Grants Funded

Abstract

Impact Statement: Ulcers are a major complication of diabetes that leads to a considerable rate of amputation and mortality. Allogeneic transplantation of adipose-derived mesenchymal stem cells (ADMSCs) is a promising method for treating the diabetic wound. However, the persistent hyperglycemia and consistently elevated inflammatory environment of diabetic wounds dramatically impairs the function of transplanted ADMSCs and the viability of the ADMSCs. The proposed studies are designed to test the hypothesis that deletion of NRIP1 can improve function of ADMSCs and the microenvironment in diabetic wounds. Confirming this hypothesis will provide a novel therapeutic target and will be a critical step forward in developing a novel therapeutic method to improve the healing of diabetic wounds.

Project Summary: Ulcers are a major complication of diabetes that leads to a considerable rate of amputation and mortality along with severe economic and social burdens. In the past decade, transplantation of adipose-derived mesenchymal stem cells (ADMSCs) has become a promising approach for treating diabetic wounds. Recently, transplantation using allogeneic ADMSCs has attracted increasing attention because MSCs, including ADMSCs, have a hypoimmunogenic phenotype, which allow them to evade immune recognition. However, in diabetic wounds, the persistent hyperglycemia and consistently elevated inflammatory environment dramatically impairs the function of transplanted ADMSCs. Our previous studies found that suppressing nuclear receptor interacting protein 1 (NRIP1) reduced apoptosis and delayed senescence of ADMSCs, and also reduced the production of pro-inflammatory cytokines in ADMSCs and macrophage. These results indicate that NRIP1 is a promising target to enhance the viability of ADMSCs and improve the microenvironment of diabetic wounds. We will determine the effects of deleting NRIP1 in the ADMSCs on cell proliferation, apoptosis, and senescence, both in vitro and in vivo models that mimic the diabetic wound environment. We will also investigate if the deletion of NRIP1 in ADMSCs can improve the microenvironment by suppressing inflammation and prompting tissue regeneration, including angiogenesis. We will develop a gene therapy method, siRNA treatment, to directly suppress NRIP1 expression in the wound area. Using this model, we will investigate the effects of suppressing NRIP1 in the diabetic wound on the viability and function of the transplanted ADMSCs. Eventually, using this model, we will thoroughly investigate if the deletion of NRIP1 in ADMSCs and diabetic wounds can improve the treatment with allogeneic transplantation of ADMSCs. For carrying out this study, we have generated a unique mouse model, in which Nrip1 is deleted and a tracking marker, green fluorescent protein (GFP), is inserted. This model will allow us accurately evaluate the effects of deleting NRIP1 on the function of ADMSCs in wound healing. Importantly, different from many other studies, the proposed work utilizes a sophisticated mouse colony, four-way-cross (FWC) colony. Mice of this colony are genetically unique; therefore, these animals mimic the heterogeneous human population and are more suitable for the study of allogeneic transplantation.

Biography
Dr. Michael W. Neumeister is Professor and Chairman of the Department of Surgery and the Elvin G. Zook Endowed Chair in the Institute for Plastic Surgery at Southern Illinois University School of Medicine. He joined the SIU faculty in 1997. He is director of the hand surgery fellowship program, Chief of microsurgery and research, and director of the Wound Care Center, Ambulatory Care Center and the Regional Burn Unit at Memorial Medical Center. Prior to joining SIU, Neumeister completed a year fellowship in hand and microsurgery at SIU School of Medicine’s Division Plastic Surgery and a 3 month microsurgery fellowship at Harvard University’s Brigham & Women’s Hospital in Boston. He completed his residency in plastic surgery at Manitoba University in Winnipeg, Manitoba and his general surgery residency at Dalhousie University in Halifax, Nova Scotia. Dr. Neumeister received his medical degree from the University of Toronto and bachelor’s in Physiology/Pharmacology from the University of Western Ontario in London, Ontario. Neumeister is board certified in plastic surgery by both the Royal College of Surgeons of Canada and the American Board of Plastic Surgeons and holds a Certificate of Added Qualification in Hand Surgery. Dr. Neumeister’s research interests include; tissue engineering, the role of stem cells in reconstruction, ischemia reperfusion, upper extremity reconstruction, peripheral nerve, and burn modulation.