Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain

Abstract

Reprogramming of adult human somatic cells to induced pluripotent stem cells (iPSCs) is a novel approach to produce patient-specific cells for autologous transplantation. Whether such cells survive long-term, differentiate to functional neurons, and induce recovery in the strokeinjured brain are unclear. We have transplanted longterm self-renewing neuroepithelial-like stem cells, generated from adult human fibroblast-derived iPSCs, into the stroke-damaged mouse and rat striatum or cortex. Recovery of forepaw movements was observed already at 1 week after transplantation. Improvement was most likely not due to neuronal replacement but was associated with increased vascular endothelial growth factor levels, probably enhancing endogenous plasticity. Transplanted cells stopped proliferating, could survive without forming tumors for at least 4 months, and differentiated to morphologically mature neurons of different subtypes. Neurons in intrastriatal grafts sent axonal projections to the globus pallidus. Grafted cells exhibited electrophysiological properties of mature neurons and received synaptic input from host neurons. Our study provides the first evidence that transplantation of human iPSC-derived cells is a safe and efficient approach to promote recovery after stroke and can be used to supply the injured brain with new neurons for replacement.

Spatiotemporal PET Imaging of Dynamic Metabolic Changes After Therapeutic Approaches of Induced Pluripotent Stem Cells, Neuronal Stem Cells, and a Chinese Patent Medicine in Stroke

“…Immunohistochemical and immunofluorescence staining verified that iPSCs and NSCs migrated to the area close to the ischemic area, where they expressed the mature neuronal marker NeuN, mature astrocyte marker GFAP, and endothelial cell marker vWF. These findings corroborate other previous studies (on NSCs or iPSCs used individually), which demonstrated that stem cells survived, migrated, and differentiated into mature neurons (26) or angiogenic cells (19) and improved functional recovery via promoting vascular endothelial growth factor expression and enhancing endogenous plasticity in the injured brain (27). Transplantation of iPSCs could improve the motor function, reduce infarct size, attenuate inflammation cytokines, and mediate neuroprotection after ischemic stroke (10,28).…”

“…NSCs had a significantly better effect within the first 2 wk, whereas iPSCs had a more steady effect over 2 wk. This observation was not entirely unexpected as it has been found that iPSCs could form functional neurons and improve the neurologic function up to 4-12 wk (19,27), whereas NSCs have significant therapeutic effects at 2 wk after transplantation (30,31), yet the prolonged effect in vivo has not been universally demonstrated. We suppose that cerebral ischemia appeared to activate the neurogenesis program: transplanted NSCs may act as a functional cell type in an earlier time course after transplantation, whereas iPSCs might differentiate into a more specific functional cell type before promoting the recovery of cerebral ischemia.…”

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

“…Mixed results have been obtained when either rodent or human iPSC-derived progenitor cells have been transplanted into stroke-damaged mouse or rat brains. Results ranged from tumor development and the absence of any effects on behavior to significant recovery of function, controllable cell proliferation, and formation of electrophysiologically active synaptic connections (25)(26)(27)(28). Among the reasons for variability are the absence of standard protocols for cell preparation and for modeling stroke and testing treatment outcomes.…”

Current Stage and Future Perspective of Stem Cell Therapy in Ischemic Stroke

“…Recent studies have showed that grafted human iPSC cells can generate functional neurons that can send projections and receive synaptic input from neighbouring neurons, which lead to improvement of motor function even in aged animals [10,25]. NSCs mechanisms of action seems to be much complex than simply neuroreplacement.…”