Abstract
Stroke is a leading cause of human death and disability in the adult population in the United States and around the world. While stroke treatment is limited, stem cell transplantation has emerged as a promising regenerative therapy to replace or repair damaged tissues and enhance functional recovery after stroke. Recently, the creation of induced pluripotent stem (iPS) cells through reprogramming of somatic cells has revolutionized cell therapy by providing an unlimited source of autologous cells for transplantation. In addition, the creation of vector-free and transgene-free human iPS (hiPS) cells provides a new generation of stem cells with a reduced risk of tumor formation that was associated with the random integration of viral vectors seen with previous techniques. However, the potential use of these cells in the treatment of ischemic stroke has not been explored. In the present investigation, we examined the neuronal differentiation of vector-free and transgene-free hiPS cells and the transplantation of hiPS cell-derived neural progenitor cells (hiPS-NPCs) in an ischemic stroke model in mice. Vector-free hiPS cells were maintained in feeder-free and serum-free conditions and differentiated into functional neurons in vitro using a newly developed differentiation protocol. Twenty eight days after transplantation in stroke mice, hiPS-NPCs showed mature neuronal markers in vivo. No tumor formation was seen up to 12 months after transplantation. Transplantation of hiPS-NPCs restored neurovascular coupling, increased trophic support and promoted behavioral recovery after stroke. These data suggest that using vector-free and transgene-free hiPS cells in stem cell therapy are safe and efficacious in enhancing recovery after focal ischemic stroke in mice.
Highlights
Stroke is a leading cause of human death and disability in the adult population in the United States and many countries around the world
We investigated the therapeutic potential of vectorfree and transgene-free human iPS (hiPS)-NPCs for the treatment of focal ischemic stroke in mice
In vitro experiments demonstrates that hiPS cells can be cultured in serum-free and feeder-free conditions in mTeSR1 and that these cells differentiate into neural precursors and can become fully mature neurons with typical electrophysiological properties
Summary
Stroke is a leading cause of human death and disability in the adult population in the United States and many countries around the world. A cocktail of transcription factors has been shown to reprogram mouse [8] and human [9,10] fibroblasts to pluripotent stem cells that have the differentiation potential of becoming all three germ layer cells. These induced pluripotent stem (iPS) cells are genetically, epigenetically [8,11], and morphologically similar (but not the same) to ES cells, with comparable differentiation capacities [12,13]. IPS cells were produced by lenti-viral constructs carrying transcription factors that include c-myc Both c-myc and the lentiviral DNA contribute to a potential cancerous transformation of iPS cells after transplantation. Despite the great potential of iPS cells, the use of vectorfree hiPS cells as a transplantation therapy for ischemic stroke has not been explored yet
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