title: Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation.
abstract: BACKGROUND
  The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes.
  
  
  OBJECTIVE
  Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire.
  
  
  RESULTS
  Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit(+) CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4(+) CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit(+) CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I.
  
  
  CONCLUSIONS
  MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.
authors.affiliation: University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL 33136, USA.
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
authors.forename: Henry
authors.initials: H
authors.lastname: Quevedo
authors.forename: Behzad N
authors.initials: BN
authors.lastname: Oskouei
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hu
authors.forename: Gary S
authors.initials: GS
authors.lastname: Feigenbaum
authors.forename: Irene S
authors.initials: IS
authors.lastname: Margitich
authors.forename: Ramesh
authors.initials: R
authors.lastname: Mazhari
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Boyle
authors.forename: Juan P
authors.initials: JP
authors.lastname: Zambrano
authors.forename: Jose E
authors.initials: JE
authors.lastname: Rodriguez
authors.forename: Raul
authors.initials: R
authors.lastname: Dulce
authors.forename: Pradip M
authors.initials: PM
authors.lastname: Pattany
authors.forename: David
authors.initials: D
authors.lastname: Valdes
authors.forename: Concepcion
authors.initials: C
authors.lastname: Revilla
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.forename: Ian
authors.initials: I
authors.lastname: McNiece
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D001706:Biopsy; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000166:cytology / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology* / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D034421:Sus scrofa
chemical_list: D017077:Culture Media, Conditioned; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit