Metformin Preconditioning of Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells Promotes Their Engraftment and Improves Post-Stroke Regeneration and Recovery
2018; Mary Ann Liebert, Inc.; Volume: 27; Issue: 16 Linguagem: Inglês
10.1089/scd.2018.0055
ISSN1557-8534
AutoresFares Ould-Brahim, Sailendra Nath Sarma, Charvi Syal, Kevin Lu, Matthew Seegobin, Anthony Carter, Matthew S. Jeffers, Carole Doré, William L. Stanford, Dale Corbett, Jing Wang,
Tópico(s)Neurogenesis and neuroplasticity mechanisms
ResumoWhile 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.
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