Abstract
BackgroundHuman mesenchymal stem cells (hMSCs) are broadly discussed as a promising cell population amongst others for regenerative therapy of ischemic heart disease and its consequences. Although cardiac-specific differentiation of hMSCs was reported in several in vitro studies, these results were sometimes controversial and not reproducible.ResultsIn our study we have analyzed different published protocols of cardiac differentiation of hMSCs and their modifications, including the use of differentiation cocktails, different biomaterial scaffolds, co-culture techniques, and two- and three-dimensional cultures. We also studied whether 5'-azacytidin and trichostatin A treatments in combination with the techniques mentioned above can increase the cardiomyogenic potential of hMSCs. We found that hMSCs failed to generate functionally active cardiomyocytes in vitro, although part of the cells demonstrated increased levels of cardiac-specific gene expression when treated with differentiation factors, chemical substances, or co-cultured with native cardiomyocytes.ConclusionThe failure of hMSCs to form cardiomyocytes makes doubtful the possibility of their use for mechanical reparation of the heart muscle.
Highlights
Human mesenchymal stem cells are broadly discussed as a promising cell population amongst others for regenerative therapy of ischemic heart disease and its consequences
When examined untreated cells for expression of cardiac markers, primary Human mesenchymal stem cells (hMSCs) showed different repertoire of cardiac-specific genes expressed depending on the source of the cells: 40 cycles PCR revealed low levels of Nkx2.5, MEF2A, and MEF2D gene expression in hMSCs isolated from bone marrow aspirate, while primary hMSCs cells from spongiosa expressed MEF2A and in a very low extent MYH7B (Fig. 1C)
The main findings of our work are as follows: i) Three-dimensional culture in the presence of insulin, dexamethasone, and ascorbic acid appeared to be the most promising method of cardiomyocyte-like cells generation from hMSCs in vitro relied on the use of simple chemical inducers of cardiac differentiation pathways. ii) Pretreatment with 5-azacytidine and trichostatin A does not lead to any significant increase of the efficacy of differentiation protocols. iii) The biomaterials Resomer® RG 503 and Texin® 950 are promising for uses as scaffolds in techniques of cardiac-like cells generation from hMSCs in vitro. iv) Even untreated hMSCs demonstrate some level of cardiac-specific gene expression, and co-culturing of hMSCs with cardiomyocytes does not result in a real transdifferentiation of hMSCs
Summary
Human mesenchymal stem cells (hMSCs) are broadly discussed as a promising cell population amongst others for regenerative therapy of ischemic heart disease and its consequences. Human mesenchymal stem cells (hMSCs) are available from bone marrow, umbilical cord blood and adipose tissue They are multipotent cells, which can differentiate into specialized tissues, including bone, cartilage, fat, tendon, muscle, and stroma [1,2], and allow autologous transplantation. Since undifferentiated MSCs tend to spontaneously differentiate into multiple lineages when transplanted in vivo [5,10], it is likely that such uncommitted stem cells may undergo unanticipated differentiation within infarcted myocardium. This can in turn reduce the clinical efficacy of the stem cell transplantation therapy for myocardial infarction. Adult MSCs may differentiate (page number not for citation purposes)
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