Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction

Abstract

We have identified a subpopulation of stem cells within adult human BM, isolated at the single-cell level, that self-renew without loss of multipotency for more than 140 population doublings and exhibit the capacity for differentiation into cells of all 3 germ layers. Based on surface marker expression, these clonally expanded human BM-derived multipotent stem cells (hBMSCs) do not appear to belong to any previously described BM-derived stem cell population. Intramyocardial transplantation of hBMSCs after myocardial infarction resulted in robust engraftment of transplanted cells, which exhibited colocalization with markers of cardiomyocyte (CMC), EC, and smooth muscle cell (SMC) identity, consistent with differentiation of hBMSCs into multiple lineages in vivo. Furthermore, upregulation of paracrine factors including angiogenic cytokines and antiapoptotic factors, and proliferation of host ECs and CMCs, were observed in the hBMSC-transplanted hearts. Coculture of hBMSCs with CMCs, ECs, or SMCs revealed that phenotypic changes of hBMSCs result from both differentiation and fusion. Collectively, the favorable effect of hBMSC transplantation after myocardial infarction appears to be due to augmentation of proliferation and preservation of host myocardial tissues as well as differentiation of hBMSCs for tissue regeneration and repair. To our knowledge, this is the first demonstration that a specific population of multipotent human BM-derived stem cells can induce both therapeutic neovascularization and endogenous and exogenous cardiomyogenesis.

Concise Review: Culture Mediated Changes in Fate and/or Potency of Stem Cells

“…Since the original description of rodent MAPC, other groups and we have published that cells with broader differentiation potential can also be culture-isolated from human tissues, including BM (MAPC, marrow isolated adult multili- [48][49][50][51][52]. The cell surface phenotype, TF expression profile and differentiation potential of these cells is summarized in Table 1.…”

Epigenetics and the plasticity of differentiation in normal and cancer stem cells

“…Mesenchymal stem cells in the bone marrow can differentiate to muscle (Ferrari et al, 1998;Dezawa et al, 2005), neural lineage cells (Kopen et al, 1999;Dezawa et al, 2004) and to various other cell types (Jiang et al, 2002). Another distinct population of bone marrow-derived stem cells can differentiate to cells of various lineages including muscle, endothelial, epithelial and neural cells (Yoon et al, 2005). Other adult stem cells that can be induced to differentiate to a different cell type, include skeletal muscle stem cells to blood cells (Jackson et al, 1999;Cao et al, 2003) and neural cells (Romero-Ramos et al, 2002); cardiac muscle stem cells to endothelial cells (Mohri et al, 2006); neural stem cells to blood and endothelial cells (Bjornson et al, 1999;Wurmser et al, 2004); hair follicle stem cells to neural lineage cells (Amoh et al, 2005a, b); and testis-derived stem cells to a wide variety of cell types (KanatsuShinohara et al, 2004;Guan et al, 2006).…”

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

“…51 Fluorescence activated cell sorting showed that this cell type does not belong to previously identified populations of multipotent bone marrow-derived cells.…”