Doxorubicin (DOX;Adriamycin) is an antitumor antibiotic widely used drug for the treatment of a variety of cancers. Unfortunately, the clinical use of this drug is limited due to severe, dose-dependent cardiac side effects that lead to irreversible chronic cardiomyopathy followed by congestive heart failure. Novel therapeutic approaches using cell transplantation are being studied to regenerate infarcted and DOX-induced cardiomyopathy (DIC) myocardium. However, there is no data yet available describing the ability of embryonic stem (ES) cells or factors released from ES cells to be used in DIC. Using a cell culture model system, our preliminary data suggest that factors released from ES cells contain anti-apoptotic, anti-fibrotic and growth factors (insulin and hepatocyte growth factors, IGF-1 and HGF) necessary inhibit adverse remodeling (including reduced apoptosis, fibrosis, cytoplasmic vacuolization and myofibrillar loss) and to stimulate resident cardiac stem cells (CSCs). We also demonstrate that TGF22 enhances ES cells derived embryoid body (EB) proliferation and cardiac myocyte differentiation. Overall, we propose central hypothesis that TGF22 treated cardiac committed (TCC)-ES cells and factors released from ES cells in DIC following transplantation will demonstrate engraftment, differentiation, remodeling, cardiac regeneration, and ultimately, function. Furthermore, our preliminary data also demonstrate the differentiation of c-kit+CSCs in DIC following ES-CM or TCC-ES cells transplantation. So, we also hypothesize that factors released (IGF-1 and HGF) from transplanted ES-CM or TCC-ES cells stimulates c-kit+CSCs and enhance cardiac regeneration. Accordingly the specific aims are as follow:
Aim 1 : a) Determine if intraperitoneal injection of (a) ES-CM attenuates DIC. (b) TCC-ES cells attenuate apoptosis and enhance cardiac repair and regeneration in DIC.
Aim 2 : Determine if intramyocardial injection of TCC-ES cells or ES-CM enhance cardiac repair and regeneration in DIC.
Aim 3 : Determine if transplantation of factors released from ES cells enhance c-kit+ CSCs proliferation, differentiation and regeneration in DIC.
Aim 4 : Determine the mechanisms of inhibited apoptosis and fibrosis following TCC- ES cell or ES-CM transplantation in DIC. The results of the proposed studies should help to define the impact of TCC-ES cells or ES-CM on cardiac repair and regeneration in DIC. We will also define mechanisms of CSCs proliferation and differentiation, and remodeling that may play a role in improved cardiac function in DIC following transplantation. Moreover, the use of TCC-ES cells or ES-CM that release various factors that stimulate tissue repair and regeneration may have promise as a new therapeutic strategy in the field of regenerative medicine.

Public Health Relevance

Doxorubicin is an antitumor antibiotic drug for the treatment of a variety of cancers in US. Unfortunately, this drug induces cardiac side effects that lead to irreversible chronic cardiomyopathy followed by congestive heart failure and death. There are no well established pharmacological agents (drugs) to completely cure the side effects of this drug. Cell therapy is a new hope to cure these side effects. We anticipate that the results from the proposed projects will have long-term implications for future cell-based therapy to treat doxorubicin induced cardiomyopathy using factors released from embryonic stem cells or embryonic stem cells.

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; 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
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
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
Yan, Binbin; Singla, Dinender K (2013) Transplanted induced pluripotent stem cells mitigate oxidative stress and improve cardiac function through the Akt cell survival pathway in diabetic cardiomyopathy. Mol Pharm 10:3425-32
Rocher, Crystal; Singla, Dinender K (2013) SMAD-PI3K-Akt-mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages. PLoS One 8:e84009
Abdelli, Latifa S; Merino, Hilda; Rocher, Crystal M et al. (2012) Cell therapy in the heart. Can J Physiol Pharmacol 90:307-15

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