Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9- mediated Apoptotic Mesenchymal Stromal/Stem Cell Romecín, Paola Alejandra López Millán, María Belén Díaz de la Guardia Quiles, Rafael Benítez, Raquel González Rey, Elena Delgado, Mario BM-MSC WJ-MSC iCasp9 switch Immunosuppression Anti-inflammatory Colitis in vivo model The financial support for this work was obtained from Health Canada (H4080-144541) to P.M. M.V. and B.L.-M. were supported by a Juan de la Cierva fellowship by the Spanish Ministry of Science and Innovation (IJCI-2017-3317) and a fellowship from the Spanish Association of Cancer Research (AECC), respectively. 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 cellfree 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. 2022-04-01T08:46:57Z 2022-04-01T08:46:57Z 2022-03-03 journal article Paola Alejandra Romecín... [et al.]. Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell, Stem Cells Translational Medicine, Volume 11, Issue 1, January 2022, Pages 88–96, [https://doi.org/10.1093/stcltm/szab007] http://hdl.handle.net/10481/74049 10.1093/stcltm/szab007 eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España Oxford University Press