Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways

Konstantinos E. Hatzistergos, Dieter Saur, Barbara Seidler, Wayne Balkan, Matthew Breton, Krystalenia Valasaki, Lauro M. Takeuchi, Ana Marie Landin, Aisha Khan, Joshua M. Hare

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Rationale: Culture-expanded cells originating from cardiac tissue that express the cell surface receptor cKit are undergoing clinical testing as a cell source for heart failure and congenital heart disease. Although accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit+ cells (CSCs), the underlying mechanism for this synergistic effect remains incompletely understood. Objective: To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and stem cell factor/cKit pathways. Methods and Results: Using genetic lineage-Tracing approaches, we show that in the postnatal murine heart, cKit+ cells proliferate, migrate, and form cardiomyocytes, but not endothelial cells. CSCs exhibit marked chemotactic and proliferative responses when cocultured with MSCs but not with cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 (an SDF1/CXCR4 antagonist) inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (P<0.0001). Furthermore, MSCs enhanced CSC proliferation via the stem cell factor/cKit and SDF1/CXCR4 pathways (P<0.0001). Conclusions: Together these findings show that MSCs exhibit profound, yet differential, effects on CSC migration, proliferation, and differentiation and suggest a mechanism underlying the improved cardiac regeneration associated with combination therapy using CSCs and MSCs. These findings have important therapeutic implications for cell-based therapy strategies that use mixtures of CSCs and MSCs.

Original languageEnglish (US)
Pages (from-to)921-930
Number of pages10
JournalCirculation research
Volume119
Issue number8
DOIs
StatePublished - Sep 30 2016

Keywords

  • CXCR4
  • coculture techniques
  • mesenchymal stromal cells
  • myocytes, cardiac
  • receptors
  • stem cell factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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