Decellularized Mouse Heart Beats Again after Regeneration with Human Heart Precursor Cells
A Pittsburgh-based team, that includes two McGowan Institute for Regenerative Medicine affiliated faculty members, has reported that they have performed a study where a mouse heart was able to contract and beat again after its own cells were stripped and replaced with human heart precursor cells. The McGowan Institute affiliated faculty members who were contributors to the study are Kimimasa Tobita, MD, research assistant, professor of developmental biology, pediatrics, and bioengineering at the University of Pittsburgh and a director of Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh of UPMC, and Guy Salama, PhD, professor within the Department of Cell Biology and Physiology at the University of Pittsburgh School of Medicine, along with scientists from Pitt School of Medicine. The findings, reported online in Nature Communications, show the promise that regenerating a functional organ by placing human induced pluripotent stem (iPS) cells – which could be personalized for the recipient – in a three-dimensional scaffold could have for transplantation, drug testing models, and understanding heart development.
In the United States, one person dies of heart disease every 34 seconds, and more than 5 million people suffer from heart failure, meaning a reduced ability to pump blood, said senior investigator Lei Yang, PhD, assistant professor of developmental biology, Pitt School of Medicine. More than half of heart disease patients do not respond to current therapies and there is a scarcity of donor organs for transplant.
“Scientists have been looking to regenerative medicine and tissue engineering approaches to find new solutions for this important problem,” Dr. Yang said. “The ability to replace a piece of tissue damaged by a heart attack, or perhaps an entire organ, could be very helpful for these patients.”
For the project, the research team first “decellularized,” or removed all the cells, from a mouse heart, a process that takes about 10 hours using a variety of agents. Then, they repopulated the remaining heart framework, or scaffold, with multipotential cardiovascular progenitor (MCP) cells. These replacement cells were produced by reverse engineering fibroblast cells from a small skin biopsy to make induced pluripotent stem cells and then treating the iPS cells with special growth factors to further induce differentiation.
“This process makes MCPs, which are precursor cells that can further differentiate into three kinds of cells the heart uses, including cardiomyocytes, endothelial cells, and smooth muscle cells,” Dr. Yang explained. “Nobody has tried using these MCPs for heart regeneration before. It turns out that the heart’s extracellular matrix – the material that is the substrate of heart scaffold – can send signals to guide the MCPs into becoming the specialized cells that are needed for proper heart function.”
After a few weeks, the mouse heart had not only been rebuilt with human cells, it also began contracting again, at the rate of 40 to 50 beats per minute, the researchers found. More work must be done to make the heart contract h3ly enough to be able to pump blood effectively, and to rebuild the heart’s electrical conduction system correctly so that the heart rate speeds up and slows down appropriately.
In the future, it might be possible to take a simple skin biopsy from a patient to derive personalized MCPs that can be used to seed a biologic scaffold and regenerate a replacement organ suitable for transplantation, Dr. Yang noted. The model also could be used as a lab-based method to preclinically test the effect of new drugs on the heart or to study how the fetal heart might develop.
“One of our next goals is to see if it’s feasible to make a patch of human heart muscle,” he added. “We could use patches to replace a region damaged by a heart attack. That might be easier to achieve because it won’t require as many cells as a whole human-sized organ would.”
Co-authors include Tung-Ying Lu, PhD, and Bo Lin, PhD, of the Department of Developmental Biology at Pitt; Jong Kim, PhD, of the UPMC Heart and Vascular Institute; and Mara Sullivan, of the Center for Biologic Imaging at Pitt.
The project was funded by the University of Pittsburgh, the American Heart Association, and the National Science Council (Taiwan).
McGowan Institute Distinguished Lecture October 10th
The McGowan Institute for Regenerative Medicine’s Fall Distinguished Lecturer is Glenn Prestwich, PhD, Presidential Professor of Medicinal Chemistry and Research Professor of Biochemistry, University of Utah. Dr. Prestwich’s lecture is entitled “The Entrepreneurial Ecosytem and Its Role in Translating Hyaluronan Materials to the Clinic.”
Dr. Prestwich is also the Director for two Utah Centers of Excellence for technology commercialization: The Center for Cell Signaling and The Center for Therapeutic Biomaterials.
Dr. Prestwich graduated with honors with a degree in Chemistry from the California Institute of Technology in 1970. He then earned a PhD in Chemistry from Stanford University. He did two NIH postdoctoral fellowships, one at Cornell University and then another at the International Centre for Insect Physiology and Ecology in Nairobi, Kenya.
The lecture is scheduled for October 10, 2013, at 4:00 pm at the University Club, Ballroom B; a reception will follow.
If you would like to meet with Dr. Prestwich during his visit, please contact Rebecca Bauroth at 412-624-5242, or firstname.lastname@example.org.
Third Annual Regenerative Rehabilitation Symposium
Like no other time in our nation’s history, the enthusiasm surrounding regenerative medicine is now being matched with clinical deliverables, and the number of clinical trials in the field is growing at an unprecedented rate. Over the next decades, stem cell and tissue engineering protocols hold the possibility of becoming the standard of care for several diseases and injuries. As we approach this exciting new era of technological advancements, rehabilitation specialists must work closely with regenerative medicine scientists in the development of clinical protocols designed to optimize functional recovery.
Indeed, much advancement in clinical practice are occurring at the interface of regenerative medicine and rehabilitation. Consider the goals of each of these fields. The broad goal of rehabilitation is to use the body’s innate healing potential to maximize function. Accordingly, the long-term goal of regenerative medicine is to repair, replace, or regenerate cells, tissues, or organs in order to maximize tissue function. Scientists in the field of regenerative medicine stand to benefit from increased incorporation of functional outcomes assessment when determining the therapeutic benefit of biological technologies being investigated. Moreover, as our understanding of mechanisms underlying tissue regeneration progresses, rehabilitation specialists will benefit from the continued incorporation of these emerging principles into the design of clinical protocols. As an increasing number of technologies reach the bedside, rehabilitation clinicians must be prepared, and there is a growing need for trained therapists and physiatrists that can help oversee the quality, safety, and validity of these new clinical treatments. The application of clinically-relevant and cost-effective approaches to elicit targeted and specific physiological responses may be an effective means to maximize efficacy and, ultimately, hasten the translation of these technologies into medical practice.
Rehabilitation specialists and regenerative medicine scientists would benefit from a shared vision of modern day clinical practice that integrates innovative technologies with a solid foundation of approaches and modalities designed to maximize functional outcomes. As first steps towards an increased interaction between the fields of rehabilitation and regenerative medicine, there is a need to standardize terminology, educate young scientists and investigators, and communicate active clinical trials such that clinicians may be fully aware of the latest advancements in this emerging field. Scientists in the field of regenerative medicine should work closely with clinicians, and more specifically, rehabilitation specialists, in order to look ahead to the critical issues that will either enable or prevent the translation of their exciting technologies. Such insights should be initiated early on in the innovation and development stages of the technology in order to maximize the efficiency of clinical translation. The proposed integration of the fields of regenerative medicine and rehabilitation has relevance to a broad scope of research interests and clinical specialties. Bridging expertise across these diverse fields will ultimately allow for illuminated opportunities to leverage scientific knowledge, expertise and methodologies. Unfortunately, few opportunities exist to bring together scientists and clinicians working in these two currently disparate fields.
Our symposium, the only one of its kind, crosses disciplinary boundaries to create a unique forum where stakeholders in the field of regenerative medicine will interact with rehabilitation clinicians and scientists to discuss the current and future landscape of the field. The annual Regenerative Rehabilitation Symposia series is a unique opportunity for students, researchers, and clinicians working in the interrelated fields of regenerative medicine and rehabilitation to meet, exchange ideas, and generate new collaborations and clinical research questions. Jointly organized by the University of Pittsburgh Rehabilitation Institute, the School of Health and Rehabilitation Sciences at the University of Pittsburgh, the McGowan Institute for Regenerative Medicine and the Rehabilitation Research and Development Center of Excellence at the Veterans Affairs Palo Alto Health Care System, the Third Annual Symposium on Regenerative Rehabilitation will be held on April 10-11, 2014 in San Francisco, CA at the Mission Bay Conference Bay at the University of California, San Francisco (UCSF).
The objectives of this event are:
- to promote the clinical translation of regenerative medicine scientific discoveries by communicating and disseminating research findings that demonstrate the synergistic relationship between regenerative medicine and rehabilitation;
- to provide a forum by which scientists and rehabilitation clinicians may interact, exchange ideas, and identify novel research directions relating to the field of regenerative rehabilitation;
- to introduce the concept of regenerative rehabilitation to graduate students, medical students and medical residents in the rehabilitation field.
To achieve these aims, we have designed a highly multidisciplinary and translational 1½-day program that includes thematically linked presentations that highlight the importance of mechanical stimulation for functional tissue regeneration. Extensive time for interaction among attendees has been incorporated into the program through the inclusion of a poster session and a poster teaser session, in which selected abstracts will be chosen and the primary author will be invited to present a short overview of their work. New to this year’s program, we have included a “Meet the Mentor” session, in which students, fellows, clinicians and novice investigators will be given the opportunity to meet in a small group setting with senior investigators conducting research relevant to the fields of regenerative medicine and rehabilitation. This is an excellent opportunity for students and junior investigators to become engaged in the emerging field of regenerative rehabilitation.
Dendritic Cell Therapy Improves Kidney Transplant Survival in Preclinical Model
A single systemic dose of special immune cells prevented rejection for almost 4 months in a preclinical animal model of kidney transplantation, according to McGowan Institute for Regenerative Medicine affiliated faculty members (pictured top to bottom)
- Ron Shapiro, MD, professor of surgery at the University of Pittsburgh and the Robert J. Corry Chair in Transplantation Surgery at the Thomas E. Starzl Transplantation Institute
- Abhinav Humar, MD, clinical director of the Thomas E. Starzl Transplantation Institute and chief, Division of Transplantation in the Department of Surgery at UPMC
- Jake Demetris, MD, professor of pathology and director, Division of Transplantation Pathology at the Thomas E. Starzl Transplantation Institute,
and experts at the University of Pittsburgh School of Medicine. Their findings, now available in the online version of the American Journal of Transplantation, could lay the foundation for eventual human trials of the technique.
Organ transplantation has saved many lives, but at the cost of sometimes lifelong requirements for powerful immunosuppressive medication that can have serious side effects, said senior investigator Angus Thomson, PhD, DSc, distinguished professor of surgery and of immunology, Pitt School of Medicine. Scientists have long sought ways to encourage the organ recipient’s immune system to accept or tolerate the donor organ to reduce the need for drugs to stave off rejection.
“This study shows it is possible to prepare the patient’s immune system for a donor kidney by administering specially treated immune cells from the donor in advance of the transplant surgery,” Dr. Thomson said. “This could be very helpful in the context of planned kidney donations from living relatives, and could one day be adapted to transplantation from deceased donors.”
For the project, the research team generated immune cells called dendritic cells (DCs) from the blood of rhesus macaques that would later provide a kidney to recipient monkeys. Dendritic cells are known to be key regulators of the immune system by showing antigens to T-cells to either activate them against the foreign protein or to suppress the T-cell response. The researchers treated the donor DCs in the lab to prevent them from fully maturing and having the capacity to trigger an immune reaction against foreign proteins.
One week before having a kidney transplant, recipient monkeys received a single infusion of treated DCs obtained from their respective donor animals. Another group of monkeys was transplanted without receiving the cells, but both groups were given the same regimen of immunosuppression drugs, a modified protocol for experimental purposes that eventually results in donor organ rejection. The researchers found that the donor kidney was rejected in about 40 days among animals that got only the drugs, but survived for about 113 days in the group that had a prior infusion of treated DCs.
The modified donor DCs sent signals to the recipient immune system to stay quiet and not launch an attack against the donor organ, explained lead author Mohamed Ezzelerab, M.D., research assistant professor, Department of Surgery, Pitt School of Medicine.
“The results indicate that we achieved immune system regulation without side effects of the DCs, but better yet, the monkeys were healthier from a clinical perspective,” he said. “They maintained a better weight, had less protein in the urine, and fewer signs of kidney damage than the other group. Ultimately, all these factors played a role in prolonging organ survival in the group that received DC therapy.”
Risk of Dementia Doubles for Elderly Patients Hospitalized with Infections
University of Pittsburgh researchers, including McGowan Institute for Regenerative Medicine affiliated faculty member Derek Angus, MD, distinguished professor of critical care medicine and the Mitchell P. Fink chair in critical care medicine in Pitt’s School of Medicine, found that elderly patients who were hospitalized with infections, such as pneumonia, were more than twice more likely to develop dementia than those who did not have an infection. The study also found that patients with dementia may be more susceptible to infection. The results of the study, funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, were published in the American Journal of Respiratory and Critical Care Medicine.
“These findings explain in part why seemingly healthy older adults progress to a state of disability following infection and how a single episode of infection may lead to cognitive decline in older adults,” said Sachin Yende, M.D., senior author of the study and associate professor in the Department of Critical Care Medicine at the University of Pittsburgh School of Medicine. “Most people think infection is a short-term illness, but patients who look and feel recovered may have downstream consequences.”
The researchers examined data from 5,888 participants over age 65, in four areas: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania, from 1989 through 1999; 639 were hospitalized with pneumonia at least once. Pneumonia is the most common infection leading to hospitalization in the United States, but the study found that any type of infection in the elderly can accelerate the onset of dementia.
Dementia is a broad term for loss of memory and other cognitive skills severe enough to impact daily life. Dementia, which is not part of normal aging, is caused by damage to brain cells that affect thinking, behavior, and feelings.
For reasons that the researchers do not yet understand, patients who showed signs of impaired cognitive function before their hospitalizations had an 11 percent higher risk for pneumonia and other infections than those with healthy cognitive function.
“Even a small change in cognition predisposed patients to pneumonia. Once they had an infection, they were at a higher risk for worsening of cognitive function and dementia. This cycle could perpetuate and ultimately lead to disability and loss of independence,” said Faraaz Shah, M.D., lead author of the study.
The scientists stress that future research should examine mechanisms for the bidirectional relationship between dementia and infection to develop interventions that reduce infection and its consequent disability.
AWARDS AND RECOGNITION
Sanjeev Shroff, PhD, Appointed New Chair of Bioengineering
McGowan Institute for Regenerative Medicine faculty member Sanjeev Shroff, PhD (pictured top), distinguished professor and Gerald E. McGinnis chair of bioengineering at the University of Pittsburgh Swanson School of Engineering, has been named chair of the Department of Bioengineering, effective September 1, 2013. He succeeds McGowan Institute for Regenerative Medicine faculty member Harvey Borovetz, PhD (pictured bottom), distinguished professor of bioengineering, who decided to step down in April 2013 after an 11-year tenure as chair. Dr. Borovetz will continue to be a faculty member in the Department of Bioengineering, Swanson School of Engineering. Dr. Shroff is the third chair of the Department of Bioengineering, which was founded in 1998.
“Dr. Shroff has built a h3 reputation as an academic, researcher and student mentor, and I am pleased to appoint him as department chair,” noted Gerald D. Holder, PhD, US Steel dean of engineering at the Swanson School. “He is respected among his colleagues at Pitt and his peers throughout the field of bioengineering, and I am enthusiastic about the leadership and experience he will bring to this new role.”
“I am very pleased and deeply honored by this appointment. I am also humbled to follow Dr. Borovetz’s remarkable tenure as chair. I derive great comfort knowing that I will be working with an outstanding group of people – faculty, students, and staff – who are united in their commitment to academic excellence,” noted Dr. Shroff.
Dr. Shroff is recognized as a distinguished scholar in cardiovascular physiology and mechano-energetics. His research has been supported by grants from American Heart Association (AHA), National Science Foundation (NSF), and National Institutes of Health (NIH), and he has received continuous funding from the NIH since 1986. He was the recipient of the prestigious Established Investigator Award from the AHA (1986-1991) and was elected as a Fellow of the American Physiological Society (1988), Fellow of American Institute for Medical and Biological Engineering (1999), and Fellow of Biomedical Engineering Society (2007). Recognized by his colleagues and peers as a consummate teacher and mentor, he has received the Carnegie Science Center Award for Excellence (University/Post-Secondary Educator) in 2007, the Swanson School’s Outstanding Educator Award in 2010, and Chancellor’s Distinguished Teaching Award in 2011. He has mentored 31 graduate students at the Swanson School (15 post-doctoral and 16 pre-doctoral), 10 of who now hold academic (faculty) positions. In 2012 Pitt Chancellor Mark A. Nordenberg named Dr. Shroff as distinguished professor, a designation that constitutes the highest honor that the University can accord a member of the professoriate and one that recognizes eminence in several fields of study, transcending accomplishments in and contributions to a single discipline, and garnering national and international recognition.
Dr. Shroff received his PhD in bioengineering from the University of Pennsylvania and was a faculty member in the University of Chicago Department of Medicine (Cardiology Division) for 17 years. He joined the Swanson School of Engineering in April 2000 as Professor and Gerald E. McGinnis endowed chair in bioengineering. He was later appointed as professor of medicine in the University of Pittsburgh School of Medicine and senior investigator in the Magee-Women’s Research Institute in 2001; a core faculty member in the McGowan Institute for Regenerative Medicine in 2002; and associate chair of bioengineering in 2008.
“Sanjeev’s future success could not be possible without the passion and dedication that his predecessor, Harvey Borovetz, brought to the Department,” Dean Holder said. “Harvey has been a tremendously effective leader over his almost 40-year career at Pitt, and in particular has been the guiding force behind the dramatic growth of our bioengineering program. The department is consistently ranked near the top 10 bioengineering departments in the country; PhD production has increased from 0 to more than 20 in recent years; its enrollment has grown such that it is now among the most sought-after departments in the Swanson School; and its research expenditures are now the highest among the School’s programs. Harvey has developed h3 collaborations with Pitt’s School of Medicine and with UPMC, as well as with other programs around the country, and helped to establish stellar programs in translational research. We are indeed fortunate that he will continue with us as faculty.”
“Dr. Shroff’s unswerving commitment to the education of both undergraduate and graduate students; his recognized leadership in cardiovascular bioengineering research; and his tireless service to the Swanson School, University of Pittsburgh and bioengineering profession make him the ideal person to lead the Department of Bioengineering as we celebrate our 15th birthday and beyond,” noted Dr. Borovetz.
Illustration: University of Pittsburgh Swanson School of Engineering.
Drs. Angus, Bahar, and Perlmutter Named Pitt Distinguished Professors
The University of Pittsburgh has awarded the title of Distinguished Professor to three McGowan Institute for Regenerative Medicine affiliated faculty members. The new Distinguished Professors are: Derek C. Angus, Distinguished Professor of Critical Care Medicine; Ivet Bahar, Distinguished Professor of Computational and Systems Biology; and David H. Perlmutter, Distinguished Professor of Pediatrics.
The rank of Distinguished Professor acknowledges extraordinary, internationally recognized scholarly attainment in an individual discipline or field. Chancellor Mark A. Nordenberg made the appointments based on the recommendations of Provost and Senior Vice Chancellor Patricia E. Beeson.
Derek C. Angus, MD, the Mitchell P. Fink Chair in Critical Care Medicine in the School of Medicine, conducts research into the clinical, epidemiologic, and translational aspects of sepsis and the related syndromes of pneumonia, acute lung injury, and multisystem organ failure, as well as the optimal delivery of acute care and intensive care services.
Dr. Angus has led multiple large National Institutes of Health (NIH) studies and published several hundred papers, including articles in JAMA, the Lancet, and The New England Journal of Medicine.
He joined the Department of Anesthesiology in 1991. He has been chair of the Department of Critical Care Medicine since 2009.
Ivet Bahar, PhD, is the founding chair of the Department of Computational and Systems Biology in the School of Medicine. Her research focuses on structure-based modeling of biomolecular machinery and on understanding how complex macromolecules interact and execute their biological functions. The examination of these structure-based systems using quantitative tools has broad applicability in emerging fields, such as polypharmacology and personalized medicine.
In 2001, she joined Pitt as a faculty member in the Department of Molecular Genetics and Biochemistry.
Dr. Bahar’s work bridges multiple disciplines, including biophysics, computational biology, structural biology, engineering, cell biology, oncology, and pharmacology. She has published more than 200 scientific articles and coauthored 13 book chapters. Her articles have been published in the Proceedings of the National Academy of Sciences, Nature Chemical Biology, PLoS Computational Biology, and Biophysics Journal.
She also is the associate director of the Drug Discovery Institute and co-director of the Clinical and Translational Science Institute’s molecular and systems modeling core. She is the founding director of the Pitt/Carnegie Mellon joint PhD program in computational biology.
David H. Perlmutter, MD is recognized as an authority on alpha-1-antitrypsin deficiency, the most common genetic cause of liver disease in children.
In the last 8 years, Dr. Perlmutter has completed 12 NIH-funded research projects on which he served as principal investigator. He has published more than 170 articles in scientific and medical journals and books.
Dr. Perlmutter joined the University in 2001 as chair of the Department of Pediatrics and the Vira I. Heinz Professor. He holds a secondary appointment in cell biology and is scientific director and physician-in-chief of Children’s Hospital.
He was instrumental in the development and funding of the Biliary Atresia Research Consortium, a multicenter study of pediatric liver disease.
He has served as president of the Society for Pediatric Research and is a member of the National Academy of Sciences’ Institute of Medicine.
Dr. Rory Cooper Awarded the Outstanding Civilian Service Medal by the U.S. Army
McGowan Institute for Regenerative Medicine affiliated faculty member Rory Cooper, PhD, has been awarded the Outstanding Civilian Service Medal by the U.S. Army for his extraordinary contributions to veterans by leveraging science, clinical research, and advanced engineering technology to improve the mobility of wounded and disabled veterans. The award was presented by the commander of the U.S. Army War College in Carlisle, Pennsylvania.
Dr. Cooper is the FISA/PVA endowed chair and a distinguished professor of the Department of Rehabilitation Science and Technology, School of Health and Rehabilitation Sciences, University of Pittsburgh, and the director, Human Engineering Research Laboratories, School of Health and Rehabilitation Sciences. He is also the center director at the Center of Excellence for Wheelchair and Related Technology, VA Rehabilitation Research & Development Center, and a senior research career scientist at the VA Rehabilitation Research and Development Service, U.S. Department of Veterans Affairs. In addition, Dr. Cooper holds a secondary appointment as professor in both the Departments of Orthopaedic Surgery and of Mechanical Engineering and Bioengineering.
The Outstanding Civilian Service Award is the third highest honor within the Department of the Army Civilian Awards scheme that the United States Department of the Army can bestow upon a private citizen. The Secretary of the Army or a major commander may award this medal for outstanding service that makes a substantial contribution or is of significance to the major Army command concerned. Outstanding Civilian Service Award honors consist of a bronze medal, lapel button, and citation certificate.
Congratulations, Dr. Cooper!
Regenerative Medicine Podcast Update
The Regenerative Medicine Podcasts remain a popular web destination. Informative and entertaining, these are the most recent interviews:
#127 –– Dr. Linda Noble-Haeusslein is the Co-Director and Principal Investigator of the Brain and Spinal Injury Center; the Co-Director of the Neurobehavioral Core for Rehabilitation; and Professor in the Departments of Neurological Surgery and of Physical Therapy and Rehabilitation at the University of California, San Francisco. Dr. Noble-Haeusslein discusses her research on the neurobiology of traumatic injury to the central nervous system.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.