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Manipulation of Induced Pluripotent Stem Cell Differentiation to Endothelial Cells

With the potential use of induced pluripotent stem cells (iPSCs) in regenerative medicine, strategies must be implemented to guide iPS cell differentiation. Without guidance, the pluripotent nature may yield tumorigenic and/or undesired cell types. Previously we observed that the endothelial cell secretome (EC‐S) derived from conditioned media (EC‐CM) guided iPS cell differentiation to an endothelial cell phenotype. Specifically, the EC‐S induced iPS cell differentiation as evidenced by LDL scavenging and tube formation in vitro. Of keen interest is the question of what product(s) of the EC‐S induce the differentiation of iPS cells. To determine this, we first confirmed that treatment of IPS cells with conditioned media from normoxic or hypoxic (1‐2% O2) endothelial cells produced differentiation of iPS cells into endothelial cells. To determine if a protein factor is responsible for the differentiation, we subjected the conditioned media to heat denaturation (10 min @ 70 C). In media obtained from normoxic endothelial cells, heat denaturation greatly reduced the differentiation of iPS cells into endothelial‐like morphology. In fact the vast majority of cells in culture retained an IPS cell phenotype. Conversely, the heat denatured conditioned media from hypoxic endothelial cells did reduce the differentiation of IPS cells into an endothelial phenotype. These results suggest that the products of the secretome that induce differentiation of iPS cells into endothelial cells are changed by hypoxia. The results also suggest that during normoxia, the active component of the secretome are proteins (the activity is lost with heat denaturation), but this changes during hypoxia to a factor (or factors) that is resistant to heat denaturation.