Mesenchymal stromal cell apoptosis is required for their therapeutic function

Abstract

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.

Humoral Immunity to Allogeneic Immunoproteasome-Expressing Mesenchymal Stromal Cells Requires Efferocytosis by Endogenous Phagocytes

“…MSCs are widely reported to influence the response of the immune system via multiple mechanisms including the secretion of soluble factors, cellular interactions, or released exosomes [ 26 , 27 , 28 ]. More recent reports have revealed another mechanism of action for MSCs via efferocytosis by endogenous phagocytes under pro-inflammatory conditions [ 29 , 30 ]. In addition, several cell surface markers have been reported to function as “eat-me or do not eat-me signals” capable of inducing or blocking efferocytosis, respectively ( Figure 6 A) [ 31 , 32 ].…”

“…In terms of the underlying mechanism, the current consensus is that MSCs mediate their suppressive effect via the production of soluble mediators or exosome release [ 35 , 36 , 37 , 38 , 39 ]. However, the new school of thought stipulates that MSCs must undergo apoptosis and/or stimulate efferocytosis by endogenous phagocytes prior to exerting their immune suppressive abilities in vivo [ 29 , 30 ]. This outcome is not different in our case, as clodronate-mediated depletion of phagocytes prior to immunisation prolongs allogeneic MSC-IPr survival in vivo while blunting antibody production.…”

“…These results suggest an important interplay occurring between myeloid cells and MSCs, which, if further enhanced, could lead to a substantial boost to humoral immunity. Nevertheless, efferocytosis by myeloid cells is not limited to monocytes/macrophages, as cDC1 and cDC2 were also shown to capture dying MSCs [ 30 ]. What is the exact nature of phagocytic cells mediating MSC-IPr efferocytosis?…”

A Brief Overview of Global Trends in MSC-Based Cell Therapy

“…Another study performed by Higashimoto et al [ 135 ] on ConA induced hepatitis mice model showed that intravenously injected GFP-labeled MSCs were accumulated only in the lung but not in the liver. In addition, a further study led by Pang et al show that intravenous administrated MSCs rapidly undergo apoptosis in the lungs of the mice, demonstrating that dying MCSs have therapeutic effects [ 136 ].…”

Editorial: Recent Advances in Potential Biomarkers for Rheumatic Diseases and in Cell-Based Therapies in the Management of Inflammatory Rheumatic Diseases

“…This makes a link with the last review on cell-based therapies. Before presenting this review, we want to highlight two recent works showing that the therapeutic effects of MSC may be related to their apoptosis in the lungs after intravenous administration and subsequent efferocytosis ( i.e ., the non-inflammatory removal of apoptotic cells by professional phagocytes) ( 6 , 7 ). Toussirot et al summarized experimental studies suggesting the potential therapeutic properties of apoptotic leukocytes in RA.…”