Mesenchymal Stem Cells To Mitigate and Treat Cutaneous Injury Following Radiation

University Of California Los Angeles, Los Angeles CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Loss of skin barrier function can dramatically increase morbidity and mortality from radiation exposure in a nuclear accident, attack, or terrorist incident. Skin damage can be the result of radiation-induced acute desquamation and/or dermal damage that is normally expressed late but can be precipitated by physical trauma, burns, or penetrating wounds. In extensive experiments, we showed that skin irradiation compromises wound healing, but perhaps more importantly whole body radiation exposure seriously impacts the healing process by depleting circulating bone marrow- derived cells. Quantitative assays of wound tensile strength showed that moderate doses of 4-7Gy to the whole body were equivalent to 15-20Gy to the skin. There are many radiation scenarios where whole body radiation exposure will compromise the skin healing process, which cannot be considered as a skin only issue. We showed that implants of mesenchymal cells could correct radiation-induced dermal deficits. This approach is however limited by the fact that only a small percent of the implanted cells remaine in the site to be active and those that do have to be capable of extensive proliferation i.e. to be mesenchymal stem cells (MSCs). To overcome these limitations, we developed techniques to rapidly and selectively isolate MSCs from varying sources based on the finding that they adhere to multiple homologous C-terminal peptides on [unreadable]- and ?-chains of fibrin(ogen), termed haptides. We made fibrin microbeads (FMBs) that are far superior to conventional techniques for the isolation, purification, and proliferation of MSCs allowing high cell numbers to be obtained rapidly for implantation. Furthermore, FMBs are biodegradable and are therefore excellent vehicles for delivering MSCs into incisions in radiation-compromised skin and keeping them viable and proliferating in the site. We also developed haptized collagen sponge sheets to support MSCs and that are a better choice for delivering MSCs to areas of radiation-induced moist desquamation. FMBs and haptized collagen sheets will be used to compare bone marrow-derived and G-CSF-mobilized MSCs for their ability to heal radiation-compromised skin incisions and areas of moist desquamation. The influence of whole body radiation exposure on skin healing will be examined to mimic the likely reality in an accidental or terrorist event. Syngeneic MSCs will be compared with allogeneic MSCs, since that latter can be more readily available in an emergency situation. In addition, the influence of G-CSF and GM- CSF treatment, which are likely to be used in a radiation exposure setting, will be tested. Effectiveness will be assessed using highly quantitative or semi-quantitative measures to establish dose-modifying factors, with findings confirmed by histology. Performance Site: UCLA, Los Angeles, CA PROGRAM NARRATIVE In individuals exposed to radiation as a result of a nuclear accident or terrorist attack, radiation can destroy wound healing ability as well as cause more superficial burn-like lesions over a wide area of skin. This study will use implants of cells that migrate into wounds called mesenchymal stem cells (MSC) to correct these forms of radiation skin damage. We will use biodegradable microbeads made from a natural protein involved in blood clotting called fibrin (FMB) to rapidly isolate and support MSCs and deliver them as implants into the wound, where they persist and proliferate. To cover wide areas of radiation-induced burns, we will add MSCs on FMBs to natural collagen sheets as a form of biological dressing. [unreadable] [unreadable] [unreadable]