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.

From natural bone grafts to tissue engineering therapeutics: Brainstorming on pharmaceutical formulative requirements and challenges

“…1), chondrocytes, adipocytes, myocytes, stromal cells, and other cells. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] Differentiation is supported by the surrounding environment (e.g., ECM, soluble mediators, growth factors, and cytokines). [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] OBs are cuboidal cells derived from MSCs ( Fig.…”

Cardiovascular development: towards biomedical applicability

“…For some reason, this issue has caught the interest of a large number of investigators, with the result that there are almost as many papers dealing with cell fusion of transplanted Cell fusion has been described in different settings, involving both direct transplantation of non-cardiac cells into the myocardium and through the general circulation. Following the initial demonstration of occasional cell fusion between bone marrow cells and cardiomyocytes in vitro [49] and in vivo [50], phenotypes consistent with cell fusion events were subsequently demonstrated in several others studies, including transfusion of cardiac progenitor cells [21] and bone marrow-derived hematopoietic stem cells injected into the myocardium [51,52], transplantation of skeletal myoblasts into normal hearts [52][53][54], transfusion of human peripheral blood CD34 pos cells into the mouse heart [55] and co-culture of human bone marrow stem cells with rat cardiomyocytes [10].…”

“…Bone marrow-derived cells, along with circulating progenitors, have been used in small clinical trials with inconclusive but generally disappointing results [6,8,9]. Unfortunately, with very few exceptions [9,10] most regenerative assays, including clinical trials, have been performed with non-cloned bone marrow-derived cell preparations, and it is thus impossible to unambiguously ascertain the nature of the regenerating cells, if any. Moreover, recent data have questioned the myogenic potential of bone marrow-derived stem cells [11][12][13], while this potential has been reaffirmed by others [10,[14][15][16].…”

“…Unfortunately, with very few exceptions [9,10] most regenerative assays, including clinical trials, have been performed with non-cloned bone marrow-derived cell preparations, and it is thus impossible to unambiguously ascertain the nature of the regenerating cells, if any. Moreover, recent data have questioned the myogenic potential of bone marrow-derived stem cells [11][12][13], while this potential has been reaffirmed by others [10,[14][15][16]. These discordant results have left an unresolved controversy about the potential and biological bases of myocardial regeneration by bone marrow-derived cells, which threatens the future of this nascent field.…”

Novel therapy for myocardial infarction: can HGF/Met be beneficial?

“…Thus, growth factors and cytokines secreted by exogenously transplanted cells may be advantageous by regulating endogenous processes which would be otherwise insufficient. Among these factors, HGF is released by several types of stem cells, including multipotent bone-marrow-derived cells [127], circulating mononuclear cells [128], endothelial progenitor cells [129,130], mesenchymal stem cells [131,132], tissue-resident c-kit?/MDR1?/Sca1? cells [105] and adipose stem cells [133,134].…”