Abstract
A major translational challenge in the fields of therapeutic angiogenesis and regenerative medicine is the need to create functional microvasculature. The purpose of this study was to assess whether a potentially autologous endothelial cell (EC) source derived from human induced pluripotent stem cells (iPSC-ECs) can form the same robust, stable microvasculature as previously documented for other sources of ECs. We utilized a well-established in vitro assay, in which endothelial cell-coated (iPSC-EC or HUVEC) beads were co-embedded with fibroblasts in a 3D fibrin matrix to assess their ability to form stable microvessels. iPSC-ECs exhibited a five-fold reduction in capillary network formation compared to HUVECs. Increasing matrix density reduced sprouting, although this effect was attenuated by distributing the NHLFs throughout the matrix. Inhibition of both MMP- and plasmin-mediated fibrinolysis was required to completely block sprouting of both HUVECs and iPSC-ECs. Further analysis revealed MMP-9 expression and activity were significantly lower in iPSC-EC/NHLF co-cultures than in HUVEC/NHLF co-cultures at later time points, which may account for the observed deficiencies in angiogenic sprouting of the iPSC-ECs. Collectively, these findings suggest fundamental differences in EC phenotypes must be better understood to enable the promise and potential of iPSC-ECs for clinical translation to be realized.
Highlights
Numerous cardiovascular diseases are characterized by ischemia, a reduction/obstruction of oxygenated blood supply to tissues, which can eventually lead to necrosis[1]
On days 7 and 14, the capillary sprouting of induced pluripotent stem cells (iPSC)-endothelial cell (EC) (1) showed significant reductions in their networks compared to the two human umbilical vein endothelial cells (HUVECs) conditions (Fig. 1A), while no capillary sprouting was evident for iPSC-ECs (2)
Their venous origins are often cited as a potential problem, despite evidence in the literature that ECs in the arterial circulation arise from a venous origin in development[40]
Summary
Numerous cardiovascular diseases are characterized by ischemia, a reduction/obstruction of oxygenated blood supply to tissues, which can eventually lead to necrosis[1]. Some strategies involve implanting engineered scaffolds or co-delivering endothelial cells (ECs) with stromal cells to promote vessel in-growth or stable, mature vasculature formation, respectively[12,13,14,15] Despite these advances, there are still critical challenges that plague their application, such as possible immunorejection from the host and the vast number of cells required for human translation[16,17,18]. IPSCs offer numerous advantages including their potential autologous nature, which could eliminate any immunological concerns during their therapeutic delivery Since these cells are derived from adult somatic cells, there is little ethical concern over their use, despite their stem cell-like lineage. While this research is promising for tissue engineering and revascularization, very little is known about how these cells behave and compare to other endothelial cell sources, in the quantity, quality, and function of the vessel-like networks formed
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