Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury
| Autor: | Andrea Lenzi, A. Isidori, Ma Venneri, Federica Barbagallo, Fabio Naro, Roberto Gimmelli, Manuela Pellegrini, S. Di Siena, Susanna Dolci, Stefania Lucia Nori, Teresa Mancuso, Eleonora Cianflone, Federica Campolo, Pellegrino Rossi, Daniele Torella, Daniele Gianfrilli, Elisa Giannetta, Lionel Feigenbaum |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology Cellular differentiation 030204 cardiovascular system & hematology 0302 clinical medicine C-KIT RECEPTOR CARDIAC STEM CELLS HEART REGENERATION MAPK AND AKT ACTIVATION Phosphorylation Receptor Settore BIO/16 Stem Cells cardiac stem cells Cell Differentiation Cell biology Proto-Oncogene Proteins c-kit cardiac repair Original Article MAPK AND AKT ACTIVATION Mitogen-Activated Protein Kinases Stem cell C-KIT RECEPTOR ERK and AKT signalling Heart regeneration Genetically modified mouse medicine.medical_specialty Transgene Immunology Mice Transgenic Biology 03 medical and health sciences Cellular and Molecular Neuroscience stem-cell factor randomized phase-1 trial myocardial-infarction c-kit(+) cells ischemic cardiomyopathy in-vivo w-locus mutations expression kinase c-Kit medicine Animals Regeneration Progenitor cell Protein kinase B Wound Healing Myocardium c-kit receptor cardiac repair stem cells Endothelial Cells Cell Biology Survival Analysis Cell Compartmentation Hematopoiesis Enzyme Activation 030104 developmental biology Amino Acid Substitution Mutation Proto-Oncogene Proteins c-akt |
| Zdroj: | Cell Death & Disease Cell death and disease 7 (2016). doi:10.1038/cddis.2016.205 info:cnr-pdr/source/autori:Di Siena S.; Gimmelli R.; Nori S.L.; Barbagallo F.; Campolo F.; Dolci S.; Rossi P.; Venneri M.A.; Giannetta E.; Gianfrilli D.; Feigenbaum L.; Lenzi A.; Naro F.; Cianflone E.; Mancuso T.; Torella D.; Isidori A.M.; Pellegrini M./titolo:Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury/doi:10.1038%2Fcddis.2016.205/rivista:Cell death and disease/anno:2016/pagina_da:/pagina_a:/intervallo_pagine:/volume:7 Europe PubMed Central |
| Popis: | 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-KitTgD814Y 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-KitTgD814Y 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-KitTgD814Y 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-KitTgD814Y 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. |
| Databáze: | OpenAIRE |
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