title: Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.
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.
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Siena
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gimmelli
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: S L
authors.initials: SL
authors.lastname: Nori
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Barbagallo
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Campolo
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Dolci
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Venneri
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giannetta
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Gianfrilli
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer research, Frederick, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lenzi
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Naro
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cianflone
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Mancuso
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Torella
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Isidori
authors.affiliation: Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pellegrini
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002451:Cell Compartmentation; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006410:Hematopoiesis; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D016019:Survival Analysis; D014945:Wound Healing
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases