Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation

Konstantinos E. Hatzistergos, Henry Quevedo, Behzad N. Oskouei, Qinghua Hu, Gary S. Feigenbaum, Irene S. Margitich, Ramesh Mazhari, Andrew J. Boyle, Juan P. Zambrano, Jose E. Rodriguez, Raul Dulce, Pradip M. Pattany, David Valdes, Concepcion Revilla, Alan W. Heldman, Ian McNiece, Joshua M. Hare

Research output: Contribution to journalArticle

528 Scopus citations

Abstract

Rationale: 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. Methods And 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.

Original languageEnglish (US)
Pages (from-to)913-922
Number of pages10
JournalCirculation research
Volume107
Issue number7
DOIs
StatePublished - Oct 1 2010

Keywords

  • cardiac stem cells
  • mesenchymal stem cells
  • myocardial infarction
  • myocardial regeneration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., Hu, Q., Feigenbaum, G. S., Margitich, I. S., Mazhari, R., Boyle, A. J., Zambrano, J. P., Rodriguez, J. E., Dulce, R., Pattany, P. M., Valdes, D., Revilla, C., Heldman, A. W., McNiece, I., & Hare, J. M. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation research, 107(7), 913-922. https://doi.org/10.1161/CIRCRESAHA.110.222703