Progenitor Cells in Diabetes Impaired Wound Healing

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Summary: Diabetic healing impairment represents a major clinical problem resulting in prolonged hospitalizations, lost time from work, and significant healthcare costs. Normal wound healing is an intricate process involving multiple growth factors, cell types, and signaling interactions. In impaired diabetic wound healing, alterations in growth factor production, cellular recruitment, angiogenesis, extracellular matrix (ECM) production, and wound contraction have all been shown to contribute. Cellular based therapy is a novel approach to diabetic impaired wound healing because of the potential to correct many of these deficits. We have recently shown that stromal progenitor cells (SPC) can correct the diabetic wound healing impairment, and that diabetic wounds are deficient in chemokines responsible for progenitor cell recruitment. In addition, lentiviral overexpression of the chemokine SDF1-a also corrects the diabetic impairments in re-epithelialization and granulation tissue production. We propose further studies to define the mechanisms of this correction and to use this insight to modify the diabetic wound healing response. Specific Aim 1: To characterize the mechanisms by which stromal progenitor cell treatment corrects the diabetic wound healing impairment. We propose to use our db/db model of diabetic impaired wound healing to characterize the mechanisms by which SPC treatment corrects the diabetic wound healing impairment. Specifically, using a novel approach of laser capture microdissection, we will examine the separate contribution of exogenous SPC and endogenous wound cells to; 1) The production of growth factors involved in re-epithelialization, granulation tissue production, and progenitor cell recruitment 2) The recruitment of progenitor cells 3) The production and quality of the extracellular matrix and wound biomechanical properties. Specific Aim 2: To characterize the potential for increased endogenous progenitor cell recruitment to correct diabetic wound healing impairment. We propose to use our db/db model of diabetic impaired wound healing to characterize the mechanism by which lentiviral overexpression of SDF-1a corrects the diabetic wound healing impairment. Specifically, we will examine; 1) The recruitment of endothelial and stromal progenitor cells, 2) The wound production of growth factors, chemokines, and ECM molecules, 3) The biomechanical properties of the wound, following lenti-SDF1-a treatment. In addition, we will examine the effect of impaired release of progenitor cells from the bone marrow on the correction of the wound healing defect with SDF-1a. Correction of the diabetic wound healing impairment has far-reaching consequences, including decreased hospitalizations, functional improvements, decreased surgical procedures, and perhaps most significantly, decrease wound care costs. Successful completion of the study aims and implementation of our proposed novel interventions would have an enormous impact on healthcare expenditures and functional outcomes in diabetic wounds and may impact the treatment of all chronic wounds.