In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, cas-pase activity not only mediates the dying process but also death-independent functions that may shape the immunoge-nicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs under-going apoptosis and identified several immunomodulatory fac-tors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted mono-cytes in vitro. Both immunomodulatory activities were depen-dent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had un-dergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mech-anism whereby caspase activation delivers ApoMSC immuno-suppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical re-sponses to MSC therapy in CD.

Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn’s disease / T.S. Cheung, C. Giacomini, M. Cereda, A. Avivar-Valderas, D. Capece, G.M. Bertolino, O. Delarosa, R. Hicks, R. Ciccocioppo, G. Franzoso, A. Galleu, F.D. Ciccarelli, F. Dazzi. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 31:12(2023 Dec 06), pp. 3531-3544. [10.1016/j.ymthe.2023.10.004]

Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn’s disease

M. Cereda;
2023

Abstract

In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, cas-pase activity not only mediates the dying process but also death-independent functions that may shape the immunoge-nicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs under-going apoptosis and identified several immunomodulatory fac-tors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted mono-cytes in vitro. Both immunomodulatory activities were depen-dent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had un-dergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mech-anism whereby caspase activation delivers ApoMSC immuno-suppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical re-sponses to MSC therapy in CD.
NFκB; apoptosis; biomarker; fistulizing Crohn’s disease; mesenchymal stromal cells; prostaglandin E2;
Settore BIO/11 - Biologia Molecolare
Settore MED/06 - Oncologia Medica
Settore MED/03 - Genetica Medica
6-dic-2023
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1050030
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