In Situ Skin Regeneration through Induction of Skin Allograft Chimerism for Treatment of Severe Burn Wounds

Burns affect >11 million people worldwide annually. A fourth of all burn injuries occur in children under age 16 and burns are a major source of morbidity and mortality in children. Treatment of large full thickness burns is a major challenge due to limitations of autogenous skin, wound infection, severe metabolic stress and other associated injuries. The long time to burn wound closure results in susceptibility to infection, prolonged pain and long hospitalization. Human deceased donor skin allografts are a temporizing option for skin cover following severe burn injury, but the grafts are soon rejected. While modern treatment provides survival from severe burns, the healing leaves an imperfect result with scarring, disfiguration, loss of critical skin functions, and increased vulnerability to late, cosmetic, psychological, and physical defects, especially in children. A breakthrough to achieve regeneration of perfect skin has thus become a major aim in wound healing. In response to these challenges, we propose to induce in situ skin regeneration through repopulation of skin allografts using our recently discovered novel stem cell mobilizing therapy. In search for better therapy for organ transplantation patients, a new two-drug combination (AMD3100=A, low-dose-FK506=F) or MRG was discovered serendipitously that enabled long-term liver and kidney allograft survival with short-term treatment and freedom from immunosuppression. This tolerance was associated with allograft chimerism (Host repopulation) and local down regulation of the immune response. AF treatment also accelerated skin wound healing and promoted hair follicle neogenesis. We hypothesize that in situ skin regeneration can be realized by host repopulation of skin allografts through pharmacological mobilization of endogenous bone marrow stem cells with a mechanism similar to protection from liver/kidney allograft rejection. Rejecting skin allografts may create a local environment which facilitates recruitment of mobilized host stem cells, while recruited stem cells may differentiate into components of skin and repopulate the allografts. Thus transplanted skin eventually become “self”. This “allograft chimerism” approach represents a paradigm shift in which skin allografts are treated as “biological scaffolds” which the host repopulates with circulating bone marrow derived stem cells, during which time the allografts are protected from rejection. The main goals of this proposal are to understand the mechanisms of skin regeneration through repopulation of skin allografts in small animal models and to demonstrate the efficacy and feasibility of our novel stem cell mobilizing therapy in repopulation of skin allografts in a preclinical large animal (swine) model of full thickness burns. This work, if successful, will cause a paradigm shift using skin allografts and stem cell mobilizing therapy to heal severe wounds/burns through scar free skin regeneration.