Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation.
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.
Hatzistergos
Konstantinos E
KE
University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL 33136, USA.
Quevedo
Henry
H
Oskouei
Behzad N
BN
Hu
Qinghua
Q
Feigenbaum
Gary S
GS
Margitich
Irene S
IS
Mazhari
Ramesh
R
Boyle
Andrew J
AJ
Zambrano
Juan P
JP
Rodriguez
Jose E
JE
Dulce
Raul
R
Pattany
Pradip M
PM
Valdes
David
D
Revilla
Concepcion
C
Heldman
Alan W
AW
McNiece
Ian
I
Hare
Joshua M
JM
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
D017077:Culture Media, Conditioned; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit