McGowan Institute?
August 2009 | VOL.8, NO. 8 | www.McGowan.pitt.edu
New Bone Tissue Engineering Program in Italy
New Bone Tissue Engineering Program in Italy
The McGowan Institute is pleased to collaborate with the Mediterranean Institute for Transplantation and Specialized Therapies (ISMETT) in the development of a Tissue Engineering Center in Italy. The new center will interface closely with the McGowan Institute. The new center is under the direction of Ranieri Cancedda, MD. The Center will focus its initial efforts on bone regeneration, with plans to expand the research program into other areas of regenerative medicine.
Dr. Cancedda is a Professor of Cell Biology and Dean of the Biotechnology School at the University of Genova, Italy. He also serves as Head of the Laboratory of Regenerative Medicine of the National Cancer Research Institute (IST), Genova. Dr Cancedda’s main research fields include:
- molecular and cell biology of cartilage and bone;
- tissue engineering and regenerative medicine of skeletal tissue; and
- osteobiology in microgravity.
Dr. Cancedda has been President of the Italian Association of Cell Biology (1990-92) as well as one of the founders and first President of the European chapter of the Tissue Engineering and Regenerative Medicine International Society (TERMIS), formerly known as the European Tissue Engineering Society. He has spent most of his professional career in studying and developing methods of tissue reconstruction using stem cells, biomaterials, and active biomolecules, such as growth factors and angiogenic molecules. He is considered in academic circles as one of the forefathers of tissue engineering.
For additional information on the Tissue Engineering Center please contact Patrick Cantini at cantinip@upmc.edu.
By Robert L. Kormos, MD, FACS
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The growth of the Artificial Heart Program at the University of Pittsburgh has led to advances in clinical understanding and outcome, new research collaborations, and continued international acknowledgment. On August 4, 2009, the Artificial Heart Program implanted Pittsburgh’s first Heartware centrifugal left ventricular assist device (LVAD, pictured left). This procedure was performed for end-stage dilated cardiomyopathy in a 57-year-old male as a bridge to cardiac transplantation. The device, which is currently under investigation by the FDA, has the benefit of not requiring the surgeon to make an abdominal incision or pocket for the device, as it sits uniquely within the pericardial space. The immediate benefit appears to be less invasive surgery with a lower risk for bleeding and infection.
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The advantages of centrifugal design have been demonstrated through experience over the past two years with the Ventrassist LVAD (pictured right), which showed more physiologic response than the traditional axial-flow rotary blood pumps. It also presented a broader range of flows leading to easier management of the patient following discharge from the hospital, with the implanted LVAD.
The implantation of the Heartware LAVD represents a milestone for the program, which aims to match the most advanced technology with patient need for circulatory support in conditions of end-stage heart failure. The program continues to grow since its inception in 1985. Approximately 57 implants have been performed in 2008, and, as of this writing, 37 devices have been utilized in 2009. The selection of devices has gradually changed from the older pulsatile systems to predominantly rotary pumps, which have been accompanied by a higher success rate to transplantation as well as better post-transplant survival. Data demonstrates that post-transplant survival at 3 years is no different between those who required a VAD bridge and those who have received a heart transplant alone. Recently, the Artificial Heart Program began a collaborative effort that includes the Heart-Lung and Esophageal Program as well as the Weight-Loss Surgery Program for patients who have both morbid obesity and congestive heart failure. We currently have enrolled two patients who received a Heartmate II LVAD as destination therapy and will then undergo gastric bypass surgery. If successful, this will result in making cardiac transplantation available to those who are considered non-candidates based upon morbid obesity.
Over the years the program has accumulated experience with over 530 pump implants, which resulted in over 100 patient years of experience with 10,000 days (28 years) of outpatient care. Through the combined efforts of the nursing team and that of Vital Engineering – the biomedical engineering group – the Artificial Heart Program was successful in receiving last year’s Joint Commission Gold Seal of Approval for Destination Therapy. Since then the quality assurance program continues to demonstrate a significant reduction in post-implant infections and a reduced length of inpatient stay from nearly 80 days in 2007 to 30 days or less in 2008. The program continues to forge new research frontiers in understanding the ability of the heart to recover under LVAD support and have had success in this regard with two patients this year, as shown.
Vital Engineering continues to demonstrate its expertise in maintaining support contracts at several outside facilities, allowing the program to renew contracts with Evaheart, Sunshine Heart, Wake Forest University, Baptist Medical Center, and the Thoratec Corp. There are also a number of ongoing opportunities with industries such as Maquet Corporation, Heartware, and Alung Technologies, as well as academic institutions, including Texas A&M Medical Center, NIH Heart Center at Suburban Hospital, and the Veterans Administration Hospital System.
The research efforts of the faculty continue to expand. In collaboration with the Cardiovascular Institute at UPMC and under the direction of cardiologist Charles McTiernan, the Artificial Heart Program is developing one of the largest pre-vad and post-vad cardiac tissue banks in North America. Through his work and that of Dr. Dennis McNamara, we have a much greater understanding of the cellular basis for myocardial recovery. Dr. McNamara’s work has also been valuable in identifying the genetic changes accompanying congestive heart failure and how those are modified by the LVAD. Others, including Dr. Jeffery Teuteberg, direct major clinical research efforts, while Dr. John Gorcsan and his team direct a multi-center effort to document the predictability of myocardial recovery utilizing echocardiography. Dr. Christian Bermudez, whose interest lies in the surgical treatment of congestive heart failure surgery, is examining the outcome of patients supported acutely with mechanical circulatory assistance and ECMO, and he is developing strategies of application to maximize outcome. Dr. Mary Amanda Dew and Dr. Robert Kormos were successful in helping a University of Pittsburgh Medical Student, Elizabeth Genovese, to obtain a Doris Duke Foundation grant to study the adverse events associated with VADs and how they affect outcome. In collaboration with the McGowan Institute and Dr. William Wagner, Josh Woolley is conducting a study that examines the effects of rotary blood pumps on the coagulation system of the blood in particular platelet dysfunction.
Dr. Kormos is also helping to spearhead the Interagency Registry for Mechanical Circulatory Support (INTERMACS) as a co-principle investigator with Dr. James Kirklin at the University of Alabama and Dr. Lynne Warner-Stevenson from Harvard. This registry now contains information on nearly 2,000 approved assist devices used as bridge to transplantation, recovery, and destination therapy, and Dr. Kormos, as the Chair of the Adverse events subcommittee, has succeeded in establishing a set of definitions now adopted by the FDA and industry and clinical investigators worldwide.
SCIENTIFIC ADVANCES
McGowan Institute for Regenerative Medicine faculty member Sebastien Gilbert, MD, Department of Thoracic Surgery, University of Pittsburgh School of Medicine, was part of a team of researchers who recently reported the first findings from a one-of-a-kind, patient-driven effort to provide lung tissue for research which might help doctors predict when patients with idiopathic pulmonary fibrosis (IPF) are becoming dangerously ill. The results could point the way to interventions that could sustain the patients until life-saving transplants can be performed. The research addresses a dilemma in IPF care that currently is unsolved.
For most patients, the lung-scarring disease progresses gradually and lung function slowly deteriorates. There is neither a cure nor effective treatment, so median survival is about 3 years. For unknown reasons, some IPF patients experience rapid declines that cause diffuse damage of the lung alveoli, the tiny sacs where the exchange of oxygen and carbon dioxide occurs.
To better understand the molecular mechanisms of disease exacerbation or acceleration, the researchers compared the gene activity profile of the lungs of 8 IPF patients whose disease was dramatically worsening when they died with those of 23 stable IPF patients and 15 people with healthy lungs.
In the first analysis of its kind, “gene activity patterns were found to be more similar among all IPF patients compared to healthy people,” said lead author Kazuhisa Konishi, M.D., a visiting postdoctoral fellow who performed the gene profiling in the lab of senior author Naftali Kaminski, M.D., associate professor of medicine, computational biology and pathology, and director of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases at the University of Pittsburgh School of Medicine and UPMC. ”But nearly 600 genes were differentially expressed between IPF patients who had accelerated disease and those who were stable.”
There was no evidence that infection or inflammation was the cause of disease acceleration, he noted. Instead, there were indications that the cells of the alveolar epithelium, which is the tissue that covers the surface of the air sacs, were rapidly dying.
“That could mean that drugs that are used to protect the epithelium in other illnesses, such as cancer, might help IPF patients survive an exacerbation,” said study co-author Kevin Gibson, M.D., associate professor in the Division of Pulmonary, Allergy and Critical Care Medicine at Pitt School of Medicine and medical director of the Simmons Center. “If we can keep them alive, there’s a chance they could get a life-saving lung transplant.”
According to a study led by McGowan Institute for Regenerative Medicine faculty member Abbe de Vallejo, PhD, associate professor of pediatrics and immunology, University of Pittsburgh School of Medicine, and immunologist at Children’s Hospital of Pittsburgh of UPMC, the secret to longevity may lie in an enzyme with the ability to promote a robust immune system into old age by maintaining the function of the thymus throughout life.
The team of researchers studied an “anti-aging” mouse model that lives longer than a typical mouse. Dr. Vallejo reports that the novel mouse model has a thymus that remains intact throughout its life. In all mammals, the thymus―the organ that produces T cells to fight disease and infection―degenerates with age.
“These findings give us hope that we may one day have the ability to restore the function of the thymus in old age, or perhaps by intervening at an early age, we may be able to delay or even prevent the degeneration of the thymus in order to maintain our immune defenses throughout life,” said Dr. de Vallejo.
The mouse model that Dr. de Vallejo’s team studied was developed by his colleague Cheryl Conover, Ph.D., an endocrinology researcher at Mayo Clinic. In this “knockout” mouse model, researchers deleted an enzyme known as pregnancy-associated plasma protein A (PAPPA). PAPPA-knockout mice live at least 30 percent longer and have significantly lower occurrence of spontaneous tumors than typical mice.
PAPPA controls the availability in tissues of a hormone known as insulin-like growth factor (IGF) that is a promoter of cell division. Hence, IGF is required for normal embryonic and postnatal growth. But IGF also is associated with tumor growth, inflammation, and cardiovascular disease in adults. By deleting PAPPA, the researchers were able to control the availability of IGF in tissues and dampen its many ill effects. In the thymus, deletion of PAPPA maintained just enough IGF to sustain production of T cells without consuming precursor cells, thereby preventing the degeneration of the thymus.
“Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune protection throughout life,” Dr. de Vallejo said. “This study has profound implications for the future study of healthy aging and longevity.”
McGowan Institute for Regenerative Medicine faculty member Ron Shapiro, MD, Surgical Director, Children's Hospital of Pittsburgh of UPMC, Professor of Surgery and Robert J. Corry Chair in Transplantation Surgery, University of Pittsburgh, recently facilitated the nation's first paired organ donation involving a pediatric patient. A paired transplant pairs donors and recipients who aren’t matches on their own and leads to a transplant where one may not have been possible.
Both recipients—Bennett, 5, and Jenny, 37—had polycystic kidney disease, a genetic disorder that leads to kidney failure, and had been on dialysis treatments. Their respective donors were Jenny’s aunt, Ruby, and Bennett’s dad, Dean. All four transplant patients are recovering well after the operations.
Jenny and Ruby registered in the Paired Donor Network first, waiting several months for a match. As soon as Bennett and Dean entered the system, registrars realized that a match could be made and contacted both families 2 hours later.
Dr. Shapiro, a leader in paired kidney exchange efforts at the Thomas E. Starzl Transplantation Institute, said it was very lucky for the hospital to find the right match for both Jenny and Bennett within its own database. It was a challenge to find matching kidneys for both patients because of antibodies present in their immune systems.
"It was like finding a needle in a haystack," Dr. Shapiro said.
Paired donations occur when an individual wants to donate an organ to a sick family member, but cannot do so because their blood types do not match. So the potential donor registers with the national Paired Donation Network and agrees to donate an organ to a different person in exchange for a matching organ from that person's family member. UPMC's chapter of the Paired Donation Network, one of a few private registries, has 40 potential donors on the list.
More than 80,000 people nationwide are waiting for a kidney, and 16,500 people received transplanted kidneys last year. Fewer than 6,000 received the organs from live donors. Read more (with video)…
AWARDS AND RECOGNITIONS
Konrad Hochedlinger, PhD, Assistant Professor in Harvard's Department of Stem Cell and Regenerative Biology and a Principal Faculty member of the Harvard Stem Cell Institute is the recipient of the inaugural Outstanding Young Investigator Award supported by the University of Pittsburgh and the International Society for Stem Cell Research (ISSCR). This award, presented at the Society’s annual meeting recently held in Barcelona, Spain, recognizes the exceptional achievements of an investigator in the early part of his or her independent career in stem cell research. Dr. Hochedlinger is also a Principal Investigator in the Massachusetts General Hospital (MGH) Center for Regenerative Medicine where he maintains his laboratory in the MGH Cancer Center.
Dr. Hochedlinger completed his graduate training at the Whitehead Institute for Biomedical Research, although his Doctoral degree was awarded by the Research Institute of Molecular Pathology, University of Vienna, in the spring of 2003. Dr. Hochedlinger, soon after joining the laboratory, demonstrated his remarkable scientific ability in an exceptionally elegant experiment.
After a brief postdoctoral experience at the Whitehead, Dr. Hochedlinger started his own laboratory at Harvard and MGH in 2006. In the few short years since then, the pace of his research in cellular reprogramming has only accelerated. Dr. Hochedlinger's laboratory has made major contributions to the literature, building upon the original observations of Shinya Yamanaka to generate induced pluripotent stem cells (iPSCs) that showed in vitro virally delivered, gene-based reprogramming of somatic cells. Dr. Hochedlinger's laboratory demonstrated improved performance of fully reprogrammed human iPSCs and creatively exploited conditional transgene expression cassettes to define the temporal events of reprogramming; his group has investigated the epigenetic modifications that accompany reprogramming and was the first to demonstrate the generation of transgene-free iPSCs via adenoviral gene transfer. Dr. Hochedlinger's laboratory contributed to the production of the first large repository of patient-specific iPSCs.
The International Society for Stem Cell Research Outstanding Young Investigator Award is an annual recognition bestowed on an exceptional young scientist. The 2010 annual meeting will be held in San Francisco, California, June 16-19, 2010, where the next Young Investigator Award will be presented.
The research work of McGowan Institute for Regenerative Medicine faculty member Andrew Schwartz, PhD, professor, Department of Neurobiology, University of Pittsburgh School of Medicine, was recently featured at a dinner in Washington, D.C. At the dinner, the Foundation for Biomedical Research gave its Michael E. DeBakey Journalism Award, television category, to the CBS News Program 60 Minutes for a segment called “Brain Power.” The award honors professional journalists whose reporting has enhanced public understanding of how the humane and responsible use of animal models leads to medical and scientific discoveries.
Last November, Scott Pelley of 60 Minutes visited Dr. Schwartz’s lab to talk about his astounding technology that his team is developing that directly connects the human brain to a computer. As Mr. Pelley reports, it's like a sudden leap in human evolution - a leap that could one day help paralyzed people to walk again and amputees to move bionic limbs. And, the connection has already been made for a few people, and for them it has been life changing.
Congratulations to Dr. Schwartz and 60 Minutes!|
#72 – Bryan Tillman, MD, PhD #73 – Major General (ret.) Gale S. Pollock |
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Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
| Authors: | Wognum S, Lagoa CE, Nagatomi J, Sacks MS, Vodovotz Y. |
| Title: | An Exploratory Pathways Analysis of Temporal Changes Induced by Spinal Cord Injury in the Rat Bladder Wall: Insights on Remodeling and Inflammation. |
| Summary: | Background: Spinal cord injuries (SCI) can lead to severe bladder pathologies associated with inflammation, fibrosis, and increased susceptibility to urinary tract infections. We sought to characterize the complex pathways of remodeling, Methodology/Principal Findings: Experimental data were obtained from the study of Nagatomi et al. (Biochem Biophys Res Commun 334: 1159). In this study, bladders from rats subjected to surgical SCI were obtained at 3, 7 or 25 days post-surgery, and Affymetrix GeneChipH Rat Genome U34A arrays were used for cRNA hybridizations. In the present study, Ingenuity Pathways Analysis (IngenuityH Systems, www.ingenuity.com) of differentially expressed genes was performed. Analysis of focus genes in networks, functional analysis, and canonical pathway analysis reinforced our previous findings related to the |
| Source: | PLoS ONE 4(6): e5852. doi:10.1371/journal.pone.0005852. |
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| Co-Investigators | |
| Title | Long-term immunosuppression-free survival of a combined composite tissue allograft (CTA) and autologous skin in a swine model |
| Description | Wide spread use of Composite Tissue Allografts such as a hand or face transplant are currently limited by the high dose and long-term immunosuppressive treatment required to prevent graft rejection. This is predominantly related to the high immunogenicity of the skin. In this study we aim to achieve long-term immunosuppression-free survival of a combined Composite Tissue Allograft (CTA) in a swine model. This shall be achieved by inducing “split tolerance” towards the musculoskeletal component of a CTA and replacement of the immunologically stringent epidermis by either a split thickness skin autograft or layers of isolated autologous and cultured keratinozytes sprayed on the graft. |
| Source | Pittsburgh Tissue Engineering Initiative via DOD |
| Term | 04/01/09 – 09/30/10 |
| Amount: | $450,450 |
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