Human induced pluripotent stem cells as a source of mesenchymal stromal cells for the treatment of cutaneous radiation injuries

Background & Aim The current management of victims of radiological burns, resulting from industrial or medical accidental exposure, consists in autologous mesenchymal stromal cell (MSC) injection associated with reparative surgery. MSCs were shown to promote tissue regeneration and angiogenesis, and control inflammation. However, several limits inherent to the use of adult stem cells were identified, such as the limited capacity for large-scale production of clinical grade MSCs, or the loss of functionality of the graft. We hypothesized that MSCs derived from pluripotent stem cells (PSCs) could represent a relevant alternative source of cell therapy product for the treatment of radiological burns. Methods, Results & Conclusion PSC-MSCs were derived from six independent human embryonic or induced pluripotent (iPS-MSCs) stem cell lines, adult MSCs were isolated from fat tissue by explant culture, and all cell lines were expanded in clinical grade-compatible culture conditions. Cutaneous radiation injury was induced by exposing mouse skin to 20 Gy X-ray irradiation, followed by full-thickness skin excision. Mice then received a local injection of 106 human adult or PSC-derived MSCs, or PBS. Animals were monitored for 2 weeks by assessing wound closure kinetics, cutaneous perfusion by laser Doppler imaging, and skin functional parameters using a Cutometer. Blood and skin tissue were collected for histological and molecular analyses, and angiogenesis assessment. Animals injected with adult or iPS-MSCs displayed accelerated wound healing kinetics compared to PBS injection, with significant 1.25-fold reduction of wound area at day 3 post-injury (p<0.01). Hematoxylin/eosin staining of skin tissue sections confirmed the improved wound reepithelialization in iPS-MSC-treated group. The viscoelastic properties of regenerated skin in iPS-MSC-treated animals were restored to levels measured in control skin from unharmed mice (p<0.05). A significant 1.4-fold increase in the dermal density of von Willebrand factor-positive blood vessels was observed in MSC-injected animals, compared to PBS-injected mice (p<0.01), associated with a mild increase of cutaneous perfusion. The iPS-MSC proangiogenic effect was further demonstrated through formation of functional tube-like structures using subcutaneous Matrigel plug assay. These results suggest that iPS-MSCs exert a beneficial effect on irradiated skin wound healing, by promoting reepithelialization and enhancing angiogenesis. The current management of victims of radiological burns, resulting from industrial or medical accidental exposure, consists in autologous mesenchymal stromal cell (MSC) injection associated with reparative surgery. MSCs were shown to promote tissue regeneration and angiogenesis, and control inflammation. However, several limits inherent to the use of adult stem cells were identified, such as the limited capacity for large-scale production of clinical grade MSCs, or the loss of functionality of the graft. We hypothesized that MSCs derived from pluripotent stem cells (PSCs) could represent a relevant alternative source of cell therapy product for the treatment of radiological burns. PSC-MSCs were derived from six independent human embryonic or induced pluripotent (iPS-MSCs) stem cell lines, adult MSCs were isolated from fat tissue by explant culture, and all cell lines were expanded in clinical grade-compatible culture conditions. Cutaneous radiation injury was induced by exposing mouse skin to 20 Gy X-ray irradiation, followed by full-thickness skin excision. Mice then received a local injection of 106 human adult or PSC-derived MSCs, or PBS. Animals were monitored for 2 weeks by assessing wound closure kinetics, cutaneous perfusion by laser Doppler imaging, and skin functional parameters using a Cutometer. Blood and skin tissue were collected for histological and molecular analyses, and angiogenesis assessment.