title: Stromal cell derived factor-1α promotes C-Kit+ cardiac stem/progenitor cell quiescence through casein kinase 1α and GSK3β.
abstract: A population of c-kit(+) cardiac stem/progenitor cells (CSPC) has been identified in the heart and shown to contribute to myocardial regeneration after infarction. Previously, we have shown the chemokine, stromal cell derived factor 1α (SDF1) is necessary for the myocardial response to infarction where chronic infusion of the CXCR4 antagonist, AMD3100, exacerbated MI. Notably, AMD3100 increased CSPC proliferation. The effect of SDF1 on CSPC proliferation was further investigated in primary cultures of magnetically sorted c-kit(+) CSPCs. SDF1 facilitated CSPC quiescence by blocking cell cycle progression at the G0 to G1 transition. SDF1 decreased casein kinase 1α (CK1α) consequently attenuating β-catenin phosphorylation, destabilization, and degradation. Increased levels of β-catenin with SDF1 were effective, increasing TCF/LEF reporter activity. SDF downregulation of CK1α was dependent on proteasomal degradation and decreased mRNA expression. CK1α siRNA knockdown verified SDF1-dependent CSPC quiescence requires CK1α downregulation and stablilization of β-catenin. Conversely, β-catenin knockdown increased CSPC proliferation. SDF1 also increased GSK3β Y216 phosphorylation responsible for increased activity. SDF1 mediated CK1α downregulation and increase in GSK3β activity affected cell cycle through Bmi-1 downregulation, increased cyclin D1 phosphorylation, and decreased cyclin D1 levels. In conclusion, SDF1 exerts a quiescent effect on resident c-kit(+) CSPCs by decreasing CK1α levels, increasing GSK3β activity, stabilizing β-catenin, and affecting regulation of the cell cycle through Bmi-1 and cyclin D1. SDF1-dependent quiescence is an important factor in stem and progenitor cell preservation under basal conditions, however, with stress or injury in which SDF1 is elevated, quiescence may limit expansion and contribution to myocardial regeneration.
authors.affiliation: Institute of Molecular Cardiology, Division of Cardiovascular Medicine, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Neviana
authors.initials: N
authors.lastname: Dimova
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.forename: Gregg
authors.initials: G
authors.lastname: Rokosh
mesh_terms: D048128:Casein Kinase Ialpha / Q000235:genetics* / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019938:Cyclin D1; D019009:Proto-Oncogene Proteins c-kit; D048128:Casein Kinase Ialpha; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: CXCR4; Casein kinase 1α; Cell cycle; Glycogen synthase kinase3β; Stromal cell derived factor 1α; β-Catenin
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