Repair Of DNA By Brca2 Gene Prevents Medulloblastoma

Investigators at St. Jude Children's Research Hospital have gained some of the first major insights into how certain genes known to prevent cancer also guide the normal development of the nervous system before birth and during infancy by repairing DNA damage.


The St. Jude researchers demonstrated that the Brca2 gene plays a dual role in the developing nervous system, eliminating errors in the DNA of newly made copies of chromosomes and suppressing the onset of the brain cancer medulloblastoma. Medulloblastoma is a cancer of the cerebellum the lower back part of the brain that controls complex motor functions and communicates with other parts of the brain. This cancer accounts for about 20 percent of childhood brain tumors, about half of which occur in children younger than six years.


The role of Brca2 is important because as the cerebellum grows in size and complexity before and shortly after birth, it rapidly produces many new nerve cells.


"Our study showed that the Brca2 gene acts as a surveillance mechanism that triggers repair of DNA that is damaged when the cell makes a duplicate set of its chromosomes each time it divides," said Peter McKinnon, Ph.D., associate member of the Genetics and Tumor Cell Biology department at St. Jude. "The enormous rate of cell divisions during growth of the cerebellum greatly increases the risk of DNA damage. So the cell must have a way to ensure that the damage is quickly repaired to prevent the accumulation of abnormal cells that can cause abnormalities, such as medulloblastoma." McKinnon is senior author of a report on this work in the advanced online version of The EMBO Journal (doi: 10.1038/sj.emboj.7601703).


When researchers eliminated Brca2 from the developing nervous system in mice, the loss of this gene led to widespread apoptosis, or cell suicide, triggered by the cell's inability to repair DNA damage. This reduced the size of the cerebellum, led to malformation in the shape of the brain and disrupted the movement of certain nerves cells that normally migrate through the cerebellum during development. When the team blocked cell suicide by eliminating both copies of p53, a gene needed to trigger apoptosis, the brain developed its normal size, but most of the mice developed medulloblastoma.


The study also gave the St. Jude researchers insights into a childhood disease called Fanconi anemia, which is caused by a mutation in the human version Brca2. Children with Fanconi anemia are at increased risk for tumors and small brain size, among other problems. In the current study, the St. Jude team showed that mice lacking Brca2 had neurologic defects similar to those of humans with Fanconi anemia who carry the mutated gene. Specifically, the loss of Brca2 led to defective DNA repair and the accumulation of mutations in the so-called progenitor cells that give rise to many regions of the nervous system. This resulted in small brain size due to apoptosis of the abnormal cells.















These findings showed that the mouse model closely copied the human characteristics of Fanconi anemia and could become a valuable tool for studying the cause and treatment of this disease.


Researchers also discovered that another gene, ATM, plays a secondary but important role in protecting the developing nervous system by triggering apoptosis in cells that have stopped dividing but still contain DNA damage. ATM prevents these abnormal cells, called granule precursors, from becoming incorporated into the developing cerebellum. In this way, ATM plays a backup role in further ensuring normal gene function after the period of rapid growth is complete.


The St. Jude team demonstrated the role of Brca2 in the developing mouse nervous system using a laboratory technique called conditional gene inactivation. This process eliminated the gene from the nervous system, but left it intact in the rest of the body. The use of this technique was important because previous studies showed that mouse embryos cannot develop when the gene is absent from all the cells of the body. The team observed how the specific loss of Brca2 activity from the nervous system affected its embryonic and postnatal development. The finding helps explain how rapidly dividing cells in the developing cerebellum identify and repair errors in the DNA that occur during the duplication of chromosomes before cell division occurs.


"Our work is a significant step in understanding the interplay of genes linked to DNA repair and their role in preventing disease," said Pierre-Olivier Frappart, Ph.D., a postdoctoral researcher in McKinnon's laboratory, who did much of the work on this project. "As more mouse models lacking specific genes in certain tissues become available, we'll be able to further determine the relationships among various DNA repair pathways during the development of the nervous system."


Other authors of the report include Youngsoo Lee and Jayne Lamont (St. Jude).


This work was supported in part by the National Institutes of Health, a Cancer Center Support Grant and ALSAC.

Wide Range Of Tissue Types Produced Using Stem Cells Derived From Adult Testes

After a decade of research, Howard Hughes Medical Institute scientists have succeeded in reprogramming adult stem cells from the testes of male mice into functional blood vessels and contractile cardiac tissue. The research offers a promising new source of stem cells for use in organ regeneration studies.



Some scientists think that organ-specific adult stem cells may offer the same therapeutic potential as embryonic stem cells, without the ethical concerns or the risk of immune rejection that are associated with embryonic stem cell therapies. However, adult stem cells may lack the plasticity and pluripotency of embryonic stem cells' capacity to generate any cell type. The study of adult stem cells has also been limited by their relative scarcity in various organs and the attendant difficulties in identifying and harvesting them, as well as differentiating them in large quantities into functional vascularized tissues.



HHMI investigator Shahin Rafii and his colleagues at Weill Cornell Medical College appear to have solved some of these problems in male mice. Using spermatogonial progenitor cells obtained from the mouse's testes, the researchers reprogrammed the cells to form multipotent adult spermatogonial-derived stem cells. If the same can be done with human cells, they say, adult stem cells may be a promising source of new therapies for men, for diseases such as vascular diseases, heart disease, Alzheimer's, Parkinson's, stroke, diabetes, and even cancer.



Scientists have had good success in deriving pluripotent stem cell lines -- those with the ability to develop into multiple cell types -- from adult testes cells. But only a small subset of cells from the testes has the potential to become pluripotent, and until now, investigators have lacked a means to identify and isolate them.



In a paper published online in the journal Nature, Rafii and colleagues at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center report that they have identified a novel cell surface marker that is expressed on a unique set of cells within adult testes known as the spermatogonial stem and progenitor cells (SPCs). The marker, GPR125, enabled the scientists to identify and harvest a large number of SPCs from adult mouse testes, then propagate and reprogram them in the lab to become stem cells that could differentiate into many cell types.



The researchers demonstrated that these multipotent adult spermatogonial-derived stem cells (MASCs) could develop in vivo into working blood vessel (endothelial) cells and tissue, as well as contractile cardiac tissue, brain cells, and a host of other cell types. They also injected MASCs from culture into mouse blastocysts -- embryonic cells -- that they implanted in mature female mice. When the blastocysts developed into mice, the researchers could see that the MASCs had differentiated into many kinds of tissue. These data suggested that the MASCs are truly multipotent: reprogrammable to differentiate into functional tissues.
















Ten years ago, Rafii observed that human testicular cancer cells share many characteristics with adult stem cells. As an oncologist, he also noticed that a large number of patients with testicular cancer develop tumors called teratomas, which contain different types of tissue. Based on these observations, he reasoned that spermatogonia, whose sole function is to generate the precursors to sperm, have the potential to readily give rise to pluripotent cells. As such, he thought, they might prove more amenable to reprogramming than other adult stem cells.



Using gene screening studies, Rafii and colleagues discovered a potential specific surface marker on SPCs. Comparison of all cells in the adult testis showed that this G-protein coupled receptor, known as GPR125, was expressed on SPCs, but not other mature germ cells. With GPR125 in hand, Rafii could isolate large numbers of SPCs from adult mouse testes.



They also established a highly sophisticated culture system in which the progenitor cells rapidly grow and divide, creating a large population of cells that can be converted into MASCs.



"It appears that these specialized GPR125-positive spermatogonial cells could be an easily obtained and manipulated source of stem cells with a similar capability to form new tissues that we see in embryonic stem cells," said Rafii. For male patients, he believes, "It could someday mean a readily available source of stem cells that gets around ethical issues linked to embryonic stem cells. It also avoids issues linked to tissue transplant rejection, since these autologous cells come from the patient's own body."



Rafii's team is currently pursuing a similar study of human testes to determine whether stem cells derived from their spermatogonial progenitor cells share the pluripotency of the mouse MASCs. "We believe this to be an easily obtainable goal in the near future," he said.



If they succeed, several steps remain before such stem cells could be applicable to humans. "We still have to learn the exact biochemical and epigenetic 'switch' that tells GPR125-positive SPCs to convert into MASCs," said Marco Seandel, a senior post-doctoral fellow in Rafii's laboratory who is the first author of the Nature paper. "Discovering that switch will be crucial to our being able to create MASCs on demand,"



There is a chance that implanted cells derived from MASCs may trigger cancer in the recipient. This is an area that requires further investigation, Rafii said. However, he noted, "So far, we haven't seen any cancer or evidence of pro-cancerous activity in adult mice that are implanted with differentiated MASC cell tissue derivatives."



Rafii and his team have worked out the growing conditions that coax spermatogonial progenitor cells to develop into MASC germ lines -- genetically stable stem cells that continue reproducing indefinitely. Stem cell studies have been limited to date by the scarcity of germ cell lines. "None of these GPR125-positive germ cell lines was previously readily available for genetic, biochemical, and cellular analysis by other laboratories," says Rafii. "We intend to share them with other researchers."



Rafii's lab is now investigating whether GPR125 can be used to isolate cells from other adult tissues that can be converted into multipotent stem cells. His group has also begun pursuing a similar effort in ovaries. "It's much more difficult," he said. "However, it is possible that reprogrammable stem cells with similar properties to GPR125-positive SPCs may also exist, although at very low numbers, in adult mouse or human ovaries." His lab is actively investigating this intriguing possibility, Rafii said.







Source: Jim Keeley


Howard Hughes Medical Institute

Diabetic Women At Increased Risk Of Vascular Disease

Diabetes is associated with the development of vascular (blood vessel) disease. As we age, vascular disease becomes more common. It has been thought that females may be more susceptible to the earlier development of vascular disease, as vascular changes are observed in females long before any significant development occurs in males. Now, a team of Georgetown University researchers has determined that the vascular activities in diabetic animals vary according to sex. This discovery may eventually have implications for the way males and females are treated medically in the future.



The Study



The study, entitled "Sex Differences in Response to Vasoactive Substances in Early Uncontrolled Diabetes," was conducted by Adam Mitchell, Adam Myers and Susan Mulroney, all of the Department of Physiology and Biophysics, Georgetown University, Washington, DC. Mr. Mitchell presented the status of the team's findings at the conference, Sex and Gender in Cardiovascular-Renal Physiology and Pathophysiology. The meeting was sponsored by the American Physiological Society (APS; the-aps/).



The Study



The researchers examined the notion that very early changes in artery activity exists in diabetic animals and differ by sex. To test their hypothesis they divided adult male and female rats into three groups. The first group (control) received no treatment. The second group received streptozotocin (STZ) to induce diabetes. The third group received STZ plus growth hormone (GH), which is thought to exacerbate disease progression in diabetes.



After eight weeks, the vascular reactivity to phenylephrine, which increases blood pressure, and acetylcholine, which reduces blood pressure, was measured in the vessels from the animals. Vascular response to these substances was also observed during exposure to L-NAME (which blocks production of nitric oxide, a potent artery relaxer) and neuropeptide Y (which augments the restriction of blood vessels).



The investigators found that:



* in the early stage of the disease, both male and female diabetics experienced significant decreases in the reactivity (i.e., how responsive the vessel is to a drug) of their blood vessels when exposed to acetylcholine. This occurred independent of the GH injections.



* while female diabetic rats had an increased response to phenylephrine, there was no such change among their male counterparts.



* female controls had a larger change in phenyleprine reactivity in the presence of L-NAME than did diabetic females, indicating that the diabetic females had a reduced level of nitric oxide, which dilates the artery and increases blood flow.



* diabetic males had the opposite reaction of diabetic females when exposed to phenylephrine and L-NAME. The diabetic males also produced more nitric oxide than did their controls.



* all diabetic rats exposed to growth hormone showed an increase in nitric oxide, regardless of gender.



Conclusions



The findings support the researchers' hypothesis of the existence of sex-related changes in vascular activity in diabetic animals. While the production of NO is significantly altered in the diabetic rats, the results show that gender and the presence of GH greatly contribute to this vascular dysfunction. According to Mitchell, "These findings show the importance of sex differences to understanding development of vascular problems early in diabetes and has implications on potential sex-specific therapeutic intervention."







The American Physiological Society (APS; the-aps/) has been an integral part of the scientific discovery process since it was established in 1887. Physiology is the study of how molecules, cells, tissues and organs function to create health or disease.



Source: Donna Krupa


American Physiological Society

Missing Molecules Hold Promise Of Therapy For Pancreatic Cancer

By determining what goes missing in human cells when the gene that is most commonly mutated in pancreatic cancer gets turned on, Johns Hopkins scientists have discovered a potential strategy for therapy.


The production of a particular cluster of genetic snippets known as microRNAs is dramatically reduced in human pancreatic tumor cells compared to healthy tissue, the researchers report in a study published Dec. 15 in Genes and Development. When the team restored this tiny regulator, called miR-143/145, back to normal levels in human pancreatic cancer cells, those cells lost their ability to form tumors.


"Our finding that these specific microRNAs are downstream of the most important oncogene in pancreatic cancer sets the stage for developing methods to deliver them to tumors," says Josh Mendell, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and an early career scientist of the Howard Hughes Medical Institute. "When we restore microRNAs to cancer cells in which their levels are repressed, the cells no longer are tumorigenic. We have every reason to believe that the efficient delivery of miR-143/145, if achievable, would be therapeutically beneficial."


The team focused its investigation on KRAS, a member of the important RAS family of oncogenes that is mutated in almost all cases of the most common form of pancreatic cancer.


The researchers conducted their studies in a multitude of model systems human cells growing in culture as well as those harvested directly from tumors, and also in mice and zebrafish. First, using cell lines derived from pancreatic tumors and growing in culture, they added gene products such as mutant KRAS and an inhibitor of mutant KRAS, and then measured the microRNA responses. Next, they conducted the same experiments using cells from patients' pancreatic tumors. Finally, they looked at pancreatic tissue from mice and zebrafish to see what happened when KRAS was activated.


Every time, the team noted the same robust findings. When KRAS was activated, the microRNA cluster miR-143/145 was powerfully repressed, to a fraction of the levels in normal, non-cancerous cells. Restoring the expression of miR-143/145 back to the level of normal cells was sufficient to confer "a very striking change in behavior of those cells," Mendell says. When human pancreatic cancer cells with low microRNA levels were injected into mice, they formed tumors within 30 days. However, when the team restored the levels of microRNAs to the levels of normal cells and injected them into mice, tumors failed to form.


"Our findings showed that repression of the miR-143/145 microRNA cluster is a very important component of the tumor-promoting cellular program that is activated when KRAS is mutated in cancer cells," says Oliver Kent, a postdoctoral fellow in the Mendell laboratory and first author on the paper.















At some point in the process of a normal cell evolving into a tumor cell, it loses microRNAs. When the KRAS gene is mutated a common event in pancreatic cancer it somehow purges cells of miR-143/145, the cluster of microRNAs that normally put the brakes on tumorigenesis.


"It is likely that some microRNAs will have very broad antitumorigenic effects in many different types of cancers," says Mendell, whose lab is building animal models to investigate how different microRNAs participate in different tumor types. "In fact, there is already evidence that miR-143/145 can suppress other types of tumors such as colon and prostate cancer. On the other hand, the effects of some microRNAs will likely be very tumor-specific."


Merely 22 nucleotides in length, microRNAs are enigmatic bits of genetic material that, despite being pint-sized, apparently are mighty. This field of study is less than a decade old; scientists still don't have a good grasp on the fundamental role of microRNAs in normal biology.


"We need a better understanding of their basic functions to more fully understand how microRNAs participate in diseases," Mendell says.


Having studied microRNAs in the context of several types of cancer, Mendell says delivery remains a major issue for nucleic acid-based therapies.


"There is a lot of work going on to develop ways to deliver microRNAs to different tissue sites," Mendell says. "I'm optimistic that the liver and even the pancreas will become accessible to these types of therapies and benefit from them."


In addition to Joshua Mendell and Oliver Kent, authors of the paper are Raghu R. Chivukula, Michael Mullendore, Erik A. Wentzel, Georg Feldmann, Kwang H. Lee, Shu Liu, Steven D. Leach and Anirban Maitra, all of Johns Hopkins.


The research was supported by the Howard Hughes Medical Institute, the Lustgarten Foundation for Pancreatic Research, the Sol Goldman Center for Pancreatic Cancer Research, the Michael Rolfe Foundation for Pancreatic Research and the National Institutes of Health.


Source: Johns Hopkins Medicine

Rare Tumor Cells In Bloodstream Can Now Be Detected By Microchip-Based Device

A team of investigators from the Massachusetts General Hospital (MGH) Biomicroelectromechanical Systems (BioMEMS) Resource Center and the MGH Cancer Center has developed a microchip-based device that can isolate, enumerate and analyze circulating tumor cells (CTCs) from a blood sample. CTCs are viable cells from solid tumors carried in the bloodstream at a level of one in a billion cell. Because of their rarity and fragility, it has not been possible to get information from CTCs that could help clinical decision-making, but the new device - called the "CTC-chip,"- has the potential to be an invaluable tool for monitoring and guiding cancer treatment.



"This use of nanofluidics to find such rare cells is revolutionary, the first application of this technology to a broad, clinically important problem," says Daniel Haber, MD, director of the MGH Cancer Center and a co-author of the report in the December 20 issue of Nature. "While much work remains to be done, this approach raises the possibility of rapidly and noninvasively monitoring tumor response to treatment, allowing changes if the treatment is not effective, and the potential of early detection screening in people at increased risk for cancer."



The existence of CTCs has been known since the mid-19th century, but since they are so hard to find, it has not been possible to adequately investigate their biology and significance. Microchip-based technologies have the ability to accurately sense and sort specific types of cells, but have only been used with microliter-sized fluid samples, the amount of blood in a fingerprick. Since CTCs are so rare, detecting them in useful quantities requires analyzing samples that are 1,000 to 10,000 times larger.



To meet that challenge the MGH BioMEMS Resource Center research team - led by Mehmet Toner, PhD, senior author of the Nature report and director of the center in the MGH Department of Surgery, and Ronald Tompkins, MD, ScD, chief of the MGH Burns Unit and a co-author - first investigated the factors required for microchip analysis of sufficiently large blood samples. The device they developed utilizes a business-card-sized silicon chip, covered with almost 80,000 microscopic posts coated with an antibody to a protein expressed on most solid tumors. The researchers also needed to calculate the correct speed and force with which the blood sample should pass through the chip to allow CTCs to adhere to the microposts.



"We developed a counterintuitive approach, using a tiny chip with critical geometric features smaller than a human hair to process large volumes of blood in a very gentle and uniform manner - almost like putting a 'hose' through a microchip," explains Toner.



Several tests utilizing cells from various types of tumors verified that CTCs were captured by posts covered with the antibody 'glue.' Even tumor cells expressing low levels of the target protein and samples containing especially low levels of CTCs were successfully analyzed by the CTC-chip. In contrast to current technology for detecting CTCs, the new microchip device does not require any pre-processing of blood samples, which could damage or destroy the fragile CTCs.
















The researchers then tested the CTC-chip against blood samples from 68 patients with five different types of tumors - lung, prostate, breast, pancreatic and colorectal. A total of 116 samples were tested, and CTCs were identified in all but one sample, giving the test a sensitivity rating of 99 percent. No CTCs were found in samples from cancer-free control volunteers. To evaluate the device's ability to monitor response to treatment, blood samples were taken from nine cancer patients during their treatment for lung, colorectal, pancreatic or esophageal tumors. Changes in levels of CTCs accurately reflected changes in tumor size as measured by standard CT scans.



"We looked at four major cancer killers and were able to consistently find these cells and correlate test results with traditional monitoring techniques," Toner says. "Some of these tumors have several potential drugs to choose from, and the ability to monitor therapeutic response in real time with this device - which has an exquisite sensitivity to CTCs - could rapidly signal whether a treatment is working or if another option should be tried."



CTCs also can provide the molecular information needed to identify tumors that are candidates for the new targeted therapies and should help researchers better understand the biology of cancer cells and the mechanisms of metastasis. Considerable work needs to be done before the CTC-chip is ready to be put to clinical use, and the MGH investigators are establishing a Center of Excellence in CTC Technologies to further explore the potential of the device, which also has been licensed to a biotechnology company for commercial development.






The research was funded by grants from the National Institutes of Health and a Doris Duke Distinguished Clinical Scientist Award. The paper's co-lead authors are Sunitha Nagrath, PhD, of the MGH BioMEMS Resource Center, and Lecia Sequist, MD, MGH Cancer Center. Additional co-authors are Shyamala Maheswaran, PhD, Daphne Bell, PhD, Lindsey Ulkus, Matthew Smith, MD, PhD, Eunice Kwak, MD, PhD, Subba Digumarthy, MD, Alona Muzikansky, and Paula Ryan, MD, MGH Cancer Center; and Daniel Irimia, MD, PhD, and Ulysses Balis, MD, MGH BioMEMS Resource Center.



Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.



Source: Sue McGreevey


Massachusetts General Hospital

Scientists Discover Molecular Pathway For Organ Tissue Regeneration And Repair

Scientists have discovered a molecular pathway that works through the immune system to regenerate damaged kidney tissues and may lead to new therapies for repairing injury in a number of organs.


The findings, reported in this week's Proceedings of the National Academy of Sciences (PNAS), come from collaborative research led by Cincinnati Children's Hospital Medical Center and the Brigham & Women's Hospital of Harvard Medical School.


The study may have significant medical ramifications as currently there are no effective treatments for acute kidney injury a growing problem in hospitals and clinics, according to the study's senior co-authors, Richard Lang, Ph.D., a researcher in the divisions of Pediatric Ophthalmology and Developmental Biology at Cincinnati Children's, and Jeremy Duffield, M.D., Ph.D., a researcher at Brigham and Women's Hospital. Acute kidney injury is a significant cause of kidney disease, cardiovascular complications and early death, affecting as many as 16 million children and adults in the United States.


The molecular repair pathway involves white blood cells called macrophages part of the immune system that respond to tissue injury by producing a protein called Wnt7b. Scientists identified the macrophage-Wnt7b pathway during experiments in mice with induced kidney injury. Wnt7b is already known to be important to the formation of kidney tissues during embryonic organ development. In this study the scientists found the protein helped initiate tissue regeneration and repair in injured kidneys.


"Our findings suggest that by migrating to the injured kidney and producing Wnt7b, macrophages are re-establishing an early molecular program for organ development that also is beneficial to tissue repair," said Dr. Lang. "This study also indicates the pathway may be important to tissue regeneration and repair in other organs."


Wnt7b is part of the Wnt family of proteins, which are known to help regulate cells as they proliferate, grow and become specific cell types for the body. Wnt proteins have also been linked to the regulation of stem cells in bone marrow and skin, which suggested to researchers of the current study that Wnt might have a role in tissue regeneration.


The researchers conducted a number of experiments of kidney injury in mice to identify the repair pathway, finding that:



-- Silencing macrophage white blood cells through a process called ablation reduced the response level of Wnt proteins to injured kidney cells.



-- Deleting the Wnt7b protein from macrophages diminished normal tissue repair functions in injured kidneys.



-- Injecting into the injured kidneys a protein calked Dkk2, which is known to help regulate the Wnt pathway during embryonic development, enhanced the macrophage-Wnt7b repair process. This also restored epithelial surface cells that line internal kidney surfaces and suggested a therapeutic potential for the pathway.


Drs. Lang and Duffield said the repair pathway may benefit other injured organs because macrophages act somewhat like a universal emergency responder in the body, rushing to injured tissues wherever damage occurs. Another factor is the central role the Wnt pathway plays in cell regulation and function throughout the body.


Other collaborating institutions in the study include: the Department of Structural Biology, St, Jude Children's Hospital, Memphis, Tenn.; the departments of Internal Medicine and Molecular Biology, University of Texas Southwest Medical Center; Department of Molecular and Developmental Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y.; Department of Molecular and Cellular Biology, Harvard University; the Visual Systems Group in the division of Pediatric Ophthalmology at Cincinnati Children's; and the Department of Ophthalmology, University of Cincinnati.


Funding support came from the National Institutes of Health, the American Society of Nephrology Gottschalk Award, the Genzyme Renal Initiatives Program, a National Taiwan Merit Award, and the Abrahamson Pediatric Eye Institute Endowment at Cincinnati Children's.


Source: Cincinnati Children's Hospital Medical Center

Rensselaer Professor Utilizing New York State Grant To Study Adult Stem Cells

Rensselaer Polytechnic Institute Assistant Professor of Biomedical Engineering Deanna Thompson is utilizing more than $300,000 in New York state funding as part of the state stem cell research program, NYSTEM, to study adult neural stem cells. The NYSTEM program is New York's $600 million publicly funded grant program to advance scientific discovery in the area of stem cells.


Working at the interface of engineering and neuroscience, her research is helping scientists and doctors develop new stem cell therapies and research tools utilizing these important cells. The adult stems cells she is investigating could play an important role in understanding and treating a variety of brain illnesses, from cancer and Alzheimer's to traumatic brain injury and stroke.


"Dr. Thompson is a young, rising star in her field and has come up with a highly innovative approach to direct, cause, and control nerve regeneration through stem cell bioengineering," said Rensselaer Biomedical Engineering leader Deepak Vashishth. "The results of her NYSTEM-funded research will provide unique insight into the stem cell niche and help develop new tools and therapies for regenerative medicine."


Neural stem cells are a specialized type of stem cell that can be found in the adult nervous system. These stem cells have the potential to repair or replace damaged nerve cells. For researchers, the ability to generate new cells or repair damaged nerve cells would be exceptionally helpful to heal a traumatic brain injury following an accident or reverse the cellular death caused by an illness like Parkinson's disease. Thompson's research is working to understand exactly how neural stem cells proliferate or differentiate into new nerve cells in the brain so that ability can be replicated to develop new medical treatments.


In order to control stem cell fate or differentiation, she must first understand the complex environment surrounding the stem cells. This environment or "niche" contains vascular and other cells, proteins, carbohydrates, and other cell products. In this niche, stem cells multiply in an orderly manner and can differentiate into new nerve cells or other non-nerve cells in the brain known as glia. Without the key control elements of the niche, a stem cell might multiply quickly, turning from a promising cure to a cancerous tumor. Without a clear understanding of the stem cell niche, a medical treatment involving stem cells could be very risky.


An element of the stem cell niche that Thompson is studying with this round of NYSTEM funding is endothelial cells. These cells line the interior of blood vessels, which are highly concentrated in the regions of the brain where neural stem cells reside. In particular, Thompson is looking at how materials produced by endothelial cells during their development influence neural stem cells' fate. According to Thompson, such control could allow for the development of stem cell therapies grown from an individual patient's own neural stem cells.















To perform her research, Thompson will utilize the resources of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer.


"Deanna's work, which is at the interface of cell biology and materials science, epitomizes the interdisciplinary research within CBIS," said CBIS Director and the Howard P. Isermann '42 Professor of Chemical and Biological Engineering Jonathan Dordick. "By studying the physiology and function of adult stem cells in a synthetic niche, Deanna has identified key determinants of neuronal cell growth and differentiation. Her work has impacted the burgeoning field of regenerative medicine and has helped CBIS make a name for itself in this critical research area."


Her work with brain cells has several other important implications beyond stem cell therapies. Another facet of her research as a member of National Science Foundation-funded Rensselaer Nanoscale Science and Engineering Center for Directed Assembly of Nanostructures involves the use of nanotechnology to repair damaged nerves in the brain and spinal cord.


"Professor Thompson's work in the Center for Directed Assembly of Nanostructures has addressed both the use of nanotubes in directing neuron growth and investigated the toxicity of carbon nanotubes in potential new medical therapies," said Linda Schadler, associate dean for academic affairs in the School of Engineering and professor in the Department of Materials Science and Engineering. "The ability to direct neuron growth is exciting in terms of helping patients repair damaged nerves. Through her work, she was also one of the first to recognize the role of glial cells in neuron growth, which may be the key to bringing this exciting technology to fruition."


Source: Rensselaer Polytechnic Institute (RPI)