The long-term goal of this project is to develop patient-specific autologous cell source from induced pluripotent stem cells (iPSC) technology as a therapy for traumatic brain injury and other neurological diseases. Many current neural transplantation approaches have encountered problems associated with the source of donor cells. The ethnic controversies, limited cell availability, poor survival, lack of functional integration of grafted cells, the risk of tumor formation and immunological rejection in vivo are prominent issues need to be overcome before neural transplantation as a therapy to be used in clinic. It is essential, therefore, to identify optimal cell sources that are more conducive for cel replacement therapies. The emerging technology of human iPSCs generation, followed by directed differentiation into uniform populations of neural progenitor cells (hNPs) and neurons, holds great promise as an approach to reverse engineer human cells obtained from TBI patients. In this project, we are focusing our efforts on reprogramming adult human neural cells isolated from neurosurgical resection tissues. The specific hypothesis of this proposal is that functional iPSC-derived neural progenitor cells can be generated from neurosurgical resection tissues and utilized as cell replacement therapy for TBI. The hypothesis is based on our observations and research developments that (a) iPSCs can be generated from patients with specific neurodegenerative disorders, (b) directed differentiation of pluripotent stem cells can lead to uniform populations of hNPs, and (c) adult human stem-like cells can be isolated from neurosurgical resection tissues and successfully cultured as neurospheres and monolayers. To test the hypothesis, in this proposal, we will first generate iPSCs from adult human neural cells isolated from neurosurgical resection tissues and evaluate their pluripotent characteristics, directed differentiation capabilities in vitro. We will then assess the transplantation potential o these iPSC-derived hNPs in vivo in the brain in both intact immunodeficient animals and injured immunocompetent animals. The two proposed specific aims are: (1) Generate and characterize iPSCs from adult human neural cells isolated from neurosurgical resection tissues. (2) Evaluate the survival, differentiation and functionality of iPSC-derived NPs in the injured environment and assess the role of gender differences on cell survival. Results from the proposed study will have significant impact in the development of patient-specific hiPSCs as autologous cell replacement strategies for TBI and other neurological disorders.
Traumatic brain injury is fundamentally untreatable and clinically devastating. Generating induced pluripotent stem cells will significantly advance our strategies towards developing patient-specific cells for cell replacement therapy for TBI. The results from this proposal will provide positive impact on the development of autologous cell replacement therapies for TBI and other neurological diseases.
|Li, Xiaowei; Tzeng, Stephany Y; Liu, Xiaoyan et al. (2016) Nanoparticle-mediated transcriptional modification enhances neuronal differentiation of human neural stem cells following transplantation in rat brain. Biomaterials 84:157-166|
|Sun, Dong (2016) The potential of neural transplantation for brain repair and regeneration following traumatic brain injury. Neural Regen Res 11:18-22|
|Sun, Dong (2016) Endogenous neurogenic cell response in the mature mammalian brain following traumatic injury. Exp Neurol 275 Pt 3:405-410|
|Patel, Kaushal; Sun, Dong (2016) Strategies targeting endogenous neurogenic cell response to improve recovery following traumatic brain injury. Brain Res 1640:104-113|
|Sun, Dong; Daniels, Teresa E; Rolfe, Andrew et al. (2015) Inhibition of injury-induced cell proliferation in the dentate gyrus of the hippocampus impairs spontaneous cognitive recovery after traumatic brain injury. J Neurotrauma 32:495-505|