Sca-1+ Cardiosphere-Derived Cells Are Enriched for Isl1-Expressing Cardiac Precursors and Improve Cardiac Function after Myocardial Injury

Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 01/2012; 7(1):e30329. DOI: 10.1371/journal.pone.0030329
Source: PubMed


Endogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI). However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs) have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear.
Using "middle aged" mice as CSs donors, we found that acute MI induced a dramatic increase in the number of CSs in a mouse model of MI, and this increase was attenuated back to baseline over time. We also observed that CSs from post-MI hearts engrafted in ischemic myocardium induced angiogenesis and restored cardiac function. To determine the role of Sca-1(+)CD45(-) cells within CSs, we cloned these from single cell isolates. Expression of Islet-1 (Isl1) in Sca-1(+)CD45(-) cells from CSs was 3-fold higher than in whole CSs. Cloned Sca-1(+)CD45(-) cells had the ability to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro. We also observed that cloned cells engrafted in ischemic myocardium induced angiogenesis, differentiated into endothelial and smooth muscle cells and improved cardiac function in post-MI hearts.
These studies demonstrate that cloned Sca-1(+)CD45(-) cells derived from CSs from infarcted "middle aged" hearts are enriched for second heart field (i.e., Isl-1(+)) precursors that give rise to both myocardial and vascular tissues, and may be an appropriate source of progenitor cells for autologous cell-therapy post-MI.

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    • "To date, multiple endogenous stem and progenitor cell populations have been isolated from the postnatal mammalian heart and these cells to varying degrees can differentiate into cardiomyocytes when transplanted into infarcted hearts (Bearzi et al., 2007; Beltrami et al., 2003; Bu et al., 2009; Chong et al., 2011; Ellison et al., 2013; Goumans et al., 2007; Hierlihy et al., 2002; Laugwitz et al., 2005; Matsuura et al., 2004; Messina et al., 2004; Oh et al., 2003; Pfister et al., 2010; Smith et al., 2007; Uchida et al., 2013; van Berlo et al., 2014; Ye et al., 2012). Other promising sources for generating cardiomyocytes in vitro are embryonic stem cells (He, 2003; Kattman et al., 2006; Kehat et al., 2001; Mummery et al., 2003; Yang et al., 2008) and induced pluripotent stem cells (Mauritz et al., 2008; Narazaki et al., 2008; Zhang A C C E P T E D M A N U S C R I P T "
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    • "We did not directly examine vascularity or composition of the myocardium in Sca-1 KO animals. We recently showed that Sca-1-expressing cells differentiate into multiple myocardial cell types in vitro, and that these cells induce angiogenesis and differentiate into endothelial and smooth muscle cells in mouse hearts following myocardial infarction 27. It is possible that Sca-1 deficiency in KO animals also may be playing a role in physical conditioning as a function of cardiovascular fitness. "
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    • "Other evidence supports the hypothesis that Isl1+ cells are not a different population from Sca-1+ CPCs. The contemporary expression of Sca-1 and Isl1 has been described both in a subpopulation of Sca-1+/c-Kit- cells identified and isolated from adult mouse hearts22 and in Sca-1+ cardiosphere-derived cells obtained from cardiac explants from normal, sham-operated or post-myocardial infarct hearts.23 In this study, only Sca-1+/CD45- cells were also positive for Isl1 and increased in number only after an acute myocardial infarct.23 "
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