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Improved Engraftment of Autologous Skin Grafts in Diabetic Mice with Adipose-Derived Stem Cells
Michael Hu, MD, MPH, MS, Wan Xing Hong, MS, Kshemendra Senarath-Yapa, MA, MBBChir, MRCS, Andrew Zimmermann, BS, Michael Chung, BS, Mikaela Esquivel, N/A, Adrian McArdle, MB, BCh, BAO(NUI), MRCSI, Graham Walmsley, AB, Zeshaan Maan, MBBS, MS, MRCS, Rebecca Garza, MD, H. Peter Lorenz, MD, Michael Longaker, MD, MBA.
Stanford, Stanford, CA, USA.
Non-healing diabetic wounds are a major health concern in the US, affecting over 1 in 10 diabetic patients. With the increasing prevalence of diabetes, a significant rise in the number of diabetic patients suffering from non-healing wounds is also expected to occur. However, therapies currently available to diabetics are often insufficient to ensure satisfactory wound healing. Thus there is an urgent need for novel therapeutic strategies to address non-healing diabetic wounds. Autologous full thickness skin grafts are one of the most common procedures used for wound closure in both diabetic and nondiabetic patients. However, in diabetic patients skin graft rejection is common because of poor circulation around the graft and surrounding wound areas.
One strategy that has been identified as particularly promising has been a cell-based therapeutic approach utilizing adipose-derived stem cells (ASCs). ASCs are an abundant and easily accessible population of adult pluripotent stem cells present in stromal tissue. They can be readily isolated from patients through minimally invasive techniques, potentially allowing for autologous transplantation. ASCs have been shown to promote wound healing in hypoxic environments by releasing various cytokines and growth factors at the wound to promote neovascularization. However, whether ASCs can increase the success of autologous full thickness skin grafts in a diabetic setting remains unclear. In this study we examine the ability of ASCs to mediate acceptance of autologous skin grafts in both wild-type and diabetic mice.
Therapeutic ASCs were isolated from fat harvested from the inguinal fat pads of transgenic FVB-L2G mice. A 6mm full thickness excisional wound was created on the dorsum of wild-type FVB mice. The right ear of each mouse was harvested and the epithelial layer used as an autologous skin graft. Skin grafts were then placed over the cutaneous wounds. Wounds were treated with or without ASCs (5 x 105) in PBS cell suspension via injection under the wound bed. As the ASCs from the L2G transgenic mice luminesce when interacting with injected luciferin, this enabled the quantification of ASC survival in vivo through bioluminescent imaging (BLI). The effectiveness of the treatments was recorded over a period of two weeks via quantification of wound healing.
ASCs were found to promote acceptance of the autologous skin grafts in diabetic mice. All wild-type mice demonstrated successful engraftment of the autologous full thickness skin graft with or without ASC treatment. Diabetic mice with ASC treatment achieved 100% engraftment whereas only 20% of grafts were taken in control diabetic mice (*p<0.03). BLI revealed survival of ASCs when assessing for engraftment two weeks following wounding.
We demonstrate complete engraftment of all full thickness skin grafts in diabetic mice with therapeutic ASCs. This cell-based application may improve the efficacy of skin grafting in both diabetic and nondiabetic patients.
Acknowledgment: Support for this research was provided by the Sarnoff Cardiovascular Foundation and the California Institute for Regenerative Medicine (CIRM).
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