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 [10.1038/cddis.2016.205].

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

BARBAGALLO, FEDERICA;DOLCI, SILVIA;ROSSI, PELLEGRINO;PELLEGRINI, MANUELA
2016

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/16
English
Con Impact Factor ISI
C-KIT RECEPTOR, CARDIAC STEM CELLS, HEART REGENERATION, MAPK AND AKT ACTIVATION
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 [10.1038/cddis.2016.205].
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/162101
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