title: C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways.
abstract: A recent phase I clinical trial (SCIPIO) has shown that autologous c-kit+ cardiac progenitor cells (CPCs) improve cardiac function and quality of life when transplanted into patients with ischemic heart disease. Although c-kit is widely used as a marker of resident CPCs, its role in the regulation of the cellular characteristics of CPCs remains unknown. We hypothesized that c-kit plays a role in the survival, growth, and migration of CPCs. To test this hypothesis, human CPCs were grown under stress conditions in the presence or absence of SCF, and the effects of SCF-mediated activation of c-kit on CPC survival/growth and migration were measured. SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions. In addition, SCF significantly promoted CPC migration in vitro. Furthermore, the pro-survival and pro-migratory effects of SCF were augmented by c-kit overexpression and abrogated by c-kit inhibition with imatinib. Mechanistically, c-kit activation in CPCs led to activation of the PI3K and the MAPK pathways. With the use of specific inhibitors, we confirmed that the SCF/c-kit-dependent survival and chemotaxis of CPCs are dependent on both pathways. Taken together, our findings suggest that c-kit promotes the survival/growth and migration of human CPCs cultured ex vivo via the activation of PI3K and MAPK pathways. These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit.
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Bathri N
authors.initials: BN
authors.lastname: Vajravelu
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Kyung U
authors.initials: KU
authors.lastname: Hong
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Tareq
authors.initials: T
authors.lastname: Al-Maqtari
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Pengxiao
authors.initials: P
authors.lastname: Cao
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Matthew C L
authors.initials: MC
authors.lastname: Keith
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moore
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D019089:Stem Cell Factor / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: D019089:Stem Cell Factor; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases