Alejandra Romecin, PaolaVinyoles, MeritxellLopez-Millan, BelenDiaz de la Guardia, RafaelAtucha, Noemi M.Querol, SergiBueno, ClaraBenitez, RaquelGonzalez-Rey, ElenaDelgado, MarioMenendez, Pablo2023-05-032023-05-032022-03-032157-6564http://hdl.handle.net/10668/19838Mesenchymal 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/BM-MSCWJ-MSCiCasp9 switchimmunosuppressionanti-inflammatorycolitis in vivo modelExperimental colitisSafety switchProteinImproveresearch articleopen access10.1093/stcltm/szab0072157-6580https://doi.org/10.1093/stcltm/szab007763662500010