The epidemic of heart failure has stimulated interest in understanding cardiac regeneration. Evidence has been reported supporting regeneration via transplantation of multiple cell types, as well as replication of postmitotic cardiomyocytes. In addition, the adult myocardium harbors endogenous c-kit(pos) cardiac stem cells (eCSCs), whose relevance for regeneration is controversial. Here, using different rodent models of diffuse myocardial damage causing acute heart failure, we show that eCSCs restore cardiac function by regenerating lost cardiomyocytes. Ablation of the eCSC abolishes regeneration and functional recovery. The regenerative process is completely restored by replacing the ablated eCSCs with the progeny of one eCSC. eCSCs recovered from the host and recloned retain their regenerative potential in vivo and in vitro. After regeneration, selective suicide of these exogenous CSCs and their progeny abolishes regeneration, severely impairing ventricular performance. These data show that c-kit(pos) eCSCs are necessary and sufficient for the regeneration and repair of myocardial damage.

In an animal model of AMI relevant to the human disease, intracoronary administration of IGF-1/HGF is a practical and effective strategy to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function.

Oncogenic Kit mutations are found in somatic gastrointestinal (GI) stromal tumors (GISTs) and mastocytosis. A mouse model for the study of constitutive activation of Kit in oncogenesis has been produced by a knock-in strategy introducing a Kit exon 11-activating mutation into the mouse genome based on a mutation found in a case of human familial GIST syndrome. Heterozygous mutant Kit V558⌬ ͞؉ mice develop symptoms of disease and eventually die from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells is evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Therefore Kit V558⌬ ͞؉ mice reproduce human familial GISTs, and they may be used as a model for the study of the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal. Kit encodes a growth factor receptor with ligand-dependent tyrosine kinase activity (1-3). Kit ligand (KitL) is the only known ligand of the Kit receptor (4). KitL binding to the receptor mediates receptor dimerization, activation of kinase activity, and autophosphorylation. Subsequently, Kit activates several signaling cascades, leading to cell proliferation, cell survival, and other cellular responses. Kit and KitL are encoded at the White spotting (W) and Steel (Sl) loci in the mouse, respectively (4-6). Mutations at the murine W and Sl loci generate deficiencies in several major cell systems during embryogenesis and in the postnatal animal: in hematopoiesis, melanogenesis, gametogenesis, and intestinal pacemaker cells. In hematopoiesis Kit receptor signaling is critical in the stem cell hierarchy, erythropoiesis, mast cell development and function, megakaryopoiesis, and lymphopoiesis (7-10). Interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal (GI) tract and they mediate inputs from the enteric nervous system to smooth muscle cells. ICC express the Kit receptor tyrosine kinase and inhibition of Kit function interferes with the autonomous movement of the GI tract (11-13).GI stromal tumor (GIST) is the most common mesenchymal neoplasm of the human intestinal tract. GISTs are a heterogeneous group of tumors, which historically had been classified either as leiomyoma, leiomyosarcoma, or GI autonomic nerve tumors (14). GISTs express Kit and they are thought to derive from a Kit ϩ or Kit low ICC progenitor or ICC through somatic mutation, based on immunophenotypic and ultrastructural similarities (15).Originally, we had identified Kit as the oncogene of an acute transforming feline retrovirus, the HZ4-FeSV (1). However, a role for Kit in human neoplasia has been emerging only more recently. First, human and murine mast cell lines were found to carry Kit-activating mutations in the activation loop of the kinas...

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