Authors:
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; and Joshua M. Hare
Summary:
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 & 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. 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.
Source:
Circulation Research; (07/29/10)