Secondary Lymphoid Organs in Mesenchymal Stromal Cell Therapy: More Than Just a Filter.

Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in inflammatory models of human disease. However, clinical translation has fallen short of expectations, with many trials failing to meet primary endpoints. Failure to fully understand their mechanisms of action is a key factor contributing to the lack of successful commercialisation. Indeed, it remains unclear how the long-ranging immunomodulatory effects of MSCs can be attributed to their secretome, when MSCs undergo apoptosis in the lung shortly after intravenous infusion. Their apoptotic fate suggests that efficacy is not based solely on their viable properties, but also on the immune response to dying MSCs. The secondary lymphoid organs (SLOs) orchestrate immune responses and play a key role in immune regulation. In this review, we will discuss how apoptotic cells can modify immune responses and highlight the importance of MSC-immune cell interactions in SLOs for therapeutic outcomes.

Mesenchymal stromal cell apoptosis is required for their therapeutic function.

Multipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies.

Biological Considerations in Scaling Up Therapeutic Cell Manufacturing.

Cell therapeutics - using cells as living drugs - have made advances in many areas of medicine. One of the most clinically studied cell-based therapy products is mesenchymal stromal cells (MSCs), which have shown promising results in promoting tissue regeneration and modulating inflammation. However, MSC therapy requires large numbers of cells, the generation of which is not feasible via conventional planar tissue culture methods. Scale-up manufacturing methods (e.g., propagation on microcarriers in stirred-tank bioreactors), however, are not specifically tailored for MSC expansion. These processes may, in principle, alter the cell secretome, a vital component underlying the immunosuppressive properties and clinical effectiveness of MSCs. This review outlines our current understanding of MSC properties and immunomodulatory function, expansion in commercial manufacturing systems, and gaps in our knowledge that need to be addressed for effective up-scaling commercialization of MSC therapy.