title: In vivo reprogramming reactive glia into iPSCs to produce new neurons in the cortex following traumatic brain injury.
abstract: Traumatic brain injury (TBI) results in a significant amount of cell death in the brain. Unfortunately, the adult mammalian brain possesses little regenerative potential following injury and little can be done to reverse the initial brain damage caused by trauma. Reprogramming adult cells to generate induced pluripotent stem cell (iPSCs) has opened new therapeutic opportunities to generate neurons in a non-neurogenic regions in the cortex. In this study we showed that retroviral mediated expression of four transcription factors, Oct4, Sox2, Klf4, and c-Myc, cooperatively reprogrammed reactive glial cells into iPSCs in the adult neocortex following TBI. These iPSCs further differentiated into a large number of neural stem cells, which further differentiated into neurons and glia in situ, and filled up the tissue cavity induced by TBI. The induced neurons showed a typical neuronal morphology with axon and dendrites, and exhibited action potential. Our results report an innovative technology to transform reactive glia into a large number of functional neurons in their natural environment of neocortex without embryo involvement and without the need to grow cells outside the body and then graft them back to the brain. Thus this technology offers hope for personalized regenerative cell therapies for repairing damaged brain.
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Department of Neurosurgery, Indiana University, 320 W 15th Street, Indianapolis, IN 46202.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Department of Neurosurgery, Indiana University, 320 W 15th Street, Indianapolis, IN 46202.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Department of Neurosurgery, Indiana University, 320 W 15th Street, Indianapolis, IN 46202.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Department of Neurosurgery, Indiana University, 320 W 15th Street, Indianapolis, IN 46202.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001691:Biological Therapy / Q000379:methods; D000070642:Brain Injuries, Traumatic / Q000628:therapy*; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000502:physiology*; D004195:Disease Models, Animal; D015870:Gene Expression; D005822:Genetic Vectors; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D008297:Male; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors