Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation.

Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.

Metformin Preconditioning of Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells Promotes Their Engraftment and Improves Post-Stroke Regeneration and Recovery.

While transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) shows therapeutic potential in animal stroke models, major concerns for translating hiPSC therapy to the clinic are efficacy and safety. Therefore, there is a demand to develop an optimal strategy to enhance the engraftment and regenerative capacity of transplanted hiPSC-NSCs to produce fully differentiated neural cells to replace lost brain tissues. Metformin, an FDA-approved drug, is an optimal neuroregenerative agent that not only promotes NSC proliferation but also drives NSCs toward differentiation. In this regard, we hypothesize that preconditioning of hiPSC-NSCs with metformin before transplantation into the stroke-damaged brain will improve engraftment and regenerative capabilities of hiPSC-NSCs, ultimately enhancing functional recovery. In this study, we show that pretreatment of hiPSC-NSCs with metformin enhances the proliferation and differentiation of hiPSC-NSCs in culture. Furthermore, metformin-preconditioned hiPSC-NSCs show increased engraftment 1 week post-transplantation in a rat endothelin-1 focal ischemic stroke model. In addition, metformin-preconditioned cell grafts exhibit increased survival compared to naive cell grafts at 7 weeks post-transplantation. Analysis of the grafts demonstrates that metformin preconditioning enhances the differentiation of hiPSC-NSCs at the expense of their proliferation. As an outcome, rats receiving metformin-preconditioned cells display accelerated gross motor recovery and reduced infarct volume. These studies represent a vital step forward in the optimization of hiPSC-NSC-based transplantation to promote post-stroke recovery.