1. Sequentially induced motor neurons from human fibroblasts facilitate locomotor recovery in a rodent spinal cord injury model.
- Author
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Lee H, Lee HY, Lee BE, Gerovska D, Park SY, Zaehres H, Araúzo-Bravo MJ, Kim JI, Ha Y, Schöler HR, and Kim JB
- Subjects
- Animals, Cell Transplantation, Disease Models, Animal, Female, Humans, LIM-Homeodomain Proteins metabolism, Male, Mice, Mice, Nude, Motor Neurons physiology, Octamer Transcription Factor-3 metabolism, Spinal Cord Injuries physiopathology, Transcription Factors metabolism, Fibroblasts physiology, Gene Expression Regulation, LIM-Homeodomain Proteins genetics, Locomotion physiology, Motor Neurons transplantation, Octamer Transcription Factor-3 genetics, Recovery of Function physiology, Spinal Cord Injuries therapy, Transcription Factors genetics
- Abstract
Generation of autologous human motor neurons holds great promise for cell replacement therapy to treat spinal cord injury (SCI). Direct conversion allows generation of target cells from somatic cells, however, current protocols are not practicable for therapeutic purposes since converted cells are post-mitotic that are not scalable. Therefore, therapeutic effects of directly converted neurons have not been elucidated yet. Here, we show that human fibroblasts can be converted into induced motor neurons (iMNs) by sequentially inducing POU5F1(OCT4) and LHX3 . Our strategy enables scalable production of pure iMNs because of the transient acquisition of proliferative iMN-intermediate cell stage which is distinct from neural progenitors. iMNs exhibited hallmarks of spinal motor neurons including transcriptional profiles, electrophysiological property, synaptic activity, and neuromuscular junction formation. Remarkably, transplantation of iMNs showed therapeutic effects, promoting locomotor functional recovery in rodent SCI model. Together, our advanced strategy will provide tools to acquire sufficient human iMNs that may represent a promising cell source for personalized cell therapy., Competing Interests: HL, HL, BL, DG, SP, HZ, MA, JK, YH, HS, JK No competing interests declared, (© 2020, Lee et al.)
- Published
- 2020
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