Abstract
Mesenchymal stromal cells (MSCs) exert broad therapeutic effects across a range of inflammatory diseases. Their therapeutic properties, largely mediated by secreted factors, can be enhanced by pre-exposure to inflammatory cytokines, a concept known as “licensing”. Yet, following intravenous infusion, MSCs fail to engraft long-term because they become trapped in the lungs. Recent evidence from in vivo models has shown that apoptosis of MSCs and subsequent clearance by host phagocytes is essential for their therapeutic efficacy. Here, we investigated the apoptotic mechanisms governing MSC death and how exposure to inflammatory cytokines, which “license” MSCs, impacts their sensitivity to cell death. Our results show that efficient killing of MSCs required triggering of the mitochondrial pathway of apoptosis, via inhibition of the pro-survival proteins MCL-1 and BCL-XL. Apoptotic bodies were readily released by MSCs during cell disassembly, a process that was inhibited in vitro and in vivo when the apoptotic effectors BAK and BAX were genetically deleted. Exposure to the inflammatory cytokines TNF and IFN-γ increased the sensitivity of MSCs to apoptosis in vitro and accelerated their in vivo clearance by host cells within the lungs after intravenous infusion. Taken together, our study demonstrates how “licensing” of MSCs facilitates their apoptosis and clearance, informing strategies for improving the therapeutic efficacy of MSCs in future human clinical trials.