Publication: Robust In vitro and in vivo immunosuppressive and anti-inflammatory properties of Inducible caspase-9-mediated apoptotic mesenchymal stromal/stem cell
Authors
Romecín, Paola Alejandra ; Vinyoles, Meritxell ; López-Millán, Belén ; Diaz de la Guardia, Rafael ; Marín Atucha, Noemí ; Querol, Sergi ; Bueno, Clara ; Benitez, Raquel ; González-Rey, Elena ; Delgado, Mario ; Menéndez, Pablo
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Facultad de Medicina
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Publisher
Oxford University Press
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DOI
https://doi.org/10.1093/stcltm/szab007
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info:eu-repo/semantics/article
Description
Abstract
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.
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Citation
Stem Cells Transl Med. 2022 Mar 3;11(1):88-96
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