Abstract
Chronic wounds are a major complication in patients with cardiovascular diseases. Cell therapies have shown potential to stimulate wound healing, but clinical trials using adult stem cells have been tempered by limited numbers of cells and invasive procurement procedures. Induced pluripotent stem cells (iPSCs) have several advantages of other cell types, for example they can be generated in abundance from patients’ somatic cells (autologous) or those from a matched donor. iPSCs can be efficiently differentiated to functional endothelial cells (iPSC-ECs). Here, we used a murine excisional wound model to test the pro-angiogenic properties of iPSC-ECs in wound healing. Two full-thickness wounds were made on the dorsum of NOD-SCID mice and splinted. iPSC-ECs (5 × 105) were topically applied to one wound, with the other serving as a control. Treatment with iPSC-ECs significantly increased wound perfusion and accelerated wound closure. Expression of endothelial cell (EC) surface marker, platelet endothelial cell adhesion molecule (PECAM-1) (CD31), and pro-angiogenic EC receptor, Tie1, mRNA was up-regulated in iPSC-EC treated wounds at 7 days post-wounding. Histological analysis of wound sections showed increased capillary density in iPSC-EC wounds at days 7 and 14 post-wounding, and increased collagen content at day 14. Anti-GFP fluorescence confirmed presence of iPSC-ECs in the wounds. Bioluminescent imaging (BLI) showed progressive decline of iPSC-ECs over time, suggesting that iPSC-ECs are acting primarily through short-term paracrine effects. These results highlight the pro-regenerative effects of iPSC-ECs and demonstrate that they are a promising potential therapy for intractable wounds.
Highlights
Due to poor circulation and prolonged tissue ischaemia, many patients with peripheral arterial disease (PAD) develop chronic wounds or ulcers on their lower limbs, which can become infected and often necessitate amputation of the affected foot or leg
Immunohistochemistry staining of the enhanced GFP (eGFP) marker identified induced pluripotent stem cell (iPSC)-endothelial cell (EC) engrafted within the wound site at day 7, and a smaller proportion remaining at 14 days post-transplantation (Figure 1C)
We have demonstrated for the first time that human iPSC-derived endothelial cell (iPSC-EC) have pro-angiogenic functionality in wound healing, promote fibroblast infiltration and collagen deposition and accelerate wound closure
Summary
Due to poor circulation and prolonged tissue ischaemia, many patients with peripheral arterial disease (PAD) develop chronic wounds or ulcers on their lower limbs, which can become infected and often necessitate amputation of the affected foot or leg. Revascularization therapies improve wound healing in patients with critical limb ischaemia, yet chronic wounds remain a major individual and societal burden, with estimated global cost of care in excess of US$ 22 billion each year [1,2]. Other treatment options include bioactive dressings and donor keratinocytes, but these have limitations and additional therapies are c 2018 The Author(s).
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