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.
Di Siena, S., Gimmelli, R., Nori, S., Barbagallo, F., Campolo, F., Dolci, S., et al. (2016). Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury. CELL DEATH & DISEASE, 7(7), e2317.
|Tipologia:||Articolo su rivista|
|Citazione:||Di Siena, S., Gimmelli, R., Nori, S., Barbagallo, F., Campolo, F., Dolci, S., et al. (2016). Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury. CELL DEATH & DISEASE, 7(7), e2317.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/16|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/cddis.2016.205|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||28-lug-2016|
|Titolo:||Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury|
|Autori:||Di Siena, S; Gimmelli, R; Nori, S; Barbagallo, F; Campolo, F; Dolci, S; Rossi, P; Venneri, M; Giannetta, E; Gianfrilli, D; Feigenbaum, L; Lenzi, A; Naro, F; Cianflone, E; Mancuso, T; Torella, D; Isidori, A; Pellegrini, M|
|Appare nelle tipologie:||01 - Articolo su rivista|