title: Vector-free and transgene-free human iPS cells differentiate into functional neurons and enhance functional recovery after ischemic stroke in mice.
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.
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Osama
authors.initials: O
authors.lastname: Mohamad
authors.forename: Danielle
authors.initials: D
authors.lastname: Drury-Stewart
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.forename: Ben
authors.initials: B
authors.lastname: Faulkner
authors.forename: Dongdong
authors.initials: D
authors.lastname: Chen
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
mesh_terms: D000200:Action Potentials; D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000503:physiopathology; D016895:Culture Media, Serum-Free; D005136:Eye Proteins / Q000378:metabolism; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology / Q000637:transplantation*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D064231:Nestin / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D011597:Psychomotor Performance; D020127:Recovery of Function; D012039:Regional Blood Flow; D012097:Repressor Proteins / Q000378:metabolism; D019076:Transgenes
chemical_list: D016895:Culture Media, Serum-Free; D005136:Eye Proteins; D018398:Homeodomain Proteins; C577484:NES protein, human; D064231:Nestin; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins