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TNF, signaling through TNFR2, has been implicated in tissue repair, a process that in the heart may be mediated by activated resident cardiac stem cells (CSCs). The objective of our study is to determine whether ligation of TNFR2 can induce activation of resident CSCs in the setting of ischemic cardiac injury. We show that in human cardiac tissue affected by ischemia heart disease (IHD), TNFR2 is expressed on intrinsic CSCs, identified as c‐kit + /CD45 − /VEGFR2 −  interstitial round cells, which are activated as determined by entry to cell cycle and expression of Lin‐28. Wild‐type mouse heart organ cultures subjected to hypoxic conditions both increase cardiac TNF expression and show induced TNFR2 and Lin‐28 expression in c‐kit +  CSCs that have entered cell cycle. These CSC responses are enhanced by exogenous TNF. TNFR2 −/−  mouse heart organ cultures subjected to hypoxia increase cardiac TNF but fail to induce CSC activation. Similarly, c‐kit +  CSCs isolated from mouse hearts exposed to hypoxia or TNF show induction of Lin‐28, TNFR2, cell cycle entry, and cardiogenic marker, α‐sarcomeric actin (α‐SA), responses more pronounced by hypoxia in combination with TNF. Knockdown of Lin‐28 by siRNA results in reduced levels of TNFR2 expression, cell cycle entry, and diminished expression of α‐SA. We conclude that hypoxia‐induced c‐kit +  CSC activation is mediated by TNF/TNFR2/Lin‐28 signaling. These observations suggest that TNFR2 signaling in resident c‐kit +  CSCs induces cardiac repair, findings which provide further understanding of the unanticipated harmful effects of TNF blockade in human IHD. S tem  C ells   2013;31:1881‐1892

TNF, acting through inducibly expressed TNFR2, drives activation and cell cycle entry of c‐Kit + cardiac stem cells in ischemic heart disease