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

Authors


  • Author contributions: K.O., J.T., J.W., P.K., and S.W.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; Y.M. and D.T.P.: collection and assembly of data and data analysis; E.M.: conception and design, collection and assembly of data, and data analysis; H.A. and J.L.: collection and assembly of data and data analysis and interpretation; O.B.: conception and design, data interpretation, financial support, and manuscript writing; O.L. and Z.K.: conception and design, data analysis and interpretation, financial support, and manuscript writing. K.O., J.T., J.W., and P.K. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS April 11, 2012.

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 stroke-injured brain are unclear. We have transplanted long-term 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. STEM CELLS2012;30:1120–1133

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