Multiple sclerosis (MS) is a chronic neuroinflammatory disease associated with progressive neurodegeneration and accumulation of neurological disability. A novel cell therapy has been developed aiming to slow or reverse neurological disability in patients with MS.
The treatment approach utilizes bone marrow cells called mesenchymal stem cell-derived neural progenitors (MSC-NPs) that are injected into the spinal fluid of the patient. Microglia are an innate immune cell in the brain known to contribute to MS disease progression. This study explores whether microglia might be a therapeutic target of MSC-NP therapy. We found that MSC-NPs inhibited the inflammatory activation of microglia and increased proregenerative markers in microglia. These effects were mediated by the factors secreted by MSC-NPs, possibly including a secreted protein called TGF-β.
The study investigated whether proinflammatory CCL2-expressing microglia might be a target of MSC-NP cell therapy.
The aim of the current study was to investigate whether MSC-NPs modulate microglial polarization. MSCs, the parent population of MSC-NPs, have an immunomodulatory effect on microglia both in vitro and in animal models. Utilizing multiple in vitro models of microglia, including human induced pluripotent stem cell (iPSC)-derived microglia, we show that MSC-NPs inhibit the proinflammatory phenotype of microglia, including the reduction of microglia-derived CCL2.
The study suggests that the promotion of beneficial microglial polarization by MSC-NPs may mediate some of the therapeutic effects of this cell therapy in MS.
In conclusion, this study is the first to show that MSC-NPs promote microglial polarization from a proinflammatory to a proregenerative phenotype based on microglial marker expression, morphology and phagocytic function. The paracrine mechanisms underlying this effect may involve TGF-β signaling in microglia.
This study is the first step in developing a robust in vitro potency assay for MSC-NPs that correlates to their predicted mechanism of action, with the potential to help predict clinical efficacy in patients with MS.
Mesenchymal stem cell-derived neural progenitors attenuate proinflammatory microglial activation via paracrine mechanisms. Violaine K Harris, Derek Bishop, Jaina Wollowitz, Gillian Carling, Alyssa L Carlson, Nicolas Daviaud, and Saud A Sadiq. Regenerative Medicine 2023 18:3, 259-273. DOI https://doi.org/10.2217/rme-2023-0005