New research from the University of Minnesota reveals endoglin as a critical factor in determining the fate of early undifferentiated cells during development. Endoglin, a receptor involved in cell signaling, has previously been known mostly for its function in blood vessels and angiogenesis. In a new paper published in the journal Nature Communications, researchers showed endoglin modulates key signaling pathways to encourage early cells to develop into blood cells at the expense of the heart.
“During the early stages of development, cells have to make decisions very quickly,” said Rita Perlingeiro, Ph.D., professor of Medicine in the University of Minnesota Medical School’s Cardiovascular Division. “Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”
June Baik, PhD, a member of the Perlingeiro’s lab, and the leading author of this study, wanted to pinpoint the mechanism underlining the dual function of endoglin in blood and cardiac cell fate. She manipulated the levels of endoglin in differentiating mouse pluripotent stem cells as well as primary heart cells from zebrafish and mice. Her findings confirmed the endoglin expression connection.
The next step was to further understand the molecular regulation associated with endoglin’s function in this differentiation process. By looking closely at the pathways of development and differentiation, the research team identified JDP2 as a novel and important downstream mediator sufficient to induce blood fate when the endoglin signaling is disturbed.
“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” said Perlingeiro. “By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.
Perlingeiro points to a great opportunity to collaborate on next steps, identifying this as an interesting area to pursue in relation to the role of endoglin in congenital heart defects.
“The importance of these studies by the Perlingeiro laboratory is the discovery of key regulatory factors governing blood and heart formation,” said Daniel Garry, M.D., Ph.D, director of the Lillehei Heart Institute at the University of Minnesota, and co-author in this study. “The clinical significance of these findings rests in the possibility of targeting these newly discovered networks to promote the development of blood or heart tissue in congenital diseases and following injuries in adults.”
Funding for this project was provided by grants from the National Institutes of Health: R01 HL085840, R01 AR055299, U01 HL100407R01, R01 AR064195, and T32AR07612, and a grant from Regenerative Medicine Minnesota.
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Last year, the 2014 Minnesota legislative session brought a big win for regenerative medicine, as legislators passed a bill allotting nearly $50 million over 10 years for regenerative medicine research, clinical translation and commercialization efforts.
Some of that research funding has now been awarded to Bruce Walcheck, Ph.D., professor in the University of Minnesota Department of Veterinary and Biomedical Sciences, whose proposal was one of six funded out of 90 applications. Bruce is the principal investigator on a new $500,000 grant for research on engineering human pluripotent stem cells to generate enhanced natural killer cells for cancer therapy. The ultimate goal: treating cancer using the patient’s immune system.
A unique scientific and medical resource, pluripotent stem cells are self-replicating and have the potential to differentiate into almost any cell in the body. They are an important starting cell population for engineering enhanced immune cells for cell-based therapies that have the potential to cure various types of cancer. The investigative team will generate natural killer cells, which are part of the human body’s first line of defense against cancer cells and virus-infected cells.
“Our long-term goal is to engineer human-induced pluripotent stem cells to generate a renewable source of super natural killer cells to enhance current therapies and the patient’s immune system in killing cancer cells,” Walcheck explained. “Natural killer cells play a vital role in the fight against cancer. In contrast to other lymphocytes, natural killer cells kill malignant cells without being restricted to specific antigens or requiring considerable expansion. Standardized natural killer cell-based immunotherapies can therefore be more readily administered to patients.”
However, during their expansion for transfer into patients and in the tumor environment, natural killer cells can down-regulate key receptors, resulting in their dysfunction. Our objective is to genetically modify human-induced pluripotent stem cells to derive natural killer cells that maintain their expression of key receptors for enhanced anticancer activity.”
The other members of the multidisciplinary investigative team are Dan Kaufman, M.D., Ph.D., professor, Medical School (coinvestigator); Jianming Wu, D.V.M., Ph.D., associate professor, College of Veterinary Medicine (coinvestigator); Jeffrey Miller, M.D., Ph.D., professor, Medical School (collaborator); Melissa Geller, M.D., associate professor and gynecologic oncologist, Medical School (collaborator); and Paul Haluska, M.D., Ph.D., associate professor of oncology, Mayo Clinic (collaborator).
Members of the Masonic Cancer Center, University of Minnesota, are involved in this research.
Allogeneic hematopoietic cell transplantation (HCT) is a complex treatment for several hematological disease groups, including many types of cancer. These cells can be derived from bone marrow and umbilical cord blood. Donors for these treatments has become increasingly more common and has resulted in the creation of many HCT centers.
In order to distinguish excellence between these centers, two voluntary center-accrediting organizations, the Foundation for the Accreditation of Cellular Therapy (FACT) and core Clinical Trial Network certification (CTN), assess patient care in each facility and give appropriate accreditations, should they apply.
In a recent study conducted by Schelomo Marmor, PhD, M.P.H., from University of Minnesota Department of Surgery, Marmor assessed if these accreditations improved clinical care and survival for HCT, a complex treatment viable for several hematological disease groups.
By using the 2008-2010 Center for International Blood & Marrow Transplant Research data, Dr. Marmor and colleagues stratified centers into three different categories: non-FACT centers, FACT-only centers and FACT and CTN centers. They then analyzed the risk of each patient and correlated patient survival characteristics with center accreditation.
Marmor concluded that when an accredited center treats a more complex patient, they perform better. However, when non-complex patients are treated FACT and non-FACT centers perform similarly.
“Foundation for the Accreditation of Cellular Therapy (FACT) accreditation alone is not sensitive enough as an indicator to differentiate transplant centers. We believe that FACT care processes have been standardized, routinized and disseminated to the point that the learning and improvement that derives from higher volume and FACT accreditation alone is no longer a major factor. FACT/CTN certified centers are now the new superior for the more complex patient,” said Marmor.
Marmor says there is an explanation as to why FACT/CTN is now the new superior.
“We attribute FACT/CTN superiority to the higher levels of collaboration between researchers and doctors,”Marmor said.
Based off these results, we now see a general obligation for collaboration, which in turn leads to higher performance. As a FACT-certified center, the AHC can use this data to continue supporting cross center collaboration in regards to all types of treatment, including HCT.
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Of the many spectacular inventions of the 1900s, it’s safe to say we never may have made it to where we are today without radar, plastics or the once-revolutionary vacuum tube triode (responsible, in case you’re wondering, for launching the age of electronics).
Medical advances made throughout the 20th century, too, are nothing to bat an eye at.
Electrocardiograms (EKGs), hearing aids and penicillin are all children of the last century. The University of Minnesota itself rolled out the first successful bone marrow and kidney transplants in the 1960s and the first successful open-heart surgery ten years before that.
Unfortunately, as medical advances crush health threats of the past, new problems are quick to arise.
How we Die: Comparing causes of death in 1900 v. 2010. In 1900′s, 53% died from infectious disease, today only 3% pic.twitter.com/gKPLcnAHQo
— Avi Roy (@agingroy) June 8, 2014
Infectious diseases, for example, were once the number one U.S. killer. Vaccines, antibiotics and an awareness of how diseases spread, however, have knocked infectious diseases down the charts. But something must one day kill us. So, heart disease and cancer have risen to the challenge. Beyond them lie Alzheimer’s and other forms of dementia, frailty and the yet-to-be-discovered.
That said, the fall of infectious disease is absolutely worth celebrating. Americans have tacked on an additional 32 years of life expectancy since the dawn of the 20th century.
Check out the recent article “How Americans Died in 1900 vs. Today, in One Chart” from PolicyMic for more. We highly recommend the read!
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Continuing with Health Talk’s coverage of May Stroke Awareness Month, today we’ll take a closer look at an ongoing study that uses stems cells to reprogram the brain after a stroke.
In the wake of a stroke, neurons within the brain are damaged. Using stems cells and stem cell technology, researchers in the Val, V. Richard Zarling, Earl Grande Stroke and Stem Cell Laboratory, within the Department of Neurosurgery and the University of Minnesota Stem Cell Institute, are exploring ways to replace and regenerate damaged neurons in the brain that will ultimately lead to functional improvement of those neurons.
“We believe that direct reprogramming of non-neuronal cells to generate new neurons within the brain is an exciting approach to repair the brain after a stroke,” said Andrew Grande, M.D., assistant professor of neurosurgery, who is leading the research along with Masato Nakafuku, M.D., of Cincinnati Children’s Hospital. “In the past we were limited to generating neurons from embryonic stem cells or other stem cell sources which then had to be transplanted into the brain. With direct reprogramming the goal is to directly reprogram one cell type already found in the brain directly into a neuron. By doing so we can avoid problems related to cell transplantation.”
Their study was recently published in the journal Nature Communications.
Grande says that the concept of direct reprogramming of neurons is complicated.
“Imagine trying to turn an apple into an orange. We’re essentially trying to convert one type of cell into a completely different cell form.”
The study was important for a number of reasons:
- This was only the second report in the world to demonstrate direct reprogramming of one cell type to another in the brain.
- Non-neuronal cells were not only converted into immature neurons but at later time points mature neurons were seen suggesting that the new neurons survive and then mature. There was even some evidence to suggest that the new neurons establish connections to other surrounding neurons.
- In the setting of stroke, a greater number of cells were converted into neurons suggesting that the environment encountered after a stroke can help facilitate this process of reprogramming.
One of the major hurdles that Grande and his team have experienced along the way is developing new neurons that are region-specific. For example, if neurons were damaged that affect speech, Grande is working to develop neurons that would replace and regenerate the same type of neurons to aid in speech recovery.
The next step for Grande in the research process is to develop translational studies to progress into larger animal models and then ultimately into human trials.
“We’re optimistic our research will have some clinical benefits hopefully in the not so distant future. Our goal is to help people restore the quality and functionality of life after a stroke,” Grande concludes.
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Each year, more people die worldwide from ischaemic heart disease than any other condition. This type of coronary artery disease is linked to a reduced blood supply to the heart.
Cardiac experts believe this type of heart disease happens because the cells that make up the heart muscle, cardiomyocytes, stop dividing and replenishing shortly after birth. A big push in research around this issue centers on creating cardiomyocytes to replace the cells failing within the heart, but because the body is no longer regenerating these naturally, they need to be developed by reprogramming other cells.
In previous studies, researchers identified successful and expedient ways to program stem cells to become cardiomyocytes, and then took another step to directly reprogram fibroblasts to create cardiomyocyte-like cells using a cocktail of cardiomyocyte-specific genes. The second method has an advantage of avoiding tumor formation, which is occasionally observed with the first method, but this method is extremely inefficient.
Looking for a new approach, University of Minnesota researchers had an interesting idea.
Hiroyuki Hirai, Ph.D., research associate, and Nobuaki Kikyo, M.D., Ph.D., associate professor, from the Masonic Cancer Center, University of Minnesota, the University of Minnesota Stem Cell Institute and Department of Genetics, Cell Biology and Development, gathered collaborators interested in testing whether or not a new fusion gene could prompt more efficient induced cardiomyocyte-like cells into production.
What they found:
- The transactivation domain of the MyoD protein is known to attract many important proteins for gene activation just like a magnet. The fusion of the MyoD domain to Mef2c, one of the introduced cardiomyocyte-specific gene, empowered Mef2c.
- The fusion gene accelerated the conversion of fibroblasts to cardiomyocyte-like cells more than 100-fold in the first two weeks.
- The maximum efficiency of the conversation was more than 15-fold higher with the fusion gene compared with the original Mef2c gene during the course of four weeks.
- The group previously showed a similar enhancement of producing stem cells from fibroblasts with the MyoD domain. This domain seems to serve as a general enhancer of cell reprogramming for the purpose of regenerative medicine.
This method of producing cardiomyocyte-like cells could make clinical care for ischaemic heart disease more effective and efficient.
You can read the whole paper, published online by the journal Cardiovascular Research.
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A research team led by pediatric blood and marrow transplantation experts Mark Osborn, Ph.D. and Jakub Tolar, M.D., Ph.D. from the Masonic Cancer Center, University of Minnesota, have discovered a remarkable new way to repair genetic defects in the skin cells of patients with the skin disease epidermolysis bullosa.
The findings, published today in the journal Molecular Therapy and highlighted in the most recent issue of Nature, represent the first time researchers been able to correct a disease-causing gene in its natural location in the human genome using engineered transcription activator-like effector nucleases.
Epidermolysis bullosa (EB) is a skin disease caused by genetic mutations. Patients suffering from EB – primarily children – lack the proteins that hold the epidermis and dermis together, which leads to painful blistering and sores. The condition is often deadly. The University of Minnesota is an international leader in the treatment of EB and the research that has led to new treatment approaches.
In their latest work, Osborn and Tolar’s team collaborated with genomic engineer Daniel Voytas, Ph.D., of the University of Minnesota’s College of Biological Sciences, to engineer transcription activator-like effector nucleases (TALENs) that target the mutation and correct the error in the skin cells of patients with the disease. Researchers then reprogrammed these cells to make pluripotent stem cells that can create many different kinds of tissues. These amended cells were then able to produce the missing protein when placed in living skin models.
“These results provide proof of principle for TALEN-based precision gene correction, and it could open the door for more individualized therapeutics,” said Osborn, an assistant professor in the University of Minnesota Medical School’s Department of Pediatrics Division of Blood and Marrow Transplantation.
By using an unbiased screening method, researchers were able to take a comprehensive approach to TALEN-mapping. This strategy helped identify three other possible locations for future research and potential therapies.
“This is the first time we’ve been able to seamlessly correct a disease-causing gene in its natural location in the human genome using the TALEN-based approach. This opened up options we did not have before when considering future therapies,” said Tolar, director of the University’s Stem Cell Institute and an associate professor in the Department of Pediatrics Division of Blood and Marrow Transplantation.
The University of Minnesota Pediatric Blood and Marrow Transplant team, led by John Wagner, M.D. and Bruce Blazar, M.D., has pioneered bone marrow transplantation as the standard of care for severe EB. Tolar and Osborn hope that the individualized “genome editing” of patient cells will provide the next generation of therapies for EB and other genetic diseases.
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A recent study led by researchers from the Masonic Cancer Center, University of Minnesota, found a process for mass-producing human natural killer (NK) cells to make them available for clinical-scale use.
Current mass-production processes for human NK cells are poorly defined, time-consuming and require supplemental cell parts to develop mature and functional NK cells. The new method proposed in the study eliminates many of the steps used in current processes, making the production of the cells easier on a large scale.
The study, published recently by Stem Cells Translational Medicine, was a collaborative effort between Masonic Cancer Center researchers within the University of Minnesota’s Stem Cell Institute (SCI) and researchers from the University of Texas.
“Our data demonstrate an improved method to develop NK cells from human pluripotent stem cells,” said Dan Kaufman, M.D., Ph.D., associate professor in the University of Minnesota Medical School’s Department of Medicine. “Using a stepwise approach, we were able to transition to a completely defined system amenable to clinical translation.”
NK cells are one of the major types of lymphocytes — white blood cells dictating immune responses to infectious or foreign substances and antigens — that function as an innate part of the immune system. NK cells are particularly effective at attacking malignant tumors, making them an important player in the effort to fight cancer naturally.
The primary method of producing NK cells is cultivation from one of two types of human pluripotent stem cells — either human embryonic stem cells (hESC) or induced pluripotent stem cells (iPSC). Current techniques for deriving NK cells from these stem cells are complicated and involve using feeder layers from animal tissues. The process developed in the new study is more efficient as it doesn’t require feeder layers or some of the other intensive steps that have been used before.
According to Kaufman, this streamlined process allows for larger-scale production of NK cells and could have far-reaching effects for the future of cancer immunotherapies.
“Our ability to now produce large numbers of cytotoxic NK cells means the prospect hESC- and iPSC-derived products for diverse clinical therapies can be realized in the not-too-distant future. Additionally, it may be possible to engineer hESCs and iPSCs with antitumor and antiviral receptors to provide an off-the-shelf product of targeted lymphocytes for immunotherapies.”
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Researchers at the University of Minnesota’s Lillehei Heart Institute have combined genetic repair with cellular reprogramming to generate stem cells capable of muscle regeneration in a mouse model for Duchenne Muscular Dystrophy (DMD).
The research, which provides proof-of-principle for the feasibility of combining induced pluripotent stem cell technology and genetic correction to treat muscular dystrophy, could present a major step forward in autologous cell-based therapies for DMD and similar conditions and should pave the way for testing the approach in reprogrammed human pluripotent cells from muscular dystrophy patients.
The research is published in Nature Communications.
To achieve a meaningful, effective muscular dystrophy therapy in the mouse model, University of Minnesota researchers combined three groundbreaking technologies.
First, researchers reprogrammed skin cells into “pluripotent” cells – cells capable of differentiation into any of the mature cell types within an organism. The researchers generated pluripotent cells from the skin of mice that carry mutations in the dystrophin and utrophin genes, causing the mice to develop a severe case of muscular dystrophy, much like the type seen in human DMD patients. This provided a platform that would mimic what would theoretically occur in human models.
The second technology employed is a genetic correction tool developed at the University of Minnesota: the Sleeping Beauty Transposon, a piece of DNA that can jump into the human genome, carrying useful genes with it. Lillehei Heart Institute researchers used Sleeping Beauty to deliver a gene called “micro-utrophin” to the pluripotent cells they were attempting to differentiate.
Much like dystrophin, human micro-utrophin can support muscle fiber strength and prevent muscle fiber injury throughout the body. But one key difference between the two is in how each is perceived by the immune system. Because dystrophin is absent in muscular dystrophy patients, its presence can prompt a devastating immune system response. But in those same patients, utrophin is active and functional, making it essentially “invisible” to the immune system. This invisibility allows the micro-utrophin to replace the dystrophin and progress the process of building and repairing muscle fiber within the body.
The third technology utilized is a method to produce skeletal muscle stem cells from pluripotent cells – a process developed in the laboratory of Rita Perlingeiro, Ph.D., the principal investigator of the latest study.
Perlingeiro’s technology involves giving pluripotent cells a short pulse of a muscle stem cell protein called Pax3. The Pax3 protein pushes the pluripotent cells to become muscle stem cells, and allows them to be expanded exponentially in number. The Pax3-induced muscle stem cells were then transplanted back into the same strain of muscular dystrophy mice from which the pluripotent stem cells were originally derived.
Combined, the platforms created muscle-generating stem cells that would not be rejected by the body’s immune system. According to Perlingeiro, the transplanted cells performed well in the dystrophic mice, generating functional muscle and responding to muscle fiber injury.
“We were pleased to find the newly formed myofibers expressed the markers of the correction, including utrophin,” said Perlingeiro, a Lillehei endowed scholar within the Lillehei Heart Institute and an associate professor in the University of Minnesota Medical School. “However, a very important question following transplantation is if these corrected cells would self-renew, and produce new muscle stem cells in addition to the new muscle fibers.”
By injuring the transplanted muscle and watching it repair itself, the researchers demonstrated that the cell transplants endowed the recipient mice with fully functional muscle stem cells.
This latest project from the U of M provides the proof-of-principle for the feasibility of combining induced pluripotent stem cell technology and genetic correction to treat muscular dystrophy.
“Utilizing corrected induced pluripotent stem cells to target this specific genetic disease proved effective in restoring function,” said Antonio Filareto, Ph.D., a postdoctoral fellow in Perlingeiro’s laboratory and the lead author on the study. “These are very exciting times for research on muscular dystrophy therapies.”
These studies pave the way for testing this approach in reprogrammed human pluripotent cells from muscular dystrophy patients.
According to Perlingeiro, “Developing methods to genetically repair muscular dystrophy in human cells, and demonstrating efficacy of muscle derived from these cells are critical near-term milestones, both for the field and for our laboratory. Testing in animal models is essential to developing effective technologies, but we remained focused on bringing these technologies into use in human cells and setting the stage for trials in human patients.”
This study was funded by NIH grants RC1AR059118, AR05529, HL085840-01 and U01 HL100407. Also contributing were the Muscular Dystrophy Centre Core Laboratories P30-AR0507220, The Dr. Bob and Jean Smith Foundation, and the Greg Marzolf Jr. Foundation.
The University of Minnesota Medical School, with its two campuses in the Twin Cities and Duluth, is a leading educator of the next generation of physicians. Our graduates and the school’s 3,800 faculty physicians and scientists advance patient care, discover biomedical research breakthroughs with more than $180 million in sponsored research annually, and enhance health through world-class patient care for the state of Minnesota and beyond. Visit www.med.umn.edu to learn more.
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We here at Health Talk are big fans of good news. If you’re the same way, let us share the story of Lauren Hood, a 2-year-old little girl from Michigan.
Last night, WCCO offered a touching look at Lauren’s experience at the University of Minnesota Amplatz Children’s Hospital where she’s recovering from a bone marrow transplant for a very rare but very serious medical condition.
According to the WCCO report from reporter James Schugel:
“Lauren Hood came to the Twin Cities from Michigan to treat a rare, potentially deadly disorder called Hurler Syndrome. She’s missing an enzyme that breaks down complex sugars in her body. If left untreated, sugars will accumulate in her body and cause bone, cardiac and other medical issues.”
Children diagnosed with Hurler Syndrome need treatment in the form of a bone marrow transplant by around age 10 or the condition can be fatal. Lauren arrived at Amplatz Children’s Hospital when her first transplant didn’t work.
Lauren’s doctor, University of Minnesota Physician pediatric bone marrow transplant expert Paul Orchard, M.D., an associate professor in the University of Minnesota Medical School, explained the purpose of the transplant to WCCO:
“The concept with the transplant is to eliminate the immune system’s blood producing cells…and replace them with normal, healthy blood cells,” said Orchard, who added that the healthy cells then provide patients the enzyme needed to break down complex sugars.
Doctors at Amplatz have treated more than 100 children with Hurler’s Syndrome. For those wondering what’s next for Lauren, she will need to return to the Twin Cities for check ups, but should recover going forward.
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The Nobel Assembly is designed to give Nobel Committee members the opportunity to learn more about topics they believe will be transformative in the coming decade.
The June meeting attended by Tolar focused on all aspects of hematopoietic stem cells, from basic biology and laboratory research to immune reconstitution and novel cell use. Tolar was one of less than 30 researchers invited to participate.
For his portion of the discussion, Tolar spoke on his laboratory research using hematopoietic stem cells in mice, and how this research developed into a transplantation program for children with the rare, deadly skin disorder called epidermolysis bullosa.
Tolar has worked with John Wagner, M.D., director of the Department of Pediatrics, Hematology-Oncology and Blood Marrow Transplantation at the University of Minnesota, to lead one of the earliest, most-successful clinical trials to date designed to treat epidermolysis bullosa.
“I was surprised and honored, on behalf of the Minneapolis transplant team, at the invitation to this conference,” said Tolar, who in addition to his pediatric work serves as director of Stem Cell/Gene Therapies at the U of M. “This was a great opportunity to exchange information and ideas with some of the top minds in the field of hematopoietic cells.”
Funding for Tolar’s research comes from the National Institutes of Health, the Children’s Cancer Research Fund, Pioneering Unique Cures for Kids (PUCK), the Department of Defense, DebRA International and a matching grant through the University of Minnesota Medical Foundation that is made possible by the EB Research Partnership and the Epidermolysis Bullosa Medical Research Foundation. In fact, between Jan 1, 2012 and December 31, 2012, The Jackson Gabriel Silver Foundation and The Epidermolysis Bullosa Medical Research Foundation pledged to match all gifts to Dr. Tolar’s EB research up to $450,000 dollar for dollar.
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