Due to lack of autologous and donor site morbidity, there is a distinct clinical need to increase the utility of skin allografts by improving their acceptance in burn patients. While skin allografts showed some efficacy in this group of patients, however, their utility is limited by their rejection by the host. Systemic immunosuppression is not warranted due to excessive risk of rejection. Mesenchymal stem cells (MSC) have profound immunomodulatory effects. The idea of implantation of MSC with allogeneic tissues constitutes an exciting approach improving its survival by creating a local immune privilege site. Importantly the immune regulation of MSC is a dynamic process. Our targeting and induction data indicate that amongst various subtypes of phosphoinositide 3-kinase (PI3K), PI3Kα pathway is a key regulator of MSC heightened immune-phenotype upon inflammatory signals (such as IFN-γ). Due to lack of autologous and donor site morbidity, there is a distinct clinical need to increase the utility of skin allografts by improving their acceptance in burn patients. Induction of PI3Kα active MSC enhances their immunosuppressive capacity. Here, we test the hypothesis that further activation of PI3K pathway pharmacologically ex vivo, should result in the formation of hyper immunosuppressive MSC. Phosphatase and tensin homolog (PTEN) is a negative regulator of the PI3K signaling. Here, we pretreated our MSC (adipose tissue-derived MSC, passage 5-7) with PTEN inhibitor (SF 1670) overnight. Our treatment markedly upregulated the expression of negative costimulatory molecules PD-L1 (+2.8±0.6-fold, p<0.05). We then seeded our MSC (0.5×10⁶/cm²) on Integra® after overnight incubation with PTEN inhibitor. The Integra enriched with MSC was placed underneath the skin allograft (Balb/C->C57BL/6, n=5). Untreated MSC emphasized a slight prolongation of allograft survival (from 10.3±0.5 to 12.3±1.1 days, p>0.05). The induced MSC showed a significant increase of allograft survival (18.7±1.5, p<0.05). Such prolongation in a skin transplant model with no systemic immunosuppression highlights the potential efficacy of our localized immune deliver. We are currently carrying combinatorial strategies to further improve the outcome of our skin transplant. We believe our approach has the potential to improve the outcome of severe burn patients.

CITATION INFORMATION: Climov M, Uehara M, Solhjou Z, Matsumine H, Bouyani N, Kefaloyianni E, Basmani B, Kasinath V, Giatsidis G, Orgill D, Abdi R. PTEN Inhibition in MSC Upregulates PD-L1 and Enhances Their Immunomodulatory Capacity Prolonging Skin Allograft Survival. Am J Transplant. 2017;17 (suppl 3).

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