Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity

Henry C. Quevedo, Konstantinos E. Hatzistergos, Behzad N. Oskouei, Gary S. Feigenbaum, Jose E. Rodriguez, David Valdes, Pradip M. Pattany, Juan P. Zambrano, Qinghua Hu, Ian McNiece, Alan W. Heldman, Joshua M. Hare

Research output: Contribution to journalArticlepeer-review

440 Scopus citations

Abstract

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 (Ypos) 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 α-sarcomeric actin. In addition, Ypos 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.

Original languageEnglish (US)
Pages (from-to)14022-14027
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number33
DOIs
StatePublished - Aug 18 2009

Keywords

  • Cardiac chimerism
  • Catheter delivery
  • Cellular cardiomyoplasty
  • Heart failure

ASJC Scopus subject areas

  • General

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