Official URL: https://doi.org/10.1016/j.ymthe.2023.11.006

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 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 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 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.