cells that rid him of the AIDS-causing virus, the Mirror reported.

Amid the sombre news being reported on the TV was the annual Crufts show.

Viewers saw Maisie the wire-haired Dachshund beat tough competition and be crowned best in show.

The lovable pup even then did her business on the floor during her victory lap in front of a giggling crowd.

Around 28,000 pooches were put through their paces at the biggest dog show in the world at Birmingham's NEC.

In more animal related good news, a seal pup that spent two months in RSPCA care was released back into the wild.

Underweight Graham was looked after for around eight weeks after being rescued in Pembrokeshire.

RSPCA animal collection officer and wildlife officer Ellie West, who released Graham back into the sea at Port Eynon, said: This seal pup who when found was very underweight initially spent a few days coughing up sea shells!

He came into the centre weighing just 16.6kg and needed fluids and antibiotics for a chest infection and was treated for lungworm. He put on weight pretty steadily after starting to eat by himself on day six and then didnt look back.

Ellie released Graham back into the sea on March 7.

The fast-food chain has announced the bargain offer will last for five weeks, meaning customers have until April 19 to grab the discount.

Those wanting a meal for less will get a mini burger, regular fries and two hot wings for just 1.99 instead of the usual 3.99.

The offer was spotted by eagle-eyed deal hunters and posted on the money-saving website LatestDeals.co.uk.

A cleaver Australian teen has come up with a clever way to get rid of plastic waste - by using prawn shells.

17-year-old Angelina Arora has used prawn shells to create a plastic that will decompose in landfill in an average of 33 days.

The teen said she is now in talks with supermarkets to use her products, News.Au reported.

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Eight feel good stories you may have missed during the coronavirus outbreak - Wales Online

Bone Marrow Stem Cells Comments Off on Eight feel good stories you may have missed during the coronavirus outbreak – Wales Online | March 20th, 2020

The latest Stem Cell Banking market study offers an all-inclusive analysis of the major strategies, corporate models, and market shares of the most noticeable players in this market. The study offers a thorough analysis of the key persuading factors, market figures in terms of revenues, segmental data, regional data, and country-wise data. Thhttps://jewishlifenews.com/uncategorized/stem-cell-bankinindustry-players/is study can be described as most wide-ranging documentation that comprises all the aspects of the evolving Stem Cell Banking market.

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Stem cell banking or preservation is a combined process of extraction, processing and storage of stem cells, so that they may be used for treatment of various medical conditions in the future, when required. Stem cells have the amazing power to get transformed into any tissue or organ in the body. In recent days, stem cells are used to treat variety of life-threatening diseases such as blood and bone marrow diseases, blood cancers, and immune disorders among others.

The market of stem cell banking is anticipated to grow with a significant rate in the coming years, owing to factors such as, development of novel technologies for stem cell preservation and processing, and storage; growing awareness on the potential of stem cells for various therapeutic conditions. Moreover, increasing investments in stem cell research is also expected to propel the growth of the stem cell banking market across the globe. On other hand rising burden of major diseases and emerging economies are expected to offer significant growth opportunities for the players operating in stem cell banking market.

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Stem Cell Banking Market: Industry Analysis And Detailed Profiles Of Top Industry Players - Jewish Life News

Bone Marrow Stem Cells Comments Off on Stem Cell Banking Market: Industry Analysis And Detailed Profiles Of Top Industry Players – Jewish Life News | March 20th, 2020

It's not your imagination, it turns out. Stress can turn a person's hair gray. It's said that if you look at before and after pictures of any eight-year U.S. president the impact of the office on hair color is clear, though in fairness, it may be that candidates dye their hair and then at some point stop doing so. Nonetheless, scientists from Harvard have not only verified the conventional wisdom on our graying noggins, but have also figured out why stress is so brutal to our follicular pigmentation.

The new research from Harvard scientists is published in the journal Nature.

Image source: Ververidis Vasilis/Evan El-Amin/Vacclav/Shutterstock/Big Think

Senior author of the study Ya-Chieh Hsu, professor of Stem Cell and Regenerative Biology at Harvard, explains what prompted her research:

"Everyone has an anecdote to share about how stress affects their body, particularly in their skin and hair the only tissues we can see from the outside. We wanted to understand if this connection is true, and if so, how stress leads to changes in diverse tissues. Hair pigmentation is such an accessible and tractable system to start with and besides, we were genuinely curious to see if stress indeed leads to hair graying."

It turns out that stress activates nerves associated with our basic fight-or-flight system, and these nerves permanently damage pigment-regenerating melanocyte stem cells in hair follicles, causing them to cease production of melanin that normal provides color to hair follicles.

Hsu's team studied the issue using mice, and was somewhat stunned at their findings. "When we started to study this, I expected that stress was bad for the body but the detrimental impact of stress that we discovered was beyond what I imagined," recalls Hsu.

The scientists stressed the mice using a combination of three methods:

Image source: Helga Lei/Shutterstock

Hsu and her colleagues first suspected an immune system reaction was at the root of graying hairs only to discover that mice without immune systems still turned gray in response to stressors. The next suspect was cortisol produced by the adrenal glands however, this proved not to be so. "Stress always elevates levels of the hormone cortisol in the body," says Jsu, "so we thought that cortisol might play a role. But surprisingly, when we removed the adrenal gland from the mice so that they couldn't produce cortisol-like hormones, their hair still turned gray under stress."

Image source: Judy Blomquist/Harvard University

Finally, the researchers investigate the possibility that the system responding to stressors was the mice's sympathetic nervous systems, the part of the nervous system that kicks into action with the fight-or-flight impulse. The sympathetic nervous system is a vast network of nerves that connects, among other places, to hair follicles in the skin. In response to stress, the system sends a rush of the chemical norepinephrine to the follicles' melanocyte stem cell, causing them to quickly burn through and deplete their stores of pigment.

Say Hsu, "After just a few days, all of the pigment-regenerating stem cells were lost. Once they're gone, you can't regenerate pigments anymore. The damage is permanent." Great for survival, not so good for hair color.

Sympathetic system nerves are magenta above. Melanocyte stem cells are yellow.

Image source: Hsu Laboratory, Harvard University

"Acute stress," says lead author of the study Bing Zhang, "particularly the fight-or-flight response, has been traditionally viewed to be beneficial for an animal's survival. But in this case, acute stress causes permanent depletion of stem cells."

The research, done in collaboration with other Harvard researchers, presents a new appreciation of the effect the sympathetic system can have on the body's cells during stress.

One of these collaborators, Harvard immunologist Isaac Chu, notes, "We know that peripheral neurons powerfully regulate organ function, blood vessels, and immunity, but less is known about how they regulate stem cells. With this study, we now know that neurons can control stem cells and their function, and can explain how they interact at the cellular and molecular levels to link stress with hair graying."

Given this finding regarding the direct impact of stress on follicular stem cells, the question of what it else it may affect becomes an obvious one. As Hsu sums it up, "By understanding precisely how stress affects stem cells that regenerate pigment, we've laid the groundwork for understanding how stress affects other tissues and organs in the body."

This importance of the study therefore goes way beyond graying heads. "Understanding how our tissues change under stress is the first critical step," says Hsu, "toward eventual treatment that can halt or revert the detrimental impact of stress. We still have a lot to learn in this area."

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Scientists figure out why stress turns your hair gray - Big Think

Skin Stem Cells Comments Off on Scientists figure out why stress turns your hair gray – Big Think | March 19th, 2020

For Earth, bleak times lay ahead. TheCOVID-19 diseaseis known to cause respiratory illness and fever, but some extra symptoms sweeping across the globe right now seem to be stress, fear, and anxiety. To provide some light relief in these dark times, weve collated 15 of our favorite good news stories to remind you that not everything is awful. Hold tight everybody, 2021 will come eventually.

The Super Pink Moon is comingYou might be stuck at home as part of your self-isolation, but luckily the night sky is about to put on quite a show as April sees the return of the Super Pink Moon. Full moons happen every month and were given different names by the Native Americans to map out the year based on significant events that ran in tandem with the occurrence of a full Moon. Aprils is known as the pink moon because it appeared at the same time as pink spring flowers. This Aprils will be a Super Pink Moon as it is the second supermoon of the year, a term used to describe the slightly enlarged appearance of the Moon as its fully illuminated by the Sun due to Earths position between the two. Quarantine or no, if you've got access to a window you should be able to catch sight of this beauty on April 7 and when you do, think of all the other people looking up at the same moon. Self isolation doesn't mean you're alone.

Mice have been cured of diabetesAn astonishing discovery at the Washington University School of Medicine in St. Louis has revealed that human stem cells could be successfully engineered to cure diabetes in mice, offering an avenue of hope for the treatment of this debilitating disease. They used human pluripotent stem cells, cells that have the capacity to become any cell in the body, to create insulin-producing pancreatic beta cells. The engineered stem cells supplemented the diabetic mices inability to produce insulin, curing them of the disease for 9 months to a year before relapse occurred.

Theres a new green fuel in townHydrogen fuel was fast shaping up to be a hopeful route for a zero-emissions means of running things, but its costly production in terms of energy was affecting hopes for it being a sustainable resource. A team in Tokyo has now managed to refine the process to yield 25 times more hydrogen than previous methods all while using thrifty ingredients including light and a specific kind of rust. Combined with all the solar power breakthroughs currently occurring, green energy is on the up.

A crash course in what not to do, according to one Stanford University psychologist.

Babies love baby talkEven if it makes your skin crawl to hear adults cooing over little uns, it turns out babies across the globe are universally partial to baby talk. The news comes fromStanford psychologist Michael Frank who led the largeststudyto date looking at how the different ways adults speak is received by babies across the world. While all babies were fans, older babies liked it best and even showed a preference for baby talk in their native language as they likely recognized it most even if they couldnt speak it yet. The overall winner was oohs and coos, so think twice before scorning your new-parent friends for embarrassing you in public the babies have spoken.

Important change in the winds for HIV treatmentShortly after a UK man became the second person cured of HIV a fantastic breakthrough in the treatment of this once devastating disease theres more good news in the UK as PrEP, a preventative drug that prevents HIV infection, will finally be available nationwide on the NHS having already been made available in Scotland. After a 3-year study involving 20,000 participants, the drug will be made available to those at higher risk of exposure from April. PrEP is already available in the US and you can find PrEP providers near you here.

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Plasters finally take a step towards racial inclusivityMajor UK superstore Tesco has taken the long-awaited step to introduce skin tone diversity into their range of bandaids. Previously, widely available bandaids, or plasters in the UK, have mainly catered to Caucasian individuals and the racial oversight was brought to light by a moving Tweet from Domonique Apollon in April 2019 after he wore a bandaid suitable for his skin tone for the first time. Longtime readers of Malorie Blackman's literary series Noughts and Crosseswill appreciate this poignant detail becoming a reality, as will those watching the current BBC dramatization available to watch via iPlayer in the US (excellent for those self-isolating).

Universal flu vaccine passes integral stageWatchers of the Pandemic documentary on Netflix (we wouldnt recommend catching up now if you missed it) may remember the plight of flu-fighting epidemiologists as the constantly shape-shifting nature of influenza meant strains were annually moving beyond existing vaccinations. Now, a universal vaccine is becoming a reality as for the first time a vaccine, called FLU-v, has been developed that can induce immune responses that last at least six months. Phase I and II of the clinical trial have been approved meaning its safety for use in human subjects and we hotly await what comes next for the groundbreaking vaccine.

Top marks for lights out in dark sky nationSometimes a bit of darkness can be a good thing, and when it comes to nighttime, the tiny South Pacific island of Niue tops the charts. The International Dark-Sky Association (IDA) is a non-profit working to protect our most precious natural spaces from light pollution, and this year chose Niue as the first entire country ever to be accredited as a Dark Sky Place. This classification recognizes responsible lighting policies that preserve the natural darkness of nighttime carrying with it endless benefits for the biological cycles of animals, plants and humans.

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People hating on National Parks created beautiful artIn a glimmering example of you cant please everybody, artist Amber Share decided to take some of the best worst reviews of National Parks in America and turn them intotourism posters, showing that we can still make something funny in the face of people's negativity. You can see the whole collection on her Instagram account @subparparks, but a personal favorite has to be the above magnificent minimization of Yellowstone.

CRISPR may hold the key for curing genetic blindnessSurgeons at Oregon Health & Science Institute have attempted to use gene hacking to cure Leber congenital amaurosis, a genetic condition that leads to the onset of blindness in early childhood. By directly gene editing within the patients eye, researchers hope to ...take people who are essentially blind and make them see," according to researchers.

The Arctic seed vault in Svalbard is thrivingLast month saw an enormous glut of 60,000 seed samples added to the ever-growing collecting in the Svalbard Global Seed Vault. Tucked beneath a mountain in Norway's Svalbard archipelago, the initiative began with hopes to create a Noahs ark for plant diversity to protect our green spaces should a global catastrophe occur up top. The collection now includes 1.05 million seed varieties including the first-ever donation from an indigenous US tribe. Nicknamed the "Doomsday vault", we may need it sooner than thought.

Sea sponges can sneeze, and the footage is amazingThe aah and choo of asneezing sea spongehas been caught on camera for the first time and the recording is hilarious. Stumbled upon almost by accident, the discovery came about while researchers were observing sea cucumbers and sea urchins sniffing the sea floor. The video shows the two-part sneeze of a tulip-shaped sponge as it expands before contracting, expelling particles as it goes. Researchers arent yet sure what the sneezes are in response to. Lets hope its not a case ofthe suds.

Vernal equinox brings early springThe times might be dark but for the Northern hemisphere, the days wont be, as spring arrives on March 19, the earliest date in 124 years. The variation in the date is the result of leap years and daylight savings time. It should be noted this is the astronomical definition of spring, which refers specifically to the position of Earth's orbit in relation to the Sun, so perhaps dont expect to hear a gay little spring song in your garden just yet.

Its possible some dinosaurs could GLOW IN THE DARKA titillating discovery published in the journal Historical Biology recently revealed that some dinosaurs may have glowed in the dark thanks to ultraviolet fluorescing feathers and horns. Many extant bird species are tetrachromats, defined by a fourth cone in their retina that means they can see the UV spectrum. Co-author Jamie Dunning's work on the photoluminescence of puffin beaks under UV light inspired the questions, could dinosaurs have this too? We'd like the answer to be yes, please. The only thing cooler than dinosaurs is glow-in-the-dark dinosaurs.

If you need more positivity in your life right now, take a look at these ingenious social distancing moments from around the world that will restore your faith in humanity.

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15 Good News Stories To Tackle The COVID-19 Sadness - IFLScience

Skin Stem Cells Comments Off on 15 Good News Stories To Tackle The COVID-19 Sadness – IFLScience | March 19th, 2020

It's not your imagination, it turns out. Stress can turn a person's hair gray. It's said that if you look at before and after pictures of any eight-year U.S. president the impact of the office on hair color is clear, though in fairness, it may be that candidates dye their hair and then at some point stop doing so. Nonetheless, scientists from Harvard have not only verified the conventional wisdom on our graying noggins, but have also figured out why stress is so brutal to our follicular pigmentation.

The new research from Harvard scientists is published in the journal Nature.

Image source: Ververidis Vasilis/Evan El-Amin/Vacclav/Shutterstock/Big Think

Senior author of the study Ya-Chieh Hsu, professor of Stem Cell and Regenerative Biology at Harvard, explains what prompted her research:

"Everyone has an anecdote to share about how stress affects their body, particularly in their skin and hair the only tissues we can see from the outside. We wanted to understand if this connection is true, and if so, how stress leads to changes in diverse tissues. Hair pigmentation is such an accessible and tractable system to start with and besides, we were genuinely curious to see if stress indeed leads to hair graying."

It turns out that stress activates nerves associated with our basic fight-or-flight system, and these nerves permanently damage pigment-regenerating melanocyte stem cells in hair follicles, causing them to cease production of melanin that normal provides color to hair follicles.

Hsu's team studied the issue using mice, and was somewhat stunned at their findings. "When we started to study this, I expected that stress was bad for the body but the detrimental impact of stress that we discovered was beyond what I imagined," recalls Hsu.

The scientists stressed the mice using a combination of three methods:

Image source: Helga Lei/Shutterstock

Hsu and her colleagues first suspected an immune system reaction was at the root of graying hairs only to discover that mice without immune systems still turned gray in response to stressors. The next suspect was cortisol produced by the adrenal glands however, this proved not to be so. "Stress always elevates levels of the hormone cortisol in the body," says Jsu, "so we thought that cortisol might play a role. But surprisingly, when we removed the adrenal gland from the mice so that they couldn't produce cortisol-like hormones, their hair still turned gray under stress."

Image source: Judy Blomquist/Harvard University

Finally, the researchers investigate the possibility that the system responding to stressors was the mice's sympathetic nervous systems, the part of the nervous system that kicks into action with the fight-or-flight impulse. The sympathetic nervous system is a vast network of nerves that connects, among other places, to hair follicles in the skin. In response to stress, the system sends a rush of the chemical norepinephrine to the follicles' melanocyte stem cell, causing them to quickly burn through and deplete their stores of pigment.

Say Hsu, "After just a few days, all of the pigment-regenerating stem cells were lost. Once they're gone, you can't regenerate pigments anymore. The damage is permanent." Great for survival, not so good for hair color.

Sympathetic system nerves are magenta above. Melanocyte stem cells are yellow.

Image source: Hsu Laboratory, Harvard University

"Acute stress," says lead author of the study Bing Zhang, "particularly the fight-or-flight response, has been traditionally viewed to be beneficial for an animal's survival. But in this case, acute stress causes permanent depletion of stem cells."

The research, done in collaboration with other Harvard researchers, presents a new appreciation of the effect the sympathetic system can have on the body's cells during stress.

One of these collaborators, Harvard immunologist Isaac Chu, notes, "We know that peripheral neurons powerfully regulate organ function, blood vessels, and immunity, but less is known about how they regulate stem cells. With this study, we now know that neurons can control stem cells and their function, and can explain how they interact at the cellular and molecular levels to link stress with hair graying."

Given this finding regarding the direct impact of stress on follicular stem cells, the question of what it else it may affect becomes an obvious one. As Hsu sums it up, "By understanding precisely how stress affects stem cells that regenerate pigment, we've laid the groundwork for understanding how stress affects other tissues and organs in the body."

This importance of the study therefore goes way beyond graying heads. "Understanding how our tissues change under stress is the first critical step," says Hsu, "toward eventual treatment that can halt or revert the detrimental impact of stress. We still have a lot to learn in this area."

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It's the sympathetic nervous system - Big Think

Skin Stem Cells Comments Off on It’s the sympathetic nervous system – Big Think | March 19th, 2020

With having published myriads of reports, Autologous Stem Cell Based Therapies Market Research imparts its stalwartness to clients existing all over the globe. Our dedicated team of experts deliver reports with accurate data extracted from trusted sources. We ride the wave of digitalization facilitate clients with the changing trends in various industries, regions and consumers. As customer satisfaction is our top priority, our analysts are available 24/7 to provide tailored business solutions to the clients.

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The key players covered in this studyRegeneusMesoblastPluristem Therapeutics IncU.S. STEM CELL, INC.Brainstorm Cell TherapeuticsTigenixMed cell Europe

Market segment by Type, the product can be split intoEmbryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem Cells

Market segment by Application, split intoNeurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

Market segment by Regions/Countries, this report coversUnited StatesEuropeChinaJapanSoutheast AsiaIndiaCentral & South America

The study objectives of this report are:To analyze global Autologous Stem Cell Based Therapies status, future forecast, growth opportunity, key market and key players.To present the Autologous Stem Cell Based Therapies development in United States, Europe and China.To strategically profile the key players and comprehensively analyze their development plan and strategies.To define, describe and forecast the market by product type, market and key regions.

In this study, the years considered to estimate the market size of Autologous Stem Cell Based Therapies are as follows:History Year: 2014-2018Base Year: 2018Estimated Year: 2019Forecast Year 2019 to 2025For the data information by region, company, type and application, 2018 is considered as the base year. Whenever data information was unavailable for the base year, the prior year has been considered.

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Ready To Use Autologous Stem Cell Based Therapies Market size and forecast, 2019-2020 - Packaging News 24

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Forecast Period 2020-2026: A comprehensive analysis of the market structure along with the forecast of the various segments and sub-segments of the market have been delivered through this Cosmetic Skin Care Market business document. The market is greatly transforming because of the moves of the key players and brands including developments, product launches, joint ventures, mergers and acquisitions that in turn changes the view of the global face of industry.

The well-established Key players in the market are: LOral, Unilever, New Avon Company, Este Lauder Companies, Espa, Kao Corporation, Johnson & Johnson Services, Inc., Procter & Gamble, Beiersdorf, THE BODY SHOP INTERNATIONAL LIMITED, Shiseido Co.,Ltd., Coty Inc., Bo International, A One Cosmetics Products, Lancme, Clinique Laboratories, llc., Galderma Laboratories, L.P., AVON Beauty Products India Pvt Ltd, Nutriglow Cosmetics Pvt. Ltd, Shree Cosmetics Ltd among others.

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What ideas and concepts are covered in the report?

The assessments accounted by all the zones and the market share registered by each region is mentioned in the report.

The study sums up the product consumption growth rate in the applicable regions along with their consumption market share.

Data regarding the Cosmetic Skin Care Industry market consumption rate of all the provinces, based on applicable regions and the product types is inculcated in the report.

Region-based analysis of the Cosmetic Skin Care Industry market:

The Cosmetic Skin Care Industry market, with regards to provincial scope is segmented into USA, Europe, Japan, China, India, and South East Asia. The report also includes information regarding the products use throughout the topographies.

Unique structure of the report

Global cosmetic skin care market is set to witness a substantial CAGR of 5.5% in the forecast period of 2019- 2026

Cosmetic Skin Care Market Trends | Industry Segment by Product (Anti-Aging Cosmetic Products, Skin Whitening Cosmetic Products, Sensitive Skin Care Products, Anti-Acne Products, Dry Skin Care Products, Warts Removal Products, Infant Skin Care Products, Anti-Scars Solution Products, Mole Removal Products, Multi Utility Products), Application (Flakiness Reduction, Stem Cells Protection against UV, Rehydrate the skins surface, Minimize wrinkles, Increase the viscosity of Aqueous, Others), Gender (Men, Women), Distribution Channel (Online, Departmental Stores and Convenience Stores, Pharmacies, Supermarket, Others), Geography (North America, Europe, Asia-Pacific, South America, Middle East and Africa) Industry Trends and Forecast to 2026

Cosmetic skin care is a variety of products which are used to improve the skins appearance and alleviate skin conditions. It consists different products such as anti- aging cosmetic products, sensitive skin care products, anti- scar solution products, warts removal products, infant skin care products and other. They contain various ingredients which are beneficial for the skin such as phytochemicals, vitamins, essential oils, and other. Their main function is to make the skin healthy and repair the skin damages.

Market Drivers:

Market Restraints:

Key Developments in the Market:

In July 2019, Colgate-Palmolive announced the acquisition of Laboratoires Filorga Cosmtiques so they can strengthen their skin-care business. This acquisition will help the company to provide better products to their customer and solidify them in them in the Asia

In June 2019, Unilever announced the acquisition of skin-care brand Tatcha. This acquisition will help the company to produce new innovative natural products and provide better solutions to their customer worldwide. This will also add Tatcha famous brands such as The Silk Canvas primer, Luminous Dewy Skin Mist, The Deep Cleanse Exfoliating Cleanser and other

Competitive Analysis:

Global cosmetic skin care market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of cosmetic skin care market for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Some of the Major Highlights of TOC covers:

Cosmetic Skin Care Industry Regional Market Analysis

Cosmetic Skin Care Industry Production by Regions

Global Cosmetic Skin Care Industry Production by Regions

Global Cosmetic Skin Care Industry Revenue by Regions

Cosmetic Skin Care Industry Consumption by Regions

Cosmetic Skin Care Industry Segment Market Analysis (by Type)

Global Cosmetic Skin Care Industry Production by Type

Global Cosmetic Skin Care Industry Revenue by Type

Cosmetic Skin Care Industry Price by Type

Cosmetic Skin Care Industry Segment Market Analysis (by Application)

Global Cosmetic Skin Care Industry Consumption by Application

Global Cosmetic Skin Care Industry Consumption Market Share by Application (2014-2019)

Cosmetic Skin Care Industry Major Manufacturers Analysis

Cosmetic Skin Care Industry Production Sites and Area Served

Product Introduction, Application and Specification

Cosmetic Skin Care Industry Production, Revenue, Ex-factory Price and Gross Margin (2014-2019)

Main Business and Markets Served

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At the Last, Cosmetic Skin Care industry report focuses on data sources, viz. primary and secondary sources, market breakdown and data triangulation, market size estimation, research programs, and design, research approach and methodology, and the publishers disclaimer.

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Cosmetic Skin Care Market comprehensive study on Key Players like L'Oral, Unilever, New Avon Company, Este Lauder Companies, Espa, Kao Corporation,...

Skin Stem Cells Comments Off on Cosmetic Skin Care Market comprehensive study on Key Players like L’Oral, Unilever, New Avon Company, Este Lauder Companies, Espa, Kao Corporation,… | March 19th, 2020

Newswise The National Institute on Aging (NIA) has extended its biobanking contract with the Coriell Institute for Medical Research for an additional five years.

The newly awarded $8.6 million funding keeps Coriell in place as the trusted steward of this collection and includes the addition of new innovative products to expand the collection. The NIA Aging Cell Repository was established at Coriell in 1974 and Coriell has continuously managed this unique resource ever since.

Coriells relationship with the NIA is among its oldest and most treasured, said Nahid Turan, Coriell's Chief Biobanking Officer. We at Coriell are committed to ensuring the success of this phenomenal collection of aging-related biospecimens, and we are thrilled at the opportunity to continue this important collaboration with NIA.

The NIA Aging Cell Repository contains a collection of high quality, well characterized human and animal cell line and DNA samples, representing aged human populations, age-related diseases, and animal models of aging and has seen significant changes in the last decade.

One major focus of the collection is now to generate valuable induced pluripotent stem cell (iPSC) lines, which can be used to model aging and perform disease in a dish experiments. These stem cells are created from skin or blood cells in the NIA collection, which were reverted into a stem cell state. From there, these cells can be coaxed into becoming nearly any other cell type in the body, including neuronal or nerve cells. Seven of these important iPSC lines have been added to the collection in the last three years, representing age related neurodegenerative disorders like Alzheimers disease as well as rare genetic diseases like Progeria and Werner Syndrome.

Late last year, the Repository also added more than 350 new cell lines collected from participants in a long-term study of aging known as The 90+ Study. Participants in this study all aged 90 years or older donated their DNA and agreed to answer questions over a period of time to help researchers better understand the lifestyle and biological factors which may contribute to advanced aging.

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Coriell Institute for Medical Research Awarded $8.6 Million Biobanking Contract from National Institute on Aging - Newswise

Skin Stem Cells Comments Off on Coriell Institute for Medical Research Awarded $8.6 Million Biobanking Contract from National Institute on Aging – Newswise | March 18th, 2020

When the World Health Organization (WHO)labeled the new COVID-19a "pandemic", that is, a disease that is occurringall over the world at the same time, there were moments reminiscentof times of war: thedeserted streets, supermarkets overwhelmed by hundreds of people scrambling for goods, and the constant media monitoring of the infection's progress the number of sick and dead increasing daily.Although our health system is not what it was in 1918, when the Spanish Fluwreaked havoc, nor will the coronavirus be as lethal as smallpox the most deadly pandemic some people will still make historical comparisons.To keep you up to date with what's happening now and what's happened in the past, here's tour of the five most devastating pandemics that we've emerged from.

HIV/AIDS

It has killed more than 25 million people worldwide, and although preventive treatments such as PrEP have been developed toreduce infections by 90%, a global cure has yet to be found.HIV originated in Africa, where apes have an HIV-like virus known as SIV.

Scientists still speculate on whether interspecies contagion occurred from hunting or eating infected chimp meat.AIDS wasn't detected as a disease until the 1980s, when it was observed in the United States, especially among homosexual patients in New York and California. It was later determined an evolution of the HIV infection, which transmitted through any passage of bodily fluid (intravenous drug usage and sexual intercourse were the most common). Doctors named it acquired immunodeficiency syndrome (AIDS)because the virus attacks the white blood cells that help fight infection.Today, there are two patients worldwide who have been cured of HIV thanks to a stem cell transplant whose donor carried a mutation known as CCR5-delta 32.

The Black Death or Bubonic Plague

It ravaged the European continent from the mid-14th century until its last outbreak three hundred years later and is responsible for more than 75 million deaths.

Although at that time the devastating epidemic was attributed to Divine Cholera and even to the passage of a comet, the origin was a bacterium that appeared in Asia and spread through parasites such as rat fleas. Its spread originated at trade ports, and was helped by the poor hygiene conditions and diet of the time period.

Death occurred in less than a week after the disease manifested, with the appearance of buboes - or swelling of nodes in the lymphatic system - accompanied by high fevers, delirium, chills and stinking suppurations. The sick were confined to their homes along with their families as means of containment. In some cases, it wiped out whole villages in Europe, which were sometimes discovered hundreds of years later.

Spanish Flu

The disease gotits name during WWI fromSpanish newspapers, which remained neutral in the conflict, and were the only ones to report on its lethality without censorship.

It is believed that Spanish Flu was responsible for between 50 and 100 million deaths and some the first cases reported were among the United States military, who could have broughtit to Europe when they landed to fight the Germans. Regardless, there are many theories around its origin.

As deadly as it is heartbreaking, there were cases in the United States of people rising with fever and dying on their way to work.

In a previous article, we commented on why its fatality rate, which is often used incomparisontoCovid-19, is wrong, as it is well over the 2% reported by WHO.

Smallpox

Holding the position of the most devastating global pandemic,Smallpoxhas contributed to the decline of entire civilizations such as the Aztec and Inca Empires when theSpanish brought the disease in their "conquest" of the New World in 1519. It is estimated that 90% of indigenous deaths during European colonization were not due to "fire," but rather, disease.

In Europe, smallpox killed 60 million people in the 18th century alone, and a hundred years later there were 300 million deaths worldwide.

Its Latin name means "spotted", because of the bumps and bruises that appeared on the faces of those afflicted. It was highly contagious and those who survived would carry marks on their skin for the rest of their lives, and some even wentblind.

One of modern medicine's greatest achievements was the creation of a vaccine for smallpox in 1979. As a result, Smallpox is considered eradicated.

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Four pandemics that changed the world - AL DIA News

Skin Stem Cells Comments Off on Four pandemics that changed the world – AL DIA News | March 18th, 2020

Jagasia was concerned that although G.V.H.D. was the most likely diagnosis, it might not be the right one. The patient had already been tested for the usual infections seen in immune-suppressed patients. So he looked for other possible causes of the patients diarrhea. He didnt find any. The patient lost another 15 pounds. When he looked in the mirror, he hardly recognized himself. Jagasia arranged for the patient to start getting intravenous nutrition and began tapering one immune-suppressing medication in order to start another.

The patients son was in medical school in another part of the state and called home frequently. When his father finally told him how sick he was, his son got scared. His father was a minimizer. If he was saying this, things must be bad.

When he got off the phone, the young man immediately turned to the internet. He typed in gastroenteritis after ... stem-cell transplant. The first results that came up referred to a paper in a medical journal, Clinical Infectious Diseases, published nearly a decade earlier that identified an unexpected culprit: norovirus.

Norovirus is one of the most common causes of gastroenteritis in the world. In the United States, its linked to an estimated 21 million cases of nausea and vomiting every year. Diarrhea can be present but is not typically as severe as other symptoms. In a normal host, the infection resolves on its own after 48 to 72 hours, thanks to the hard work of the immune system. Even so, norovirus was not a common cause of diarrhea in those who are immunosuppressed. But in the medical-journal paper, the first of its kind, 12 patients who had a stem-cell transplant and developed a persistent diarrheal illness were found to have norovirus. And of those 12, 11 were initially thought to have G.V.H.D. In most of those cases, it was only after the immune-suppressing medications were reduced that the patients own defenses could come to the rescue and vanquish the virus.

The son immediately sent the paper to his father. Had he been tested for norovirus? he asked. The patient wasnt sure. He forwarded the journal article to Jagasia and asked if hed had this test. He hadnt. Jagasia was 99 percent certain that this was a wild-goose chase. Hed never seen norovirus in patients with compromised immune systems. Still, testing was easy.

When the test came back positive, Jagasia was stunned. He repeated the test. Positive again. He immediately started to taper the immune-suppressing medications. As the doses came down, the diarrhea slowed, and after a few weeks, it stopped completely. With the help of the IV nutrition, and a slowly improving appetite, the patient began to gain back the weight he lost. From the patients point of view, his son saved his life.

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His Immune System Went Out of Whack. The Usual Treatment Didnt Work. Why? - The New York Times

Skin Stem Cells Comments Off on His Immune System Went Out of Whack. The Usual Treatment Didnt Work. Why? – The New York Times | March 18th, 2020

A research team led by Professor Michael Sieweke, from the Center for Regenerative Therapies TU Dresden (CRTD) and the Center of Immunology of Marseille Luminy (CNRS, INSERM, Aix-Marseille University), has uncovered a surprising property of blood stem cells that contributes to boosting our immunity.

Not only do the stem cells ensure the continuous renewal of blood cells and contribute to the immune response triggered by an infection, but they can also remember previous infectious encounters to drive a more rapid and more efficient immune response in the future.

These cells are found within the soft tissue, or bone marrow, in the centre of large bones such as the hip and thigh bones.

The new findings should have a significant impact on future vaccination strategies and pave the way for new treatments of an underperforming or over-reacting immune system.

Stem cells in our bodies act as reservoirs of cells that divide to produce new stem cells, as well as a myriad of different types of specialised cells that are required to secure tissue renewal and function.

Commonly called blood stem cells, the hematopoietic stem cells (HSC) are found in the bone marrow, the soft tissue that is in the centre of large bones such as the hips or thighs. The role of the cells is to renew the repertoire of blood cells, including cells of the immune system, which are crucial to fight infections and other diseases.

Work from Professor Michael Siewekes laboratory and others over the past years has proven the dogma that HSCs were unspecialised cells, blind to external signals such as infections, was wrong, and has shown that HSCs can actually sense external factors to specifically produce subtypes of immune cells on demand to fight an infection.

Beyond their role in an emergency immune response, the question remained as to the function of HSCs in responding to repeated infectious episodes. The immune system is known to have a memory that allows it to better respond to returning infectious agents. The present study now establishes a central role for blood stem cells in this memory.

Professor Michael Sieweke, Humboldt Professor at TU Dresden, CNRS Research Director and last author of the publication, explained how they found the memory was stored within the cells: The first exposure to LPS causes marks to be deposited on the DNA of the stem cells, right around genes that are important for an immune response. Much like bookmarks, the marks on the DNA ensure that these genes are easily found, accessible and activated for a rapid response if a second infection by a similar agent was to come.

The authors further explored how the memory was inscribed on the DNA, and found C/EBPb to be the major actor, describing a new function for this factor, which is also important for emergency immune responses. Together, these findings should lead to improvements in tuning the immune system or better vaccination strategies.

Sieweke concluded: The ability of the immune system to keep track of previous infections and respond more efficiently the second time they are encountered is the founding principle of vaccines.

Now that we understand how blood stem cells bookmark immune response circuits, we should be able to optimise immunisation strategies to broaden the protection to infectious agents. It could also more generally lead to new ways to boost the immune response when it underperforms or turn it off when it overreacts.

The results of this research are published in Cell Stem Cellon March 12, 2020.

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Stem cells: what do bones have to do with boosting immunity? - Health Europa

Bone Marrow Stem Cells Comments Off on Stem cells: what do bones have to do with boosting immunity? – Health Europa | March 17th, 2020

A BUCKLEY man is one step closer to a clean bill of health after receiving life-saving treatment.

The Leader previously reported that Matt Davies was given 12-months to live without a stem cell transplant, which sparked a massive support network, with thousands signing up to become a donor.

Wife Sarah Davies urged people to sign up to become a donor, which could save the lives of many people and over 7,000 had signed up from her link alone.

Before Christmas, Matt was given the news that there was a match for him and he could start his treatment in January.

She told the Leader: It was a success, at the moment the cells in his body are 99.5 per cent donor and 0.5 per cent his. In time they will be 100 per cent donor so its definitely working which is fantastic.

We are on day 67 and on day 100 we can have a bone marrow scan to find out what stage we are.

GvHD is our biggest worry at the moment. Small amounts after a transplant can be good because it means his body is fighting but in huge amounts it can be damaging. It is starting to affect his gut now.

Because we live in Wales and have done for several years, we couldnt get the funding for the therapy which is what the Christie does, but we are now in the process of getting the drug for him, we are in constant talks so its a frustrating game at the moment.

We need to start this medication to get rid of this GvHD before it becomes chronic, so we are still in the process of getting that drug but hes doing really well.

Graft versus host disease (GvHD) is a condition that might occur after a transplant. In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells then attack the body.

Matt was diagnosed with cancer last year and beat it, however less than eight months later after having his three-monthly routine bone marrow results he was told the leukaemia was back and his only option was a stem cell transplant.

He has since made significant progress however the pair say they are worried about the latest coronavirus outbreak due to Matt essentially having no immune system.

Sarah said: At the moment with coronavirus its very scary because he has a low immune system, he is basically starting from scratch with his immune system so cant get immunisations until he is one year old. We have decided to take the kids out of school because we dont want him catching anything.

Hes done absolutely fantastic and is now back to eating.

Matt has been really lucky. They are pleased with his progress, but they would like his GvHD levels to be lower.

Although Matt faced no real complications during the treatment however has lost a significant amount of weight.

A JustGiving Page has been set up to raise funds for the Christie in Manchester where Matt has been receiving his treatment.

Sarah added: Even still now I will be walking somewhere and random people who Ive never met before will ask me how he is doing. Its actually been so positive. I dont think people realise how much it has helped, just them asking it has really helped us get through this and knowing that a lot of people are supporting us.

On social media we have spoken to so many people in similar situations as ours, its about helping one another, and we have made friends for life.

Thank you so much for your support, it means a lot to us and its lovely for us to read all the comments, even if we cannot reply to them all.

Matts progress can be found on social media via the Team Davies Facebook and Instagram page.

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Buckley couple thank community for their support as dad-of-two receives life-saving treatment | The Leader - LeaderLive

Bone Marrow Stem Cells Comments Off on Buckley couple thank community for their support as dad-of-two receives life-saving treatment | The Leader – LeaderLive | March 17th, 2020

Today, we will see why Fate Therapeutics (FATE) is an attractive pick in March 2020.

Fate Therapeutics is a clinical-stage biopharmaceutical company focused on the development of next-generation cellular immunotherapies for cancer and immune disorders. The company has pioneered proprietary iPSC (induced pluripotent stem cell) platform technology to develop off-the-shelf cell-based cancer immunotherapy products. Current patient-derived autologous and allogeneic cell therapies suffer from drawbacks such as high costs, manufacturing complexity, product heterogeneity, and high turnaround time. These methods, including patient and donor-derived approaches to cell therapy, also require batch-to-batch sourcing and engineering of millions of primary cells.

Fate Therapeutics aims to be the game-changer in cell-based cancer immunotherapy space by enabling the development of off-the-shelf cell products derived from master cell lines. The company aims to develop less costly, homogenous, and multi-dose or multi-cycle cell therapies with small turnaround time. The resultant cell therapy products are expected to be well-defined and uniform in the composition and can be mass-produced at a significant scale in a cost-effective manner and can be delivered off-the-shelf for broad patient accessibility.

The company's cell therapy pipeline comprises immune-oncology programs including off-the-shelf NK- and T-cell product candidates derived from master iPSC lines, and immuno-regulatory programs, including product candidates to prevent life-threatening complications in patients undergoing hematopoietic cell transplantation and to promote immune tolerance in patients with autoimmune disease.

Human-induced Pluripotent Stem cells are generated by reprogramming adult somatic cells to a pluripotent state. Fibroblasts are the most commonly used primary somatic cell type for the generation of induced pluripotent stem cells. They are reprogrammed using retroviruses. Pluripotent cells are capable of differentiating in all cell types that make up the body.

A single human iPSC can potentially differentiate into more than 200 cell types and provides a renewable source for making cells.

NK (natural killer) cells are the body's first line of defense against tumors and various pathogens. Fate Therapeutics is leveraging its iPSC platform to produce off-the-shelf NK cell therapy products.

FT500 is Fate Therapeutics' first off-the-shelf iPSC-derived NK-cell product candidate. The FT500 study is an open-label, multi-dose Phase 1 clinical trial designed to evaluate FT500 for the treatment of advanced solid tumors.

The dose-escalation stage of the study was originally designed to assess the safety and tolerability of three once-weekly doses of FT500, without IL-2 cytokine support, as a monotherapy and in combination with one of three FDA-approved ICI (immune checkpoint inhibitor) therapies in patients that have failed prior ICI therapy.

Data for the first 12 patients in the Phase 1 study has demonstrated clean safety for the iPSC platform. The cutoff date considered was November 28, 2019. It was seen that there were no reported dose-limiting toxicities, no FT500 related Grade 3 or greater adverse events or serious adverse events, and no incidents of cytokine release syndrome, neurotoxicity, or graft-versus-host disease.

Further, the trial also involved the evaluation of a multi-dose treatment course consisting of outpatient lympho-conditioning followed by three once-weekly doses of FT500 over up to two 30-day treatment cycles. Here, based on patients' T-cell and antibody repertoire, no anti-product immune responses against FT500 were evident over the multi-dose treatment course.

A total of 62 doses of FT500 were administered to these 12 patients in a safe and well-tolerated manner. Initial clinical data thus provides strong evidence that multiple doses of iPSC-derived NK-cells can be delivered off-the-shelf without patient matching.

In December 2019, the company disclosed plans to amend the trial protocol by including IL-2 cytokine support with each dose of FT500 after completion of 300 million cells per dose cohort in the ICI combination arm. The company has commenced dose-expansion part of Phase 1 trial with 300 million cells per dose and is focusing on enrolling NSCLC patients who are refractory to or have relapsed following CBT. This tumor type is highly susceptible to NK-cell recognition and killing. The study is enrolling at three clinical sites in the U.S. Fate Therapeutics expects expansion data readout from the trial in the second half of 2020.

Fate Therapeutics is studying the second product candidate from iPSC product platform and off-the-shelf NK-cell cancer immunotherapy, FT516, in an open-label, multi-dose Phase 1 trial. This product has been engineered to augment antibody-dependent cellular cytotoxicity.

In December 2019, the company announced results for two patients dosed with FT516. FT516 was administered as a monotherapy to the first patient who was suffering from relapsed/refractory AML (acute myeloid leukemia). The company dosed FT516 in combination with rituximab to the second patient who was suffering from high-risk DLBCL (diffuse large B-cell lymphoma) and had relapsed after multiple rituximab combination regimens, autologous hematopoietic stem cell transplant, and CAR (chimeric antigen receptor) T-cell therapy. The patients had received a first treatment cycle consisting of outpatient lympho-conditioning, three once-weekly doses of FT516 and IL-2 to better promote NK-cell activity.

Initial clinical data based on bone marrow biopsy at day 42 demonstrated no morphologic evidence of leukemia. There was even evidence of hematopoietic recovery following the completion of the first FT516 treatment cycle in the AML patient. There was also no circulating leukemia cells in the patient's peripheral blood. The patient even reported the recovery of neutrophils without growth factor support. The data did not demonstrate dose-limiting toxicities, although serious adverse events were seen. Initial dose escalation data may be read out in the second half of 2020.

This initial clinical evidence highlights the high probability of engineered iPSC-derived NK-cells demonstrating anti-tumor activity in AML indication. Besides, there is a body of data that has demonstrated clinical proof-of-concept for donor-derived NK-cell therapy in relapsed refractory AML and relapsed refractory DLBCL.

In December 2019, FDA accepted FT516's second IND application for studying the product in combination with PDL1, PD1, EGFR and HER2-targeting monoclonal antibody therapies in solid tumor indications. Initially, the company plans to prioritize the combination of FT516 and avelumab in patients with advanced solid tumors who are refractory to or have relapsed following, at least one line of anti-PDL1 monoclonal antibody therapy. The company plans to initiate enrollment in a clinical trial for FT516 and avelumab in mid-2020.

Fate Therapeutics is studying off-the-shelf multi-antigen targeted CAR NK-cell product candidate, FT596, in solid tumor indications.

In December 2019, Fate Therapeutics reported favorable in vivo preclinical data for FT596.

Here, in humanized mouse models of lymphoma and leukemia, FT596's efficacy was comparable to that of primary CAR T-cells in promoting tumor clearance and extending survival. FT596 combined with rituximab also showed the enhanced killing of lymphoma cells in vivo as compared to rituximab alone. FT596 can thus emerge to be best-in-class off-the-shelf treatment in B-cell malignancies. Fate Therapeutics has started enrolling patients in the open-label Phase I study. Initial dose escalation data readout on FT596 is expected in the second half of 2020.

Fate Therapeutics has high hopes for FT596, considering that initial clinical data from a donor-derived CAR19 NK-cell program at MD Anderson, demonstrated a 73% overall response rate in patients with relapsed refractory non-Hodgkin's lymphoma and chronic lymphocytic leukemia with no major toxicities. Hence, while the efficacy seemed similar to CAR T therapy, the safety profile was differentiated in favor of CAR NK-cell therapies.

Although early, this data has highlighted CAR NK-cells' capacity to confer a high level of efficacy without the CAR-T cell therapy-related toxicities. Fate Therapeutics expects FT596 to effectively replace patient-specific and allogeneic CAR19 T-cell immunotherapies. The latter single-antigen specific and hence pose a risk of disease relapse due to antigen escape as well as cause significant toxicities due to off-target activity. FT596, on the other hand, has been engineered with three active anti-tumoral functional components.

Fate Therapeutics aims to be the first company to introduce off-the-shelf iPSC-derived CAR T-cell therapy to patients, FT819, by submitting IND in the second quarter of 2020. The company expects to file an IND application for off-the-shelf CRISPR-edited, iPSC-derived NK-cell product candidate, FT538, by early May 2020. The company has also planned IND submission for FT576 in the second half of 2020.

Although Fate Therapeutics is pioneering a revolutionary approach for mass production of off-shelf cell therapy products, its pipeline is very early stage. There has not been sufficient data from its clinical programs to make an informed estimate about the success probability of these programs. In this backdrop, the company is exposed to significant R&D failure risks. In case data readouts from FT500 and FT596 clinical programs do not match expectations, the company may witness increased share price volatility.

At the end of 2019, the company had cash worth $261 million on its balance sheet. The company spent cash worth $83.2 million on operating activities in 2019. This is a proxy for the 2019 cash burn rate. We assume that the annual cash burn rate in 2020 will be around $120 million, considering that three assets have entered in-human trials. Hence, the company seems to have cash that can sustain operations until the end of 2021. However, if cash is needed at a faster pace, the company may land up requiring more funds. This can lead to equity dilution.

According to finviz, the 12-month consensus target price of Fate Therapeutics is $37.94. On March 4, Citi analyst Yigal Nochomovitz reiterated the "Buy" rating and increased target price from $26 to $41. On March 4, Barclays analyst Peter Lawson also initiated coverage of Fate Therapeutics with an Overweight rating and $40 price target.

On March 3, BMO Capital analyst Do Kim raised the firm's price target on Fate Therapeutics to $28 from $22 and reiterated the "Market Perform" rating. On March 3, Guggenheim analyst Michael Schmidt reiterated the "Buy" rating and increased target price from $25 to $41. On March 3, Roth Capital analyst Tony Butler reiterated the "Neutral" rating but increased the target price from $20 to $30. On March 3, BTIG analyst Amanda Murphy reiterated the "Buy" rating and increased target price from $27 to $42. The analyst has also raised the estimated value of the company's iPSC platform from $740 million to $2.0 billion.

On March 3, Oppenheimer analyst Matthew Biegler reiterated the "Outperform" rating and increased the target price from $27 to $36. Piper Sandler analyst, Edward Tenthoff also reiterated the "Overweight" rating and raised the target price from $28 to $57.

In September 2019, Fate Therapeutics launched in-house GMP (Good Manufacturing Practices) manufacturing facility at headquarters in San Diego, California. This is custom designed to use clonal master iPSC lines as a renewable cell source for the consistent and scaled manufacture of off-the-shelf NK-cell and CAR T-cell products. The company has already produced hundreds of cryopreserved, infusion-ready doses of FT500, FT516, and FT596 at a low cost per dose. Currently stored in inventory, these doses are immediately available for use in the clinical settings.

The full control of cGMP production and the technical expertise to genetically engineer iPSCs and create qualified clonal master lines for clinical use implies that the company has operational expertise and redundancies required for the consistent cost-effective manufacturing and clinical supply of off-the-shelf cell products.

I believe that the 12-month target price of $30 fairly reflects the growth potential as well as risks associated with early-stage Fate Therapeutics. I consider this company to be a good pick for aggressive biotech investors with an investment horizon of at least one year.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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