Therapeutic Effects of Human STRO-3-Selected Mesenchymal Precursor Cells and their Soluble Factors in Experimental Myocardial Ischemia

Abstract

Background: The STRO-3 antigen has previously been shown to identify a subset of adult human bone marrow (BM)-derived mesenchymal lineage precursors, which may have cardioprotective potential. We sought to characterize STRO-3+-immunoselected and culture-expanded mesenchymal precursor cells (MPCs) with respect to their biology and therapeutic potential in myocardial ischemia. Methods and Results: Immunoselection of STRO-3+ MPCs enriched for fibroblastic colony forming units from unfractionated BM MNCs. Compared to mesenchymal stem cells conventionally isolated by plastic adherence, MPCs demonstrated increased proliferative capacity during culture-expansion, expressed higher levels of early “stem cell” markers and various proangiogenic and cardioprotective cytokines, and exhibited greater trilineage developmental efficiency. Intramyocardial injection of MPCs into a rat model of myocardial infarction (MI) promoted LV recovery and inhibited LV dilatation. These beneficial effects were associated with cardioprotective and proangiogenic effects at the tissue level, despite poor engraftment of cells. Treatment of MI rats with MPC-conditioned medium (CM) preserved LV function and dimensions, reduced myocyte apoptosis and fibrosis, and augmented neovascularization, involving both resident vascular cells and circulating endothelial progenitor cells (EPCs). Profiling of CM revealed various cardioprotective and proangiogenic factors, which had biological activity in cultures of myocytes, tissue-resident vascular cells and EPCs. Conclusions: Prospective immunoselection of STRO-3+ MPCs from BM MNCs confers advantage in maintaining a population of immature mesenchymal precursor cells during ex vivo expansion. Transplantation of culture-expanded MPCs into the post-MI heart results in therapeutic benefit, attributable at least in part to paracrine mechanisms of action. Thus, MPCs represent a promising therapy for myocardial ischemia.