Dissecting the molecular pathways of apoptosis in mesenchymal stromal cell therapy

Abstract

Background & Aim Due to their immunosuppressive and anti-inflammatory activities, mesenchymal stromal cells (MSCs) have been extensively utilized in clinical trials to treat a wide range of autoimmune and inflammatory diseases. However, the mechanism underlying MSC therapeutic activity remains poorly understood. Our data show that MSCs undergo apoptosis in the lungs and are undetectable shortly after intravenous administration into mice. In support of this finding, a recent study demonstrated that induction of MSC apoptosis by recipient cytotoxic cells is necessary for immunomodulation in graft-versus-host disease. We are therefore interested in elucidating the molecular pathways of apoptosis that underline MSC therapeutic effect. Methods, Results & Conclusion Using pharmacological compounds that selectively inhibit pro-survival proteins to induce apoptosis in MSCs, we show that mouse and human bone marrow (BM) MSCs engage different molecules for survival. In addition, we are genetically manipulating the apoptotic pathways in mouse and human BM MSCs to gain a greater understanding of how these cells exert their therapeutic effects in vivo, an outstanding question in MSC therapy.