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Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury

2016; Springer Nature; Volume: 7; Issue: 7 Linguagem: Inglês

10.1038/cddis.2016.205

2041-4889

Sara Di Siena, Roberto Gimmelli, Stefania Lucia Nori, Federica Barbagallo, Federica Campolo, Susanna Dolci, Pellegrino Rossi, Mary Anna Venneri, Elisa Giannetta, Daniele Gianfrilli, Lionel Feigenbaum, Andrea Lenzi, Fabio Naro, Eleonora Cianflone, Teresa Mancuso, Daniele Torella, Andrea M. Isidori, Manuela Pellegrini,

Tissue Engineering and Regenerative Medicine

Abstract The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-Kit TgD814Y receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit TgD814Y mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit + cardiac cell number was not different compared with wt mice. However, when c-Kit TgD814Y mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit + CD31 + endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45 − c-Kit + cardiac stem cells isolated from transgenic c-Kit TgD814Y mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival.