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

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

Research output: Contribution to journalArticle

42 Citations (Scopus)

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. While accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit cells (CSCs), the underlying mechanism for this synergistic effect remain incompletely understood. OBJECTIVE.: To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and SCF/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 co-cultured with MSCs but not cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (p<0.0001). Furthermore, MSCs enhanced CSC proliferation via the SCF/cKit and SDF1/CXCR4 pathways (p<0.0001). CONCLUSIONS.: Together these findings show that MSCs exhibit profound, yet differential, effects upon 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 employ mixtures of CSCs and MSCs.

Original languageEnglish (US)
JournalCirculation Research
DOIs
StateAccepted/In press - Aug 3 2016

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Mesenchymal Stromal Cells
Stem Cells
Cell Surface Receptors
Chemotaxis
Stromal Cells
Cell- and Tissue-Based Therapy
Cardiac Myocytes
Regeneration
Heart Diseases
Endothelial Cells
Heart Failure
Cell Culture Techniques
Therapeutics

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Cardiology and Cardiovascular Medicine

Cite this

Stimulatory Effects of MSCs on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. / Hatzistergos, Konstantinos E.; Saur, Dieter; Seidler, Barbara; Balkan, Wayne E; Breton, Matthew; Valasaki, Krystalenia; Takeuchi, Lauro M.; Landin, Ana Marie; Khan, Aisha; Hare, Joshua.

In: Circulation Research, 03.08.2016.

Research output: Contribution to journalArticle

Hatzistergos, Konstantinos E. ; Saur, Dieter ; Seidler, Barbara ; Balkan, Wayne E ; Breton, Matthew ; Valasaki, Krystalenia ; Takeuchi, Lauro M. ; Landin, Ana Marie ; Khan, Aisha ; Hare, Joshua. / Stimulatory Effects of MSCs on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. In: Circulation Research. 2016.
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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. While accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit cells (CSCs), the underlying mechanism for this synergistic effect remain incompletely understood. OBJECTIVE.: To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and SCF/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 co-cultured with MSCs but not cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (p<0.0001). Furthermore, MSCs enhanced CSC proliferation via the SCF/cKit and SDF1/CXCR4 pathways (p<0.0001). CONCLUSIONS.: Together these findings show that MSCs exhibit profound, yet differential, effects upon 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 employ mixtures of CSCs and MSCs.",
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AU - Breton, Matthew

AU - Valasaki, Krystalenia

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AU - Hare, Joshua

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N2 - 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. While accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit cells (CSCs), the underlying mechanism for this synergistic effect remain incompletely understood. OBJECTIVE.: To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and SCF/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 co-cultured with MSCs but not cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (p<0.0001). Furthermore, MSCs enhanced CSC proliferation via the SCF/cKit and SDF1/CXCR4 pathways (p<0.0001). CONCLUSIONS.: Together these findings show that MSCs exhibit profound, yet differential, effects upon 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 employ mixtures of CSCs and MSCs.

AB - 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. While accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit cells (CSCs), the underlying mechanism for this synergistic effect remain incompletely understood. OBJECTIVE.: To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and SCF/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 co-cultured with MSCs but not cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (p<0.0001). Furthermore, MSCs enhanced CSC proliferation via the SCF/cKit and SDF1/CXCR4 pathways (p<0.0001). CONCLUSIONS.: Together these findings show that MSCs exhibit profound, yet differential, effects upon 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 employ mixtures of CSCs and MSCs.

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