Abstract 17517: A Unique Cardiac Stem Cell Population Regenerates the Lost Myocardium in the Infarcted Heart
We have demonstrated that tissue inhibitor of metalloproteinase-1 (TIMP-1), released from embryonic stem (ES) cells, inhibits adverse cardiac remodeling and improves cardiac function. However, whether these beneficial effects are attributable to the inhibition of cardiac remodeling or the activation of c-kit positive (cardiac progenitor) cells remains elusive. Therefore, we hypothesized that intramyocardial delivery of ES-TIMP1-conditioned medium (CM), following myocardial infarction (MI), activates TIMP-1 specific endogenous stem cells (CSCs) and enhances cardiac regeneration. Accordingly, C57BL6 mice underwent coronary artery ligation followed by intramyocardial delivery of 20μl of either culture media (CC), ES conditioned media (CM), ES-TIMP1-CM or TIMP1. Immunostaining analysis of c-kit, and CD63 (TIMP-1 receptor) demonstrated a significant (p<0.05) increase in c-kit+ cells following ES-TIMP1-CM and TIMP1 treatments compared with controls. Interestingly, up to 60% of these cells co-expressed CD63 receptor. Furthermore, cell specific immmunostaining data revealed that ES-TIMP1-CM significantly (p<0.05) enhances cardiac myocyte and vascular smooth muscle cell differentiation relative to controls. Next, the levels of beta-catenin were significantly increased along with the levels of CD63, suggesting beta-catenin pathway is activated which induces cardiac myocyte differentiation in the ES-TIMP1-CM group. Furthermore, TUNEL, Masson’s Trichrome staining and echocardiography analysis showed ES-TIMP1-CM treatment inhibits cardiac apoptosis, fibrosis and improves cardiac function. Overall, this study demonstrates that TIMP-1 targets a unique CD63+/c-kit+ cell population in the MI heart leading to cardiac regeneration through CD63/β-catenin pathway as well as inhibits cardiac remodeling and improves cardiac function.
- © 2013 by American Heart Association, Inc.