Abstract
Human pluripotent stem cells (hPSCs) can provide unlimited supply for mesenchymal stem cells (MSCs) and adipocytes that can be used for therapeutic applications. Here we developed a simple and highly efficient all-trans-retinoic acid (RA)-based method for generating an off-the-shelf and scalable number of human pluripotent stem cell (hPSC)-derived MSCs with enhanced adipogenic potential. We showed that short exposure of multiple hPSC lines (hESCs/hiPSCs) to 10 μM RA dramatically enhances embryoid body (EB) formation through regulation of genes activating signaling pathways associated with cell proliferation, survival and adhesion, among others. Disruption of cell adhesion induced the subsequent differentiation of the highly expanded RA-derived EB-forming cells into a pure population of multipotent MSCs (up to 1542-fold increase in comparison to RA-untreated counterparts). Interestingly, the RA-derived MSCs displayed enhanced differentiation potential into adipocytes. Thus, these findings present a novel RA-based approach for providing an unlimited source of MSCs and adipocytes that can be used for regenerative medicine, drug screening and disease modeling applications.
Highlights
Mesenchymal stem cells (MSCs) have been demonstrated to be a promising option for cellular therapies given their curative properties of immunomodulation, trophic support and homing, and differentiation into specific cells of a damaged tissue, as well as their poor immunogenicity allowing allogenic transplantation without strong immunosuppressants [1]
To test whether retinoic acid (RA) can enhance the generation of mesenchymal stem cells (MSCs) from Human pluripotent stem cells (hPSCs), we first checked the effect of this retinoid on the formation of embryoid body (EB), i.e., intermediates in the hPSC to MSC differentiation
HPSCs were dissociated into small aggregates and cultured in suspension to allow EB formation
Summary
Mesenchymal stem cells (MSCs) have been demonstrated to be a promising option for cellular therapies given their curative properties of immunomodulation, trophic support and homing, and differentiation into specific cells of a damaged tissue, as well as their poor immunogenicity allowing allogenic transplantation without strong immunosuppressants [1]. Difficulties in obtaining therapeutic numbers of MSCs with appropriate differentiation capabilities have hampered the use of these multipotent cells in clinics. MSCs compose a negligible fraction of cells within in vivo tissues and need to be subjected to the process of in vitro expansion [2]. Isolation of MSCs from adult sources involves invasive and often painful procedures with possible donor site morbidity [2]. Whatever the source, the isolated MSCs show heterogeneity in their proliferation and differentiation capabilities, which are further reduced during in vitro expansion [3].The variations in the properties of isolated MSCs are due to the differences in the nature of their niche, donor age and their isolation, as well as culturing methods
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