Title

Notch-1 Mediated Cardiac Protection following Embryonic and Induced Pluripotent Stem Cell Transplantation in Doxorubicin-Induced Heart Failure

Authors

Authors

H. Merino;D. K. Singla

Comments

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Abbreviated Journal Title

PLoS One

Keywords

MYOCARDIAL-INFARCTION; INDUCED CARDIOMYOPATHY; MYOCYTE DIFFERENTIATION; INDUCED CARDIOTOXICITY; INHIBIT APOPTOSIS; OXIDATIVE STRESS; MECHANISMS; CARDIOMYOCYTES; PROLIFERATION; REGENERATION; Multidisciplinary Sciences

Abstract

Doxorubicin (DOX), an effective chemotherapeutic drug used in the treatment of various cancers, is limited in its clinical applications due to cardiotoxicity. Recent studies suggest that transplanted adult stem cells inhibit DOX-induced cardiotoxicity. However, the effects of transplanted embryonic stem (ES) and induced pluripotent stem (iPS) cells are completely unknown in DOX-induced left ventricular dysfunction following myocardial infarction (MI). In brief, C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+ cell culture (CC) media, DOX-MI+ ES cells, and DOX-MI+ iPS cells. Mice were injected with cumulative dose of 12 mg/kg of DOX and 2 weeks later, MI was induced by coronary artery ligation. Following ligation, 5x10(4) ES or iPS cells were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice were sacrificed, and hearts were harvested for further analyses. Our data reveal apoptosis was significantly inhibited in ES and iPS cell transplanted hearts compared with respective controls (DOX-MI+ES: 0.48 +/- 0.06% and DOX-MI+iPS: 0.33 +/- 0.05% vs. DOX-MI: 1.04 +/- 0.07% and DOX-MI+CC: 0.96 +/- 0.21%; p<0.05). Furthermore, a significant increase in levels of Notch-1 (p<0.05), Hes1 (p<0.05), and pAkt (p<0.05) were observed whereas a decrease in the levels of PTEN (p<0.05), a negative regulator of Akt, was evident following stem cell transplantation. Moreover, hearts transplanted with stem cells demonstrated decreased vascular and interstitial fibrosis (p<0.05) as well as MMP-9 expression (p<0.01) compared with controls. Additionally, heart function was significantly improved (p<0.05) in both cell-transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the Notch pathway.

Journal Title

Plos One

Volume

9

Issue/Number

7

Publication Date

1-1-2014

Document Type

Article

Language

English

First Page

9

WOS Identifier

WOS:000341354100055

ISSN

1932-6203

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