The overall aim of this Award was to test the central hypothesis that bone marrow derived stem cells have the ability to differentiate and adopt cardiac phenotype when transplanted in young as well as aging hearts with experimental myocardial infarction. To support this hypothesis, the initial studies were designed and conducted to understand the basic properties of BMSCs and compare them in vitro from young and aging donor animals. Furthermore, we have elucidated that cardiac transdifferentiation of BMSCs can be achieved in vitro under specific set of cell culture conditions. The second phase of experiments was performed in vivo in experimental animal models to extrapolate our in vitro findings and observe that the transplanted BMSCs are able to achieve cardiomyocytes phenotype and integrate with the host myocardium. To accomplish these aims, state of the art integrated approaches including our well-established co-culture conditions, in vivo experimental animal model, histological studies combined with confocal microscopy and ultra-structure analysis by transmission electron microscopy, molecular studies by western blotting, fluorescent in situ hybridization, real time and classical PCR, siRNA techniques, and heart function studies using Pressure- volume loops and echocardiography were employed. Aging significantly affected the stem cells which were slower in their proliferation and propagation ability in vitro. Similarly when subjected to anoxia, younger MSCs showed more resistance and survived better as indicated by low level LDH release (an indicator of cellular injury) and reduced TUNEL positivity. Genetic modulation of the cells with AKT and angiopoietinl or their pharmacological preconditioning prior to transplantation promoted their survival as well as angiogenic and myogenic potential in young and aging animal hearts

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Schwartz, Lisa
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University of Illinois at Chicago
Schools of Medicine
United States
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Okada, Motoi; Kim, Ha Won; Matsu-ura, Kaoru et al. (2016) Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 34:148-59
Matsu-ura, Toru; Sasaki, Hiroshi; Okada, Motoi et al. (2016) Attenuation of teratoma formation by p27 overexpression in induced pluripotent stem cells. Stem Cell Res Ther 7:30
Yu, Bin; Kim, Ha Won; Gong, Min et al. (2015) Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 182:349-60
Feng, Yuliang; Huang, Wei; Meng, Wei et al. (2014) Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells 32:462-72
Feng, Yuliang; Huang, Wei; Wani, Mashhood et al. (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9:e88685
Konoplyannikov, Mikhail; Haider, Khawaja Husnain; Lai, Vien Khach et al. (2013) Activation of diverse signaling pathways by ex-vivo delivery of multiple cytokines for myocardial repair. Stem Cells Dev 22:204-15
Igura, Koichi; Okada, Motoi; Kim, Ha Won et al. (2013) Identification of small juvenile stem cells in aged bone marrow and their therapeutic potential for repair of the ischemic heart. Am J Physiol Heart Circ Physiol 305:H1354-62
Kim, Sun Wook; Kim, Ha Won; Huang, Wei et al. (2013) Cardiac stem cells with electrical stimulation improve ischaemic heart function through regulation of connective tissue growth factor and miR-378. Cardiovasc Res 100:241-51
Idris, Niagara Muhammad; Ashraf, Muhammad; Ahmed, Rafeeq P H et al. (2012) Activation of IL-11/STAT3 pathway in preconditioned human skeletal myoblasts blocks apoptotic cascade under oxidant stress. Regen Med 7:47-57
Kim, Ha Won; Mallick, Faryal; Durrani, Shazia et al. (2012) Concomitant activation of miR-107/PDCD10 and hypoxamir-210/Casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells. Antioxid Redox Signal 17:1053-65

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