Is mesenchymal stromal cell apoptosis necessary for their immunomodulatory capacity

Background & Aim Mesenchymal stromal cells (MSCs) exhibit therapeutic potential in a broad range of disease conditions. However, the lack of clarity around their mechanism of action presents a significant hurdle in their clinical utility. MSCs do not survive intravenous administration and MSC apoptosis can induce immunomodulatory effects, not unlike other apoptotic cell types. Therefore we sought to understand the role of apoptosis in MSC therapy. Methods, Results & Conclusion Using various methods of labelling and tracking MSCs, as well as different MSC/recipient strain combinations, we showed that MSCs underwent caspase 3-dependent apoptosis in the lungs and were efferocytosed by a hierarchy of lung phagocytes. In alveolar macrophages, this process induced transcriptional modification to shut down inflammation. Treatment with pharmacological compounds that selectively inhibit regulators of apoptosis revealed the molecular players involved in MSC apoptosis and survival. By manipulating the apoptotic status of MSCs and assaying their therapeutic efficacy in disease models commonly used to define MSC potency, we were able to address whether apoptosis is necessary in MSC therapy. Our data have significant implications for the development of MSC potency assays and biomanufacturing for clinical translation.