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2016 Scientific Report

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STEFAN JOVINGE, M.D., PH.D. Dr. Jovinge received his M.D. (1991) and his Ph.D. (1997) at Karolinska Institute in Stockholm. Since December 2013 he has been the Medical Director of Research at the Frederik Meijer Heart and Vascular Institute and a Professor at VARI. He also directs the DeVos Cardiovascular Research Program, is a Professor at the MSU College of Human Medicine, and is a Consulting Professor at Stanford University. STAFF PAULA DAVIDSON, M.S. DAWNA DYLEWSKI, B.S. ELLEN ELLIS EMILY EUGSTER, M.A. JENS FORSBERG, PH.D. LISA KEFENE, M.A., MB(ASCP), RLAT ERIC KORT, M.D. BRITTANY MERRIFIELD, B.S. HSIAO-YUN YEH (CHRISTY) MILLIRON, PH.D. JORDAN PRAHL, B.S. LAURA TARNAWSKI, M.S. MATTHEW WEILAND, M.S. LAURA WINKLER, PH.D. RESEARCH INTERESTS The DeVos Cardiovascular Research Program is a joint effort between VARI and Spectrum Health. The basic science lab is the Jovinge laboratory at VARI, and a corresponding clinical research unit resides within the Fred Meijer Heart and Vascular Institute. Cardiovascular diseases are among the major causes of death and disability worldwide. While the incidence of ischemic heart diseases has started to decline, congestive heart failure is still rising. Medical treatment for the latter is supportive, and the only available therapy is heart transplantation. To regenerate myocardium after disease or damage is one of the major challenges in medicine. Our group is working on true heart muscle regeneration along two axes: external and internal (cardiac) cell sources. The most robust external source for generating heart muscle cells has been stem cells, either from an embryonic stem cell (ESC) system or from reprogrammed pluripotent stem cells (iPSCs). The main drawback to the stem cell approach is that their differentiation will generate a multitude of different cell types at different stages of development. A mixed cell population of undifferentiated cells always has the potential to create tumors. Also, the use of ESCs creates a need for lifelong immunosuppressive treatment. iPSCs, however, could be generated from the patient’s own peripheral blood cells, a technique established by our group in Grand Rapids. To be able to use these sources, we have developed strategies based on establishing surface marker expression—similar to those for bone-marrow cells—to help select homogenous, safe populations to transplant. 34 Van Andel Research Institute | Scientific Report

The second axis we focus on is endogenous generation within the heart. Although adult human heart muscle cells are to a small extent generated after birth, the internal source of such cells and their cell cycle regulation are unknown. Some data indicate that cardiac progenitors could be involved, and other data suggest that differentiated heart muscle cells might be the source. We and our collaborators have rejected the view that adult heart muscle cells are not capable of undergoing a complete cell division. With the use of 14 C dating, the adult heart has been shown to have a regenerative capacity. This has opened a completely new field of induced local generation of heart muscle cells, which is now being explored. The final phase of patient studies will involve the administration of cells or compounds to stimulate endogenous regeneration. To prepare cells for transplantation into humans, an accredited Good Manufacturing Practice facility will be established in collaboration with Stanford University, and the first safety studies (Phase II) will be followed by studies evaluating the best route for delivering the treatment and the best timing. In the final stage, randomized prospective clinical trials will be launched. Our program’s eventual aims are clinical concept studies of heart muscle cell regeneration in patients, either by cell transplantation or stimulation of endogenous sources. The program’s clinical side involves a multistep process to prepare for these studies. Patients with the most severe heart disease, i.e., those needing mechanical support, are being studied to optimize treatments that will be used in later safety studies. We have already derived mortality prediction algorithms for patients on bedside heart-lung machines. RECENT PUBLICATIONS Bergmann, Olaf, Sofia Zdunek, Anastasia Felker, Mehran Salehpour, Kanar Alkass, Samuel Bernard, Staffan L. Sjostrom, Mirosława Szewcykowska, Teresa Jackowska, et al. 2015. Dynamics of cell generation and turnover in the human heart. Cell 161(7): 1566–1575. Raulf, Alexandra, Hannes Horder, Laura Tarnawski, Caroline Geisen, Annika Ottersbach, Wilhelm Röll, Stefan Jovinge, Bernd K. Fleischmann, and Michael Hesse. 2015. Transgenic systems for unequivocal identification of cardiac myocyte nuclei and analysis of cardiomyocyte cell cycle status. Basic Research in Cardiology 110(3): 33. Tarnawski, Laura, Xiaojie Xian, Gustavo Monnerat, Iain C. Macauley, Daniela Malan, Andrew Borgman, Sean M. Wu, Bernd K. Fleischmann, and Stefan Jovinge. 2015. Integrin based isolation enables purification of murine lineage committed cardiomyocytes. PLoS One 10(8): e0135880. CENTER FOR EPIGENETICS 35

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