Apoptotic MSCs, COX2/PGE2 and clinical efficacy in Crohn fistula

The clinical application of mesenchymal stromal cells (MSCs) has been approved for use in pediatric graft-versus-host disease (GvHD) and perianal fistulizing Crohn disease. MSCs have also been investigated in an array of other inflammatory disease indications. Despite promising results in patients who respond to MSC administration, a significant proportion of patients do not respond, and this has significantly dampened enthusiasm for MSC-based cell therapy. A better understanding of the mechanism of action (MOA) involved in the therapeutic effects of MSCs may help to stratify patients who will respond to MSC administration. In this issue of Molecular Therapy, Cheung et al. publish their findings on the role of caspase-mediated apoptosis of MSCs, leading to the release of immunosuppressive factors, including prostaglandin E2 (PGE2), which correlated with clinical responsiveness in Crohn's disease patients. 1 Cheung T.S. Giacomini C. Cereda M. Avivar-Valderas A. Capece D. Bertolino G.M. delaRosa O. Hicks R. Ciccocioppo R. Franzoso G. et al. Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn's disease. Mol. Ther. 2023; 31: 3531-3544 Abstract Full Text Full Text PDF Scopus (1) Google Scholar The authors build upon on their previous study that identified a correlation between the induction of apoptosis mediated by peripheral blood mononuclear cells (PBMCs) from patients with GvHD who responded to MSC administration. 2 Galleu A. Riffo-Vasquez Y. Trento C. Lomas C. Dolcetti L. Cheung T.S. von Bonin M. Barbieri L. Halai K. Ward S. et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl. Med. 2017; 9eaam7828 Crossref PubMed Scopus (445) Google Scholar In the present article, Cheung et al. demonstrate once again a correlation between apoptosis induction in MSCs and a role for cyclooxygenase 2 (COX2)/PGE2 in mediating immunosuppressive effects in patients with Crohn's disease who responded to MSC therapy. 1 Cheung T.S. Giacomini C. Cereda M. Avivar-Valderas A. Capece D. Bertolino G.M. delaRosa O. Hicks R. Ciccocioppo R. Franzoso G. et al. Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn's disease. Mol. Ther. 2023; 31: 3531-3544 Abstract Full Text Full Text PDF Scopus (1) Google Scholar The significance of this study is that it identifies potential assays that could be used to stratify patients based on the capacity of patient PBMCs to induce MSC apoptosis and/or the use of PGE2 levels produced from PBMC-induced apoptotic MSCs. Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn's diseaseCheung et al.Molecular TherapyOctober 7, 2023In BriefDazzi and colleagues identify a new mechanism whereby caspase activation in MSCs induces a NFκB-dependent secretome that actively effects immunomodulation via COX2/PGE2, corroborating apoptosis is critical for MSC immunosuppression. The levels of PGE2 and apoptosis induced in MSC by patients' immune cells predicts clinical responses to MSC in Crohn's disease. Full-Text PDF Open Access