Title

Embryonic Stem Cells Improve Cardiac Function in Doxorubicin-Induced Cardiomyopathy Mediated Through Multiple Mechanisms

Authors

Authors

D. K. Singla; A. Ahmed; R. Singla;B. B. Yan

Comments

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Abbreviated Journal Title

Cell Transplant.

Keywords

Stem cells; Heart; Doxorubicin (DOX); Apoptosis; Fibrosis; BONE-MARROW-CELLS; MYOCARDIAL-INFARCTION; INHIBIT APOPTOSIS; ADRIAMYCIN; CARDIOMYOPATHY; ADULT CARDIOMYOCYTES; H9C2 CELLS; HEART; SURVIVAL; PATHWAY; REPAIR; Cell & Tissue Engineering; Medicine, Research & Experimental; Transplantation

Abstract

Doxorubicin (DOX) is an effective anti neoplastic agent used for the treatment of a variety of cancers. Unfortunately, its use is limited as this drug induces cardiotoxicity and heart failure as a side effect. There is no report that describes whether transplanted embryonic stem (ES) cells or their conditioned medium (CM) in DOX-induced cardiomyopathy (DIC) can repair and regenerate myocardium. Therefore, we transplanted ES cells or CM in DIC to examine apoptosis. fibrosis, cytoplasmic vacuolization, and myofibrillar loss and their associated Akt and ERK pathway. Moreover, we also determined activation of endogenous c-kit(+ve) cardiac stem cells (CSCs), levels of FIGF and IGF-1, growth factors required for c-kit cell activation, and their differentiation into cardiac myocytes, which also contributes in cardiac regeneration and improved heart function. We generated DIC in C57Bl/6 mice (cumulative dose of DOX 12 mg/kg body weight. IP), and animals were treated with ES cells, CM, or cell culture medium in controls. Two weeks post-DIC, ES cells or CM transplanted hearts showed a significant (p<0.05) decrease in cardiac apoptotic nuclei and their regulation with Akt and ERK pathway. Cardiac fibrosis observed in the ES cell or CM groups was significantly less compared with DOX and cell culture medium groups (p<0.05). Next, cytoplasmic vacuolization and myofibrillar loss was reduced (p<0.05) following treatment with ES cells or CM. Moreover, our data also demonstrated increased levels of c-kit(+ve) CSCs in ES cells or CM hearts and differentiated cardiac myocytes from these CSCs, suggesting endogenous cardiac regeneration. Importantly, the levels of HFG and IGF-1 were significantly increased in ES cells or CM transplanted hearts. In conclusion, we reported that transplanted ES cells or CM in DIC hearts significantly decreases various adverse pathological mechanisms as well as enhances cardiac regeneration that effectively contributes to improved heart function.

Journal Title

Cell Transplantation

Volume

21

Issue/Number

9

Publication Date

1-1-2012

Document Type

Article

Language

English

First Page

1919

Last Page

1930

WOS Identifier

WOS:000312431600009

ISSN

0963-6897

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