Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity.
The mechanism(s) underlying cardiac reparative effects of bone marrow-derived mesenchymal stem cells (MSC) remain highly controversial. Here we tested the hypothesis that MSCs regenerate chronically infarcted myocardium through mechanisms comprising long-term engraftment and trilineage differentiation. Twelve weeks after myocardial infarction, female swine received catheter-based transendocardial injections of either placebo (n = 4) or male allogeneic MSCs (200 million; n = 6). Animals underwent serial cardiac magnetic resonance imaging, and in vivo cell fate was determined by co-localization of Y-chromosome (Y(pos)) cells with markers of cardiac, vascular muscle, and endothelial lineages. MSCs engrafted in infarct and border zones and differentiated into cardiomyocytes as ascertained by co-localization with GATA-4, Nkx2.5, and alpha-sarcomeric actin. In addition, Y(pos) MSCs exhibited vascular smooth muscle and endothelial cell differentiation, contributing to large and small vessel formation. Infarct size was reduced from 19.3 +/- 1.7% to 13.9 +/- 2.0% (P < 0.001), and ejection fraction (EF) increased from 35.0 +/- 1.7% to 41.3 +/- 2.7% (P < 0.05) in MSC but not placebo pigs over 12 weeks. This was accompanied by increases in regional contractility and myocardial blood flow (MBF), particularly in the infarct border zone. Importantly, MSC engraftment correlated with functional recovery in contractility (R = 0.85, P < 0.05) and MBF (R = 0.76, P < 0.01). Together these findings demonstrate long-term MSC survival, engraftment, and trilineage differentiation following transplantation into chronically scarred myocardium. MSCs are an adult stem cell with the capacity for cardiomyogenesis and vasculogenesis which contribute, at least in part, to their ability to repair chronically scarred myocardium.
Quevedo
Henry C
HC
Interdisciplinary Stem Cell Institute and Department of Medicine, Cardiovascular Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Hatzistergos
Konstantinos E
KE
Oskouei
Behzad N
BN
Feigenbaum
Gary S
GS
Rodriguez
Jose E
JE
Valdes
David
D
Pattany
Pradip M
PM
Zambrano
Juan P
JP
Hu
Qinghua
Q
McNiece
Ian
I
Heldman
Alan W
AW
Hare
Joshua M
JM
D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D009202:Cardiomyopathies / Q000473:pathology*; D002454:Cell Differentiation; D002470:Cell Survival; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D007511:Ischemia / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010919:Placebos; D013552:Swine; D013556:Swine, Miniature; D014157:Transcription Factors / Q000378:metabolism; D014998:Y Chromosome / Q000378:metabolism*
D000199:Actins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D010919:Placebos; D014157:Transcription Factors