TGF-β2 treatment enhances cytoprotective factors released from embryonic stem cells and inhibits apoptosis in infarcted myocardium

We investigated whether factors released from mouse embryonic stem (ES) cells primed with and without transforming growth factor (TGF)-β2 inhibit iodoacetic acid (IAA)- and H(2)O(2)-induced apoptosis in the cell culture system as well as after transplantation in the infarcted heart. We generated con...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2011-04, Vol.300 (4), p.H1442-H1450
Main Authors: Singla, Dinender K, Singla, Reetu D, Lamm, Stephanie, Glass, Carley
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Cell Line
Cell Survival - drug effects
Culture Media, Conditioned - pharmacology
Cytoprotection - drug effects
Embryonic Stem Cells - metabolism
Embryonic Stem Cells - secretion
Female
Hydrogen Peroxide - pharmacology
Indoleacetic Acids - pharmacology
Integrative Cardiovascular Physiology and Pathophysiology
Interleukin-10 - secretion
Male
Matrix Metalloproteinase 1 - secretion
Mice
Mice, Inbred C57BL
Myocardial Infarction - drug therapy
Myocardial Infarction - therapy
Stem Cell Factor - secretion
Stem Cell Transplantation
Tissue Inhibitor of Metalloproteinase-1 - secretion
Transforming Growth Factor beta2 - pharmacology
Vascular Endothelial Growth Factors - secretion
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Summary:We investigated whether factors released from mouse embryonic stem (ES) cells primed with and without transforming growth factor (TGF)-β2 inhibit iodoacetic acid (IAA)- and H(2)O(2)-induced apoptosis in the cell culture system as well as after transplantation in the infarcted heart. We generated conditioned media (CMs) from ES cells primed with and without TGF-β2 and determined their effects on IAA- and H(2)O(2)-induced apoptosis in H9c2 cells. We also transplanted both ES-CMs in the infarcted heart to determine the effects on apoptosis and cardiac function after myocardial infarction (MI) at day (D)1 and D14. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, apoptotic ELISA, and cell viability data demonstrated significantly (P < 0.05) reduced apoptosis with ES-CM compared with controls in both cell culture models. Moreover, TGF-β2-primed ES-CM (T-ES-CM) demonstrated enhanced beneficial effects, with further reduced (P < 0.05) apoptosis compared with ES-CM, suggesting the a presence of additional cytoprotective released factors after TGF-β2 treatment. Next, our in vivo apoptosis data suggested significant decrease in apoptosis with both ES-CMs compared with MI alone at D1 and D14. Notably, T-ES-CM demonstrated significant (P < 0.05) inhibition of apoptosis and fibrosis with improved cardiac function compared with ES-CM at D14, whereas no such effects were observed at D1. Next, we confirmed that apoptosis is mediated through a prosurvival Akt pathway. Moreover, we determined that after TGF-β2 treatment there was a two- to fivefold increase in cytoprotective released factors (interleukin-10, stem cell factor, tissue inhibitor of matrix metalloproteinase-1, and VEGF) with T-ES-CM compared with ES-CM. In conclusion, we suggest that factors released from ES cells with and without TGF-β2 treatment contain antiapoptotic factors that inhibit apoptosis in vitro and in vivo. We also suggest that T-ES-CM demonstrates additional beneficial effects that provide useful information for future therapeutic applications in regenerative medicine.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00917.2010