title: Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Breton
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Krystalenia
authors.initials: K
authors.lastname: Valasaki
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Lauro M
authors.initials: LM
authors.lastname: Takeuchi
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Ana Marie
authors.initials: AM
authors.lastname: Landin
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.).
authors.forename: Aisha
authors.initials: A
authors.lastname: Khan
authors.affiliation: From the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, FL (K.E.H., W.B., M.B., K.V., L.M.T., A.M.L., A.K., J.M.H.); Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Germany (D.S., B.S.); and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (D.S., B.S.). jhare@med.miami.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D018920:Coculture Techniques; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010865:Pilot Projects; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D019089:Stem Cell Factor / Q000096:biosynthesis*; D013552:Swine
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit
keywords: coculture techniques; mesenchymal stromal cells; myocytes, cardiac; receptors, CXCR4; stem cell factor