Enhancement of stem cell regenerative properties by hydrogen sulfide: a novel wound dressing to augment stem cell therapies

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Abstract Despite significant improvements in the care of burn patients, approximately 40,000 patients are hospitalized yearly in the United States for the treatment of severe burns, an injury associated with slow recovery and high costs of care. Because delayed wound healing prolongs hospitalization and increases risk of infection, identification of safe and effective treatments that promote wound healing would facilitate recovery and improve outcomes for burn patients. The application of adult adipose-derived stem cells (ADSC) to regenerate skin in burn wounds is becoming increasingly recognized for its potential as an effective treatment to accelerate healing and recovery. However, methods to improve cell delivery to wounds, and ADSC viability and reparative functions are needed to increase the efficacy of this developing regenerative therapy. Hydrogen sulfide (H2S) is a gaseous biological mediator with a range of effects in various tissues. Recently it has been shown that H2S can increase the proliferation, viability and functions of bone marrow- and adipose-derived stem cells, confirmed by our preliminary data. We propose that local H2S treatment can enhance the regenerative properties of ADSC therapy and accelerate burn wound repair. However, the effective application of H2S to wounds is challenging due to a lack of stable H2S donors or inducing agents that can be topically delivered with controlled release. A biocompatible hyaluronic acid (HA)-based hydrogel, loaded with a slow- release H2S donor, has been developed and used as a dressing to enhance non-burn wound healing. Further, a HA-hydrogel with encapsulated MSC has been developed. In this project, a dual-loaded HA-based hydrogel, containing both an H2S donor and ADSC, will be developed and applied to burn wounds as a dressing. We hypothesize that application of a dual-loaded ADSC/H2S-releasing dressing to burn wounds will accelerate healing through effects of H2S on ADSC survival, proliferation and production of trophic factors that stimulate healing responses. This will be tested through the following aims: 1) To demonstrate improvement of ADSC wound therapy by H2S using dual-loaded ADSC-H2S releasing wound dressings in an ovine model of severe injury and autologous grafting.; 2) To characterize the effects of H2S on ADSC properties and functions that promote wound healing, under normal and hypoxic conditions (model of ischemic wound environment); 3) To demonstrate that H2S increases therapeutic efficacy of human ADSC for the treatment of burn wounds. This project will not only identify a novel wound dressing to improve healing, but it will also establish H2S as a treatment to augment regenerative stem cell therapies for the treatment of burns and other diseases and will provide insight into regulation of ADSC biology by H2S.