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Category Archives: Stem Cell Research
Posted: September 7, 2017 at 5:48 pm
Why build something from the ground up when one can just renovate an already existing structure? Essentially, thats what researchers from the University of Washington School of Medicine in St. Louis had in mind when they developed a method for transforming adult human skin cells into motor neurons in a lab. They published their work in the journal Cell Stem Cell.
In this study, we only used skin cells from healthy adults ranging in age from early 20s to late 60s, senior author Andrew S. Yoo said in a press release. Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons. In the future, we would like to study skin cells from patients with disorders of motor neurons. Our conversion process should model late-onset aspects of the disease using neurons derived from patients with the condition.
They did this by exposing skin cells in a lab to certain molecular signals usually found at high levels in the human brain. They focused on two short snippets of RNA: microRNAs (mRNAs) called miR-9 and miR-124, which are involved in repurposing the genetic instructions of the cell. These mRNAs, combined with certain transcription factors, successfully turned skin cells into spinal cord motor neurons within just 30 days. These new cells closely resembled normal mouse motor neurons in terms of which genes were turned on and off, and how they functioned.
Usually, when researchers find ways to replace damaged cells or organs, they resort to using stem cells. In particular, they use embryonic stem cells (a type of pluripotent stem cells) to grow the cells or organs needed.
While this type of stem cell has the potential to grow into whatever adult cell type is needed, the procedure carries some ethical concerns. In bypassing a stem cell phase, the new cell transformation technique doesnt have any of these ethical issues.
Keeping the original age of the converted cells can be crucial for studying neurodegenerative diseases that lead to paralysis, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy, the condition the new research focused on. In particular, researchers hope that it could enhance the understanding of these diseases in order to improve regenerative medicine.
Going back through a pluripotent stem cell phase is a bit like demolishing a house and building a new one from the ground up, Yoo explained. What were doing is more like renovation. We change the interior but leave the original structure, which retains the characteristics of the aging adult neurons that we want to study.
Like embryonic stem cells, the technique can also allow for converting human skin cells into other cell types by using different transcription factors. Before this technique can be applied to actual humans with neurodegenerative diseases, the researchers still need to find out how much the cells made in their lab match native human motor neurons. Still, its a promising start.
Posted: at 5:48 pm
Stem cells possess the unique ability to differentiate into many distinct cell types in the body, including brain cells, but they also retain the ability to produce more stem cells, a process termed self-renewal. There are multiple types of stem cell, such as embryonic stem (ES) cells, induced pluripotent stem (iPS) cells, and adult or somatic stem cells. While various types of stem cells share similar properties there are differences as well. For example, ES cells and iPS cells are able to differentiate into any type of cell, whereas adult stem cells are more restricted in their potential. The promise of all stem cells for use in future therapies is exciting, but significant technical hurdles remain that will only be overcome through years of intensive research.
NINDS supports a diverse array of research on stem cells, from studies of the basic biology of stem cells in the developing and adult mammalian brain, to studies focusing on nervous system disorders such as ALS or spinal cord injury. Other examples of NINDS funded research include using iPS cells to derive dopamine-producing neurons that might alleviate symptoms in patients with Parkinsons disease, and using ES cells to generate cerebral organoids to model Zika virus infection. To search the complete list of stem cell research projects funded by NIH please go to NIH RePORTER. The NIHs total investment in SCI can be found in categorical spending.
For information on NINDS clinical trials please see the Clinical Research section, or search ClinicalTrials.gov.
A complete, searchable list of funding opportunities is available under Funding. Please be aware that if you plan to request $500,000 or more in direct costs you must contact the appropriate Program Director at least 6 weeks before submission to obtain approval. For more information please see the eRA User Guide ($500K requests).
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Focus on Stem Cell Research | National Institute of …
Posted: at 5:48 pm
In developing fetuses, infection by the Zika virus can result in devastating neurological damage, most notably microcephaly and other brain malformations. In a new study, published today in The Journal of Experimental Medicine, researchers at the University of California San Diego School of Medicine and Washington University School of Medicine in St. Louis report the virus specifically targets and kills brain cancer stem cells.
The findings suggest the lethal power of the virus notorious for causing infected babies to be born with under-sized, misshapen heads could be directed at malignant cells in adult brains. Doing so might potentially improve survival rates for patients diagnosed with glioblastomas, the most common and aggressive form of brain cancer, with a median survival rate of just over 14 months after diagnosis.
The Zika virus specifically targets neuroprogenitor cells in fetal and adult brains. Our research shows it also selectively targets and kills cancer stem cells, which tend to be resistant to standard treatments and a big reason why glioblastomas recur after surgery and result in shorter patient survival rates, said Jeremy Rich, MD, professor of medicine at UC San Diego School of Medicine. Rich is co-senior author of the study with Michael S. Diamond, MD, PhD, professor, and Milan G. Chheda, MD, assistant professor, both at Washington University School of Medicine in St. Louis.
Transmission electron microscope image of negative-stained, Fortaleza-strain Zika virus (red), isolated from a microcephaly case in Brazil. Image courtesy of NIAID.
This year, more than 12,000 Americans will be diagnosed with glioblastomas, according to the American Brain Tumor Association. Among them: U.S. Senator John McCain, who announced his diagnosis in July. They are highly malignant. The two-year survival rate is 30 percent.
Standard treatment is aggressive: surgery, followed by chemotherapy and radiation. Yet most tumors recur within six months, fueled by a small population of glioblastoma stem cells that resist and survive treatment, continuing to divide and produce new tumor cells to replace those killed by cancer drugs.
For Zhe Zhu, MD, PhD, a postdoctoral scholar in Richs lab and first author of the study, the hyper-reproductive capabilities of glioblastoma stem cells reminded him of neuroprogenitor cells, which fuel the explosive growth of developing brains. Zika virus specifically targets and kills neuroprogenitor cells.
So Zhu, with Rich, Diamond, Chheda and other collaborators, investigated whether the Zika virus might also target and kill cultured glioblastoma stem cells derived from patients being treated for the disease. They infected cultured tumors with one of two strains of the virus. Both strains spread through the tumors, infecting and killing stem cells while largely avoiding other tumor cells.
The findings, the authors said, suggest that chemotherapy-radiation treatment and a Zika infection appear to produce complementary results. Standard treatment kills most tumor cells but typically leaves stem cells intact. The Zika virus attacks stem cells but bypasses ordinary tumor cells.
We see Zika one day being used in combination with current therapies to eradicate the whole tumor, said Chheda, an assistant professor of medicine and of neurology at Washington University School of Medicine.
To find out whether the virus could boost treatment efficacy in a live animal, researchers injected either the Zika virus or a saltwater placebo directly into glioblastoma tumors in 18 and 15 mice, respectively. Two weeks after injection, tumors were significantly smaller in the Zika-treated mice, who survived significantly longer than those given the placebo.
The scientists note that the idea of injecting a virus notorious for causing brain damage into patients brains seems alarming, but they say Zika may prove a safe therapy with further testing because its primary target neuroprogenitor cells are rare in adult brains. The opposite is true of fetal brains, which is part of the reason why a Zika infection before birth produces widespread and severe brain damage while a normal Zika infection in adults typically causes mild symptoms or none at all.
The researchers also conducted studies of the virus using brain tissue from epilepsy patients that showed the virus does not infect non-cancerous brain cells.
As an additional safety feature, the research team introduced two mutations that weakened the viruss ability to combat natural cellular defenses against infection, reasoning that while the mutated virus would still be able to grow in tumor cells, which have a poor anti-viral defense system, it would be quickly eliminated in healthy cells with a robust anti-viral response.
When they tested the mutated viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.
Were going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading, said Diamond, a professor of molecular microbiology, pathology and immunology. Once we add a couple more, I think its going to be impossible for the virus to overcome them and cause disease.
Co-authors of the study include: Matthew Gorman, Estefania Fernandez, Lisa McKenzie, Jiani Chai, Justin M. Richner, and Rong Zhang, Washington University, St. Louis; Christopher Hubert, and Briana Prager, Cleveland Clinic; Chao Shan, and Pei-Yong Shi, University of Texas Medical Branch; and Xiuxing Wang, UC San Diego.
Funding for this research came, in part, from the National Institutes of Health (R01 AI073755, R01 AI104972, CA197718, CA154130, CA169117, CA171652, NS087913, NS089272), the Pardee Foundation, the Concern Foundation, the Cancer Research Foundation and the McDonnell Center for Cellular and Molecular Neurobiology of Washington University.
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Zika Virus Targets and Kills Brain Cancer Stem Cells – UC San Diego Health
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Professor Che Connon and Dr Stephen Swioklo of Atelerix, a spin-out from Newcastle University, is offering the transformative hydrogel technology for the storage and transport of viable cells including stem cells and cell-based assays at ambient temperatures. Credit: Newcastle University
Atelerix, a spin-out from Newcastle University, UK is offering the transformative hydrogel technology for the storage and transport of viable cells including stem cells and cell-based assays at ambient temperatures. This overcomes the barriers presented by the current need for cryo-shipping as it is simple, cell-friendly and offers immediate access to stem cell therapy.
This opens up the market for the supply of cells and assays in a ready-to-use format, allowing suppliers to increase the range of assays available to consumers and to scale up their businesses.
The breakthrough, patented invention, provides dramatic improvements to an everyday process in a rapidly growing market.
Scientific founder, Professor Che Connon of Newcastle University, has been working on the underpinning technology for five years. He said: “Encapsulating cells in the alginate hydrogel is a simple, low cost system capable of preserving the viability and functionality of cells at temperatures between 4 and 21C for extended periods of time.
“Used as a method of cell storage and transport, it overcomes the acknowledged problems associated with cryo-shipping. Cells are encapsulated by in situ formation of the gel for shipping in plates or vials, and can be rapidly released from the gel by the addition of a simple buffer.”
Atelerix is set to revolutionise the market with their use of encapsulated stem cells as Dr Mick McLean, CEO for Atelerix explained: “Understanding both the technology and its commercial potential is essential for the translation of great science into an exciting business opportunity.
“Putting these elements in place by working together with the expert scientific team means that Atelerix has a clear value proposition – we enable the transport and storage of human cells at room temperature.”
The hydrogel technology allows immediate access to cells and can be used in a range of applications where high quality cells are essential.
The shipping of cells from one location to another for clinical and research use is a widespread and everyday practice, and consequently there are many potential commercial outlets for the hydrogel encapsulation technology.
Atelerix, the commercial spin-out from Newcastle University is targeting three key areas:
First Northern Accelerator spin-out company
Atelerix, is the first spin out company created under a new joint collaborative project between Newcastle and Durham Universities, UK.
The Northern Accelerator project, which is part-funded by the European Regional Development Fund (ERDF), is creating high technology spin-out companies by attracting talented business leaders to the innovative commercial opportunities both created and developed in the north east of England.
Through this, experienced life sciences business leader Mick McLean was brought in to work alongside the founder academics, Professor Che Connon and Dr Stephen Swioklo.
Dr McLean said: “Working alongside the University team on the strategy for the Intellectual Property and the corporate framework has really helped give the business a base from which to expand as it starts to move on from its academic roots.”
David Huntley, Head of Company Creation at Newcastle University and overall Project Manager, said: “Atelerix is an excellent example of the clear benefits of the Northern Accelerator programme. By combining Mick’s business skills with the technical excellence of the scientific team’s world-leading background research, we have created a brand new technology business that we believe will make a real and significant commercial impact.”
Explore further: Seaweed offers the solution to transporting stem cells and wound treatment
More information: Previous research: Stephen Swioklo et al. Alginate-Encapsulation for the Improved Hypothermic Preservation of Human Adipose-Derived Stem Cells, STEM CELLS Translational Medicine (2016). DOI: 10.5966/sctm.2015-0131
Posted: at 5:48 pm
Italian Minister for Education, University, and Research Valeria Fedeli
AP Photo/Luca Bruno
By Marta PaterliniSep. 7, 2017 , 4:50 PM
Plagued by budget cuts and attacks on science, Italian scientists have had little to cheer about recently. But on Sunday, they received a welcome surprise when Valeria Fedeli, the minister for education, university, and research, announced that Italy will put an extra 400 million into its main basic science fund, the Research Projects of National Interest (PRIN). The money, to be spent over 3 years, will more than quadruple PRINs annual funding.
The biggest part of the increase, 250 million, will come out of unused reserves at the Italian Institute of Technology (IIT), a government-funded private foundation in Genoa that has recently come under criticism.
This is the largest investment in competitive funds for basic research of the last 20 years, says Elena Cattaneo, a stem cell biologist at the University of Milan and a senator for life in the Italian Parliament who had lobbied for the shift to basic science. PRIN funding has been going up and down since 2002, according to a group of academics calling itselfReturn On Academic ReSearch (ROARS), but overall has been modest. The latest funding round, in 2015, provided only 95 million for 3years.
Cattaneo had argued that IIT, founded in 2003 to foster innovation, could easily cough up the funds for a hike at PRIN. Scientists have criticized IIT for a lack of transparency in the way it allocates its fundingcurrently some 98 million annually from the Ministry of Economy and Financeand for its role in the creation of a new research hub at the site of the World Expo 2015 in Milan. Cattaneo has also been very vocal about the accumulation of hundreds of millions in public money in a private body.By reallocating the funds, the government has acknowledged the value of basic research, she says.
IITs scientific director, Roberto Cingolani, says the institutes large surplus is primarily the result of savings during its early years. Three years ago, we started to plan an expansion of the institute in Genoa, that would have cost about 200 million, he saysa plan that is now off the table. Cingolani says he is disappointed by the criticisms of IIT, but glad that the cut there will benefit basic research.
ROARS member Alberto Baccini, a professor of political economics at the University of Siena, applauds the decision as well and credits Cattaneo. We must acknowledge [her] crusade, he says.
A spokesperson for the research ministry could not provide details today about how the money will be spent. Its important that the process uses uniform assessment criteria and is transparent, Baccini says. (He notes that its impossible to find the projects awarded under the 2015 funding bolus for PRIN online.) The problem is not just the lack of money, but also that funding is handed out without a method, really, he says.
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Italian scientists welcome surprise 400 million boost for basic research – Science Magazine
Posted: August 29, 2017 at 7:44 am
Adult stem cells can be extracted from human fat. Patrick T. Fallon /The Washington Post/Getty Images hide caption
Adult stem cells can be extracted from human fat.
The Food and Drug Administration is cracking down on “unscrupulous” clinics selling unproven and potentially dangerous treatments involving stem cells.
Hundreds of clinics around the country have started selling stem cell therapies that supposedly use stem cells but have not been approved as safe and effective by the FDA, according to the agency.
“There are a small number of unscrupulous actors who have seized on the clinical promise of regenerative medicine, while exploiting the uncertainty, in order to make deceptive, and sometimes corrupt assurances to patients based on unproven and, in some cases, dangerously dubious products,” FDA Commissioner Scott Gottlieb said in a statement Monday.
The FDA has taken action against clinics in California and Florida.
The agency sent a warning letter to the US Stem Cell Clinic of Sunrise, Fla., and its chief scientific officer, Kristin Comella, for “marketing stem cell products without FDA approval and significant deviations from current good manufacturing practice requirements.”
The clinic is one of many around the country that claim to use stem cells derived from a person’s own fat to treat a variety of conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and lung and heart diseases, the FDA says.
The Florida clinic had been previously linked to several cases of blindness caused by attempts to use fat stem cells to treat macular degeneration.
The FDA also said it has taken “decisive action” to “prevent the use of a potentially dangerous and unproven treatment” offered by StemImmune Inc. of San Diego, Calif., and administered to patients at California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, Calif.
As part of that action, the U.S. Marshals Service seized five vials of live vaccinia virus vaccine that is supposed to be reserved for people at high risk for smallpox but was being used as part of a stem-cell treatment for cancer, according to the FDA. “The unproven and potentially dangerous treatment was being injected intravenously and directly into patients’ tumors,” according to an FDA statement.
Smallpox essentially has been eradicated from the planet, but samples are kept in reserve in the U.S. and Russia, and vaccines are kept on hand as a result.
But Elliot Lander, medical director of the California Stem Cell Treatment Centers, denounced the FDA’s actions in an interview with Shots.
“I think it’s egregious,” Lander says. “I think they made a mistake. I’m really baffled by this.”
While his clinics do charge some patients for treatments that use stem cells derived from fat, Lander says, none of the cancer patients were charged and the treatments were administered as part of a carefully designed research study.
“Nobody was charged a single penny,” Lander says. “We’re just trying to move the field forward.”
In a written statement, U.S. Stem Cell also defended its activities.
“The safety and health of our patients are our number one priority and the strict standards that we have in place follow the laws of the Food and Drug Administration,” according to the statement.
“We have helped thousands of patients harness their own healing potential,” the statement says. “It would be a mistake to limit these therapies from patients who need them when we are adhering to top industry standards.”
But stem-cell researchers praised the FDA’s actions.
“This is spectacular,” says George Daley, dean of the Harvard Medical School and a leading stem-cell researcher. “This is the right thing to do.”
Daley praised the FDA’s promise to provide clear guidance soon for vetting legitimate stem-cell therapies while cracking down on “snake-oil salesmen” marketing unproven treatments.
Stem-cell research is “a major revolution in medicine. It’s bound to ultimately deliver cures,” Daley says. “But it’s so early in the field,” he adds. “Unfortunately, there are unscrupulous practitioners and clinics that are marketing therapies to patients, often at great expense, that haven’t been proven to work and may be unsafe.”
“I see this is a major, positive step by the FDA,” says Paul Knoepfler, a professor of cell biology at the University of of California, Davis, who has documented the proliferation of stem-cell clinics.
“I’m hoping that this signals a historic shift by the FDA to tackle the big problem of stem-cell clinics selling unapproved and sometimes dangerous stem cell “treatments” that may not be real treatments,” Knoepfler says.
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FDA Cracks Down On Stem-Cell Clinics Selling Unapproved Treatments – NPR
Posted: at 7:44 am
Representative imageBy Priyanka V Gupta
New Delhi: Indian Council of Medical Research (ICMR) will soon release the final document on guidelines for stem cell research, the draft of which was available on the ICMR and the DBT (Department of Biotechnology) websites for public reviews till July 31 this year. The guidelines are expected to help in curbing the unethical practices in regenerative medicine. The information was shared by Dr Geeta Jotwani, deputy director general, ICMR, at a recent event where MoU was signed between ABLE (Association of Biotechnology Led Enterprise) and FIRM (Forum for Innovative Regenerative Medicine) for industry research collaborations.
Dr Jotwani said, On the directives of DCGI (Drug Controller General of India), ICMR has been framing the guidelines for stem cell research and therapy since 2001. Unfortunately, there is no therapy available other than bone marrow transplantation, for which also no standard of care has been laid out. In that direction, we have been making periodic efforts by releasing the guideline documents in 2002, 2007, 2013 and now the updated documentation for 2017 is under finalization.
ICMR has been proactively working towards educating the stakeholders about the ethical practices in stem cell research and therapy, for which a special committee, called National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT), has been formed to advise the scientists community. Regenerative medicine is an innovative science. As part of ICMR, more research is involved than getting into conclusion that we are ready for application. We are proactively making efforts to educate, create awareness and give directions to our scientists community and clinicians on how they should go about the research part of stem cell therapy, said Dr Jotwani.
There are many clinicians entering into unethical practices and promising general public about the available care in almost all sorts of incurable conditions, including autism, according to Dr Jotwani.
She said, We are always concerned about what the end users are getting and the promises that are being made to them. Hence, we are proactively being involved in interacting with different government agencies as well as the industry to curb the unethical practices for which we also established NAC-SCRT under the Department of Health Research, Government of India. The committee, which comprises of different government agencies as well as ethics and social groups, legal experts, representatives of drug controllers office and CDSCO (Central Drug Standard Control Organization), deliberates on the issues of upcoming technologies and takes proactive role in the regenerative medicine.
Bone Marrow Protein May Be Target for Improving Stem Cell Transplants – Penn: Office of University Communications
Posted: at 7:44 am
Bone marrow contains hematopoetic stem cells, the precursors to every blood cell type. These cells spring into action following bone marrow transplants, bone marrow injury and during systemic infection, creating new blood cells, including immune cells, in a process known as hematopoiesis.
A new study led by University of Pennsylvania and Technical University of Dresden scientists has identified an important regulator of this process, a protein called Del-1. Targeting it, the researchers noted, could be an effective way to improve stem cell transplants for both donors and recipients. There may also be ways to modulate levels of Del-1 in patients with certain blood cancers to enhance immune cell production. The findings are reported this week in The Journal of Clinical Investigation.
Because the hematopoetic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications, said George Hajishengallis, the Thomas W. Evans Centennial Professor in the Department of Microbiology in Penns School of Dental Medicine and a senior author on the work.
I think that Del-1 represents a major regulator of the hematopoetic stem cell niche, said Triantafyllos Chavakis, co-senior author on the study and a professor at the Technical University of Dresden. It will be worthwhile to study its expression in the context of hematopoetic malignancy.
For Hajishengallis, the route to studying Del-1 in the bone marrow began in his field of dental medicine. Working with Chavakis, he had identified Del-1 as a potential drug target for gum disease after finding that it prevents inflammatory cells from moving into the gums.
Both scientists and their labs had discovered that Del-1 was also expressed in the bone marrow and began following up to see what its function was there.
In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes [white blood cells] from the marrow into the periphery, Hajishengallis said, something analogous to what it was doing in the gingiva. But it turned out it had a much more important and global role than what I had imagined.
The researchers investigations revealed that Del-1 was expressed by at least three cell types in the bone marrow that support hematopoetic stem cells: endothelial cells, CAR cells and osteoblasts. Using mice deficient in Del-1, they found that the protein promotes proliferation and differentiation of hematopoetic stem cells, sending more of these progenitor cells down a path toward becoming myeloid cells, such as macrophages and neutrophils, rather than lymphocytes, such as T cells and B cells.
In bone marrow transplant experiments, the team discovered that the presence of Del-1 in recipient bone marrow is required for the transplanted stem cells to engraft in the recipient and to facilitate the process of myelopoesis, the production of myeloid cells.
When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to those with normal Del-1 levels.
We saw roles for Del-1 in both steady state and emergency conditions, Hajishengallis said.
Hajishengallis, Chavakis and their colleagues identified the protein on hematopoetic stem cells with which Del-1 interacts, the 3 integrin, perhaps pointing to a target for therapeutic interventions down the line.
The scientists see potential applications in bone marrow and stem cell transplants, for both donors and recipients. In donors, blocking the interaction between Del-1 and hematopoetic stem cells could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation. Transplant recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.
In addition, people undergoing chemotherapy who develop febrile neutropenia, associated with low levels of white blood cells, might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.
Its easy to think of practical applications for these findings, said Hajishengallis. Now we need to find out whether it works in practice, so our studies continue.
Ioannis Mitroulis, Lan-Sun Chen and Rashim Pal Singh of TU-Dresden were co-lead authors on the study, and Ben Wielockx of TU-Dresden was a co-senior author along with Hajishengallis and Chavakis. They were joined by coauthors Tetsuhiro Kajikawa, Kavita Hosur, Tomoki Maekawa and Baomei Wang of Penn Dental Medicine; Ioannis Kourtzelis, Matina Economopoulou, Maria Troullinaki, Athanasios Ziogas, Klara Ruppova, Pallavi Subramanian, Panayotis Verginis, Malte Wobus, Martin Bornhuser and Tatyana Grinenko of TU-Dresden; Torsten Tonn of the German Red Cross Blood Donation Service in Dresden; and Marianna Di Scala and Andrs Hidalgo of the Spanish National Center for Cardiovascular Research.
The study was supported by the Deutsche Forschungsgemeinschaft, European Commission, European Research Council and National Institutes of Health (grants AI068730, DE024153, DE024716, DE0152 54 and DE026152).
It’s Not a Rat’s Race for Human Stem Cells Grafted to Repair Spinal Cord Injuries – UC San Diego Health
Posted: at 7:44 am
More than one-and-a-half years after implantation, researchers at University of California San Diego School of Medicine and the San Diego Veterans Administration Medical Center report that human neural stem cells (NSCs) grafted into spinal cord injuries in laboratory rats displayed continued growth and maturity, with functional recovery beginning one year after grafting.
The findings are published in the September issue of the Journal of Clinical Investigation.
The NSCs retained an intrinsic human rate of maturation despite being placed in a traumatic rodent environment, said Paul Lu, PhD, associate professor of neurosciences and lead author of the study. Thats a finding of great importance in planning for human clinical trials.
Neural stem cells differentiate into neurons and glia or support cells. Researchers like Lu and colleague, Mark Tuszynski, MD, PhD, professor of neuroscience and director of the UC San Diego Translational Neuroscience Institute, have explored their potential as a sort of patch and remedy for spinal cord injuries, implanting NSCs derived from induced pluripotent stem cells into animal models of spinal cord injuries to repair damage. In previously published animal studies, Lu and Tuszynski have shown NSCs can survive implantation and make new connections, even beginning to restore limited physical function, such as foot movement, that had been lost to paralyzing injury.
But major questions remained: At what rate do the NSCs mature? And for how long? Rat biology works at a much faster pace than human. The gestational period for a human is 280 days; for a rat, its 21. The brain of a 2- or 3-year-old human child is comparable in body/brain weight ratios to a 20-day-old rat. It was possible that human NSCs in animal models would not accurately reflect functioning in future human patients.
Most NSC grafting studies have been short-term, measuring survival times in weeks to a few months, said Tuszynski. Thats not enough time to fully measure the growth and maturation rate of human NSCs or what changes might occur farther out from the original grafting. These are important considerations, not just for the basic science of stem cell biology, but for the practical design of translational human trials using NSCs for spinal cord injuries. We need to better understand the long-term nature and time course so that we can accurately assess results and success.
Lu and colleagues used the widely available, well-characterized H9 human NSC line derived from human embryonic stem cells. The H9 NSCs were modified to express green fluorescent protein and embedded in fibrin matrices containing a growth factor cocktail. The matrices were then transplanted into spinal cord lesions of immunodeficient rats two weeks after injury, which had impaired functioning of the forelimb. Control rats underwent a similar process, but without the NSCs.
The scientists then monitored growth and development of the implanted grafts over time, noting significant early, unrefined growth followed by the appearance of markers indicating maturing nerve cells after several months. As the grafts aged, the cells continued to display gradual, normal development processes, including natural pruning and redistribution to focus development on fewer but more mature cells.
To our surprise, we found evidence of continued stem cell maturation throughout the period, said Lu. It was clear that these neural stem cells retained their intrinsic maturation programs despite a prolonged presence in a challenging environment. The recovery of forelimb function in the rats supports the basic therapeutic idea, but importantly, improvement occurred only after mature cell markers of both neuronal and glial lineages were expressed.
The lengthy study reported other findings of note: Implanted NSCs did not migrate from their lesion sites, but supportive astrocytes did, a potential safety concern. However, the scientists did not observe any adverse effects from glial outgrowth, such as tumor formation or deterioration of forelimb function over time. Tuszynski said modified grafting procedures could minimize cell leakage.
The bottom line is that clinical outcome measures for future trials need to be focused on long time points after grafting, said Tuszynski. Reliance on short time points for primary outcome measures may produce misleadingly negative interpretation of results. We need to take into account the prolonged developmental biology of neural stem cells. Success, it would seem, will take time.
Co-authors of this study are: Steven Ceto, Yaozhi Wang, Lori Graham, Di Wu, Hiromi Kumamaru, and Eileen Staufenberg, all at UC San Diego.
Funding for this research came, in part, from the Veterans Administration, the National Institutes of Health (NS09881, EB014986), the Craig H. Neilsen Foundation, the California Institute for Regenerative Medicine, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Bernard and Anne Spitzer Charitable Trust.