Mesenchymal stromal cell apoptosis is required for their therapeutic function

ABSTRACT: The demonstration that mesenchymal stromal cells (MSCs) can ameliorate a wide range of diseases in preclinical models has led to many clinical trials investigating their use as a treatment modality. Their therapeutic effects are often attributed to their secretome, a proposition predicated on their long-term survival. However, the majority of MSCs do not survive in vivo administration. We sought to reconcile the immunosuppressive effects of MSC therapy with their short lifespan. We showed that almost all MSCs underwent apoptosis associated with caspase-3 activation within 1 hour of intravenous administration and were efferocytosed by lung phagocytes. The potent immunosuppressive effects of MSCs did not require them to remain viable, but instead involved efferocytosis-induced transcriptional changes in metabolic and inflammatory pathways in alveolar macrophages. We identified the mitochondrial pathway as the predominant mechanism involved in MSC apoptosis, as deletion of the effectors BAK/BAX prevented their death. Importantly, BAK/BAX deficiency in MSCs weakened their immunosuppressive effects in 2 different disease models used to define MSC potency. Our data showed that apoptosis of MSCs and their subsequent efferocytosis and macrophage immunometabolic reprogramming are key steps underlying their mode of action. These findings have significant implications for the development of MSC potency assays and biomanufacturing for clinical translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE156240 | GEO | 2021/09/16

REPOSITORIES: GEO