RT Journal Article T1 Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell A1 Alejandra Romecin, Paola A1 Vinyoles, Meritxell A1 Lopez-Millan, Belen A1 Diaz de la Guardia, Rafael A1 Atucha, Noemi M. A1 Querol, Sergi A1 Bueno, Clara A1 Benitez, Raquel A1 Gonzalez-Rey, Elena A1 Delgado, Mario A1 Menendez, Pablo K1 BM-MSC K1 WJ-MSC K1 iCasp9 switch K1 immunosuppression K1 anti-inflammatory K1 colitis in vivo model K1 Experimental colitis K1 Safety switch K1 Protein K1 Improve AB Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cell-free therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a "suicide gene" switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both "parental" alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs. PB Oxford univ press SN 2157-6564 YR 2022 FD 2022-03-03 LK http://hdl.handle.net/10668/19838 UL http://hdl.handle.net/10668/19838 LA en DS RISalud RD Apr 9, 2025