A Pilot Study to Develop New Therapy Approach for Diabetic Foot Ulcers
Diabetic foot ulcers (DFU) represent a major clinical and scientific problem that demands solutions. DFUs affect more than 6 million Americans, significantly reduces their quality of life, carries a high mortality due to associated complications, burdening health care system with costs over $20 billion. Despite urgent need for new effective therapies no new efficacious therapy was approved for past 20 years. Therefore, we propose this innovative pilot project to pre-clinically test a new strategy in the cell-based therapy that involves catalase-modified diabetic adipocyte-derived stem cells (ASCs) and their exosomes. One major contributor to impaired healing, are the hormonal changes associated with diabetes and aging. A key factor associated with the gradual change in hormones is enhanced oxidant stress as evidenced by decreased expression of superoxide dismutase and catalase. Recent studies have shown that mesenchymal stem cells derived from diabetic and elderly individuals have similar phenotype, including increased oxidative stress and impaired regenerative capability that precludes their use as autologous therapy. Our preliminary data suggest that reversing oxidant stress in aging ASCs by the knock-in of catalase improves their ability to promote wound healing, while knock-down of catalase in young ASCs renders the young ASC repair phenotype ineffective. Thus, we propose the hypothesis that catalase replete diabetic ASCs will promote tissue repair by restoring a healthy ASC oxidant status. We will test our hypothesis using DFU 3D organoid human skin wound models that utilizes primary cells derived from DFU patients. Aim 1 fill focus to determine whether catalase replete diabetic ASCs achieve reprogramming of the delayed healing using 3D DFU human organoid culture whereas Aim 2 will evaluate therapeutic potential of exosomes derived from catalase replete ASCs. The goal of this project is to pre-clinically test the novel strategy to convert diabetic ASCs and their exosomes into potent therapy that promotes healing of DFUs, which will provide novel therapeutic strategy for patients suffering from diabetic foot ulcers.