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Wound Healing Potential Of Human Ipsc-derived Vascular Smooth Muscle Cells
Henry Hsia, Biraja Dash, Ocean Setia, Hassan Peyvandi, Lara Lopes, James Nie, Alan Dardik.
Yale School of Medicine, New Haven, CT, USA.

BACKGROUND: While proangiogenic cell therapy has already been shown to promote healing, their lack of availability in abundance is a major limitation. In this current study, we investigated the wound healing potential of naïve vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (hiPSC) embedded within collagen scaffolds with the aim of using iPSC-derived VSMCs to enhance angiogenesis and promote healing. METHODS: VSMCs were efficiently differentiated from hiPSCs using an embryoid body method. Highly pure and functional hiPSC-VSMCs were embedded in a hypoxia-inducing rolled scaffold made using type I collagen. Unrolled flat scaffolds were also created as normoxic controls. Scaffolds were assessed for growth factor production using biochemical assays and also implanted onto a nude mouse splinted back acute wound model. RESULTS: The hypoxia activated VSMCs in the scaffolds, demonstrating cell viability and maintenance of their phenotype. The VSMC scaffold released significantly greater levels of proangiogenic growth factors such as VEGF and IL-8 compared to control flat, normoxic VSMC scaffolds. Both hypoxic and normoxic scaffolds released paracrine factors such as bFGF, SDF-1αand Ang-1. In anin vivosplinted back acute wound model in nude mice, the rolled VSMC scaffolds showed enhanced endogenous vascularization and formation of chimeric vessels as well as better re-epithelialization and dermis regeneration compared to control scaffolds. CONCLUSIONS: These data suggest that hypoxic rolled VSMC scaffolds may be useful in promoting accelerated wound closure and warrant further investigation into their translational potential for promoting regenerative healing.

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