We have shown that transplantation of undifferentiated embryonic stem (ES) cells results in improved left ventricular (LV) function after myocardial infarction (MI) in mice despite the fact that 80-90% of transplanted cells die and there is limited engraftment and differentiation. In vitro preliminary data indicate that factors released from ES cells are anti-apoptotic and anti-fibrotic. In vivo preliminary data suggest that transplantation of ES cells post-MI in C57Bl/6 mice results in cardiac regeneration as well as improved remodeling (including reduced apoptosis and fibrosis). Accordingly, we propose the overall hypothesis that these factors released from dying and surviving stem cells favorably influence myocardial remodeling and, ultimately, function. Our preliminary data indicate that TIMP-1 is anti-apoptotic in an in vitro model simulating the post-MI heart. Therefore, we also hypothesize that the favorable effects on remodeling of factors released from ES cells are mediated by both """"""""classic"""""""" cell survival as well as TIMP-1 pathways. The specific questions we will address in this application are: 1) What factors are released from ES cells in cell culture and in vivo following post-MI transplantation and do they influence remodeling? 2) Is ES cell transplantation required to favorably influence remodeling or could ES cell-conditioned medium (CM) alone produce the same results? 3) What mechanisms are responsible for inhibition of apoptosis and fibrosis observed following CM or cell transplantation? Specific Aims are as follows; 1: Determine if ES-CM a) contains concentrations of released factors that inhibit apoptosis, and b) inhibits apoptosis via activation of phosphatidylinositol-3-OH kinase (PI3K/Akt1) and the extra-cellular signal regulated kinases (ERK1/2) survival pathways in vitro in the setting of oxidative stress simulating the post-MI heart. 2: Determine factors released from transplanted ES cells that attenuate remodeling post-MI. 3: Determine if intramyocardial injection of ES-CM attenuates remodeling post-MI. 4: Determine the mechanisms of inhibition of apoptosis and fibrosis following ES cell transplantation or ES-CM injection post-MI. Results of these studies will define the effect of transplanted ES cells or ES-CM on cardiac regeneration and remodeling and mechanisms of inhibition of apoptosis and fibrosis that may play a role in improved cardiac function. Identification and delineation of favorable effects of factors released from ES cells might lead to a new therapeutic strategy that could be an alternative to or combined with cell transplantation. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Adhikari, Bishow B
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University of Central Florida
Other Basic Sciences
Schools of Medicine
United States
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Merino, Hilda; Singla, Dinender K (2018) Secreted Frizzled-Related Protein-2 Inhibits Doxorubicin-Induced Apoptosis Mediated through the Akt-mTOR Pathway in Soleus Muscle. Oxid Med Cell Longev 2018:6043064
Singla, Dinender; Wang, Jing (2016) Fibroblast Growth Factor-9 Activates c-Kit Progenitor Cells and Enhances Angiogenesis in the Infarcted Diabetic Heart. Oxid Med Cell Longev 2016:5810908
Abdelli, Latifa S; Singla, Dinender K (2015) A CD63(+ve)/c-kit(+ve) stem cell population isolated from the mouse heart. Mol Cell Biochem 406:101-9
Singla, Dinender K; Singla, Reetu D; Abdelli, Latifa S et al. (2015) Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart. PLoS One 10:e0120739
Singla, Dinender K; Abdelli, Latifa S (2015) Embryonic Stem Cells and Released Factors Stimulate c-kit(+)/FLK-1(+) Progenitor Cells and Promote Neovascularization in Doxorubicin-Induced Cardiomyopathy. Cell Transplant 24:1043-52
Singla, Dinender K (2015) Akt-mTOR Pathway Inhibits Apoptosis and Fibrosis in Doxorubicin-Induced Cardiotoxicity Following Embryonic Stem Cell Transplantation. Cell Transplant 24:1031-42
Singla, Reetu D; Wang, Jing; Singla, Dinender K (2014) Regulation of Notch 1 signaling in THP-1 cells enhances M2 macrophage differentiation. Am J Physiol Heart Circ Physiol 307:H1634-42
Merino, Hilda; Singla, Dinender K (2014) Notch-1 mediated cardiac protection following embryonic and induced pluripotent stem cell transplantation in doxorubicin-induced heart failure. PLoS One 9:e101024
Urbina, Princess; Singla, Dinender K (2014) BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 307:H762-72
Yan, Binbin; Singla, Reetu D; Abdelli, Latifa S et al. (2013) Regulation of PTEN/Akt pathway enhances cardiomyogenesis and attenuates adverse left ventricular remodeling following thymosin ?4 Overexpressing embryonic stem cell transplantation in the infarcted heart. PLoS One 8:e75580

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