Document Detail

Embryonic stem cells improve cardiac function in Doxorubicin-induced cardiomyopathy mediated through multiple mechanisms.
MedLine Citation:
PMID:  22449713     Owner:  NLM     Status:  MEDLINE    
Doxorubicin (DOX) is an effective antineoplastic 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 HGF 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.
Dinender K Singla; Aisha Ahmed; Reetu Singla; Binbin Yan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-03-22
Journal Detail:
Title:  Cell transplantation     Volume:  21     ISSN:  1555-3892     ISO Abbreviation:  Cell Transplant     Publication Date:  2012  
Date Detail:
Created Date:  2013-01-29     Completed Date:  2013-12-06     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  9208854     Medline TA:  Cell Transplant     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1919-30     Citation Subset:  IM    
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MeSH Terms
Apoptosis / drug effects
Cardiomyopathies / chemically induced*,  pathology,  surgery*
Cell Differentiation / physiology
Disease Models, Animal
Doxorubicin / adverse effects*
Embryonic Stem Cells / metabolism,  pathology,  transplantation*
Fibrosis / chemically induced,  pathology
Mice, Inbred C57BL
Myocytes, Cardiac / metabolism,  pathology
Stem Cell Transplantation / methods*
Grant Support
1R01HL090646-01/HL/NHLBI NIH HHS; 5R01HL094467-02/HL/NHLBI NIH HHS; R01 HL090646/HL/NHLBI NIH HHS; R01 HL090646-01/HL/NHLBI NIH HHS; R01 HL094467/HL/NHLBI NIH HHS; R01 HL094467-02/HL/NHLBI NIH HHS
Reg. No./Substance:

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