Preconditioning of Human Neural Stem Cells with Metformin to Promote Post-Stroke Recovery

Abstract

The generation of human induced pluripotent stem cells (hiPSCs) from human fibroblasts has revolutionized cell therapy by providing a source of autologous cells for transplantation. Several studies have demonstrated that transplantation of hiPSC-derived neural stem cells (hiPSC-NSCs) increases regeneration and recovery following stroke, supporting their therapeutic potential. However, major concerns for translating hiPSC transplantation therapy to the clinic are efficacy and safety. Therefore, there is demand to develop an optimal strategy to enhance the engraftment and regenerative capacity of transplanted hiPSC-NSCs. The recent published work shows that metformin, an FDA approved drug, is an optimal neuroregenerative agent that not only promotes the proliferation of neural stem cells but also enhances their neuronal 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, further enhancing cell-mediated functional recovery. Here we show that treatment of hiPSC-NSCs with metformin enhances the proliferation and differentiation of hiPSC-NSCs in culture even after withdrawal of metformin treatment, showing its promise as a novel preconditioning strategy. Furthermore, transplantation of preconditioned hiPSC-NSCs into a rat endothelin-1 ischemic stroke model showed an improved engraftment capability 1-week post-transplant. In addition, metformin preconditioned grafts survived longer compared to naïve grafts and were detectable at 8 weeks post-stroke. However, cell transplantation did not result in improve functional recovery when compared to sham group in this model. These studies represent a vital step in the optimization of hiPSC-NSC based transplantation to promote post-stroke recovery.