Stromal Cell Derived Factor-1[alpha] Promotes C-Kit+ Cardiac Stem/Progenitor Cell Quiescence Through Casein Kinase 1[alpha] and GSK3[beta]

• Published in: Stem cells (Dayton, Ohio) Vol. 32; no. 2; p. 487
• Main Authors: Dimova, Neviana, Wysoczynski, Marcin, Rokosh, Gregg
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2014
• Subjects: Cell cycle; Phosphorylation
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.1534

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 1[alpha] (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 1[alpha] (CK1[alpha]) consequently attenuating [beta]-catenin phosphorylation, destabilization, and degradation. Increased levels of [beta]-catenin with SDF1 were effective, increasing TCF/LEF reporter activity. SDF downregulation of CK1[alpha] was dependent on proteasomal degradation and decreased mRNA expression. CK1[alpha] siRNA knockdown verified SDF1-dependent CSPC quiescence requires CK1[alpha] downregulation and stablilization of [beta]-catenin. Conversely, [beta]-catenin knockdown increased CSPC proliferation. SDF1 also increased GSK3[beta] Y216 phosphorylation responsible for increased activity. SDF1 mediated CK1[alpha] downregulation and increase in GSK3[beta] 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 CK1[alpha] levels, increasing GSK3[beta] activity, stabilizing [beta]-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. Stem Cells 2014;32:487-499 [PUBLICATION ABSTRACT]