SummaryEpigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling. However, the underlying regulatory mechanism remains to be elucidated. Here we identified a heart-enriched long non-coding (lnc)RNA, named Cardiac Hypertrophy Associated Epigenetic Regulator (Chaer), necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with Polycomb Repressor Complex 2 (PRC2) catalytic subunit through a 66-mer motif, interferes with its targeting to genomic locus, and subsequently inhibits histone H3 lysine 27 methylation at hypertrophic genes. This interaction is transiently induced upon hormone or stress stimulation in an mTORC1 dependent manner, and is prerequisite for epigenetic reprogramming and induction of hypertrophic genes. Inhibition of Chaer in intact heart before, but not after, the onset of pressure overload significantly attenuates cardiac hypertrophy and dysfunction. Therefore, our study reveals that stress-induced pathological gene activation in heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.

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Given the established anti-inflammatory properties of mesenchymal stromal cells (MSCs), we investigated their effect on inflammatory cell infiltration of ischemic cardiac tissue and cardiac function. We employed two types of MSCs, human bone marrow-derived (BM) MSCs and human umbilical cord perivascular cells in an experimental acute myocardial infarction (MI) model with the immune-deficient NOD/SCID gamma null mouse. Cells were infused 48 h after induction of MI and mice assessed 24 h later (72 h after MI) for bone marrow (BM), circulating and cardiac tissue-infiltrating monocytes/macrophages. We showed that in the presence of either MSC type, overall macrophage/monocyte levels were reduced, including pro-inflammatory M1-type macrophages, while the proportion of alternatively activated M2-type macrophages was significantly increased in the circulation and heart but not the BM. Moreover, we found decreased expression of IL-1β and IL-6, increased IL-10 expression and fewer apoptotic cardiomyocytes without changes in angiogenesis in the infarct area. Fractional shortening was enhanced 2 weeks after cell infusion but was similar to medium controls 16 weeks after MI. In vitro studies showed that BM MSCs increased the frequency of alternatively activated monocytes/macrophages, in part by MSC-mediated secretion of IL-10. Our data suggest a new mechanism for MSC-mediated enhancement of cardiac function, possibly via an IL-10 mediated switch from infiltration of pro-inflammatory to anti-inflammatory macrophages at the infarct site. Additional studies are warranted confirming the role of IL-10 and augmenting the anti-inflammatory effects of MSCs in cardiac regeneration.