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.
['Ould-Brahim|Fares|F|', 'Sarma|Sailendra Nath|SN|', 'Syal|Charvi|C|', 'Lu|Kevin Jiaqi|KJ|', 'Seegobin|Matthew|M|', 'Carter|Anthony|A|', 'Jeffers|Matthew S|MS|', 'Doré|Carole|C|', 'Stanford|William L|WL|', 'Corbett|Dale|D|', 'Wang|Jing|J|']
D000818:Animals D001921:Brain D002454:Cell Differentiation D004195:Disease Models, Animal D006801:Humans D057026:Induced Pluripotent Stem Cells D008297:Male D008687:Metformin D058953:Neural Stem Cells D009474:Neurons D051381:Rats D020127:Recovery of Function D020521:Stroke D000071939:Stroke Rehabilitation
metformin preconditioning regeneration transplantation functional recovery focal ischemic stroke human iPSC-derived neural stem cells