Human spinal GABA neurons alleviate spasticity and improve locomotion in rats with spinal cord injury

• Published in: Cell reports (Cambridge) 2021-03, Vol.34 (12), p.108889-108889, Article 108889
• Main Authors: Gong, ChenZi, Zheng, Xiaolong, Guo, FangLiang, Wang, YaNan, Zhang, Song, Chen, Jing, Sun, XueJiao, Shah, Sayed Zulfiqar Ali, Zheng, YiFeng, Li, Xiao, Yin, Yatao, Li, Qian, Huang, XiaoLin, Guo, Tiecheng, Han, Xiaohua, Zhang, Su-Chun, Wang, Wei, Chen, Hong
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Cell Differentiation; Cell Survival; clozapine-N-oxide; DREADD; GABAergic Neurons - pathology; H-reflex; human embryonic stem cell; human pluripotent stem cells; Humans; Locomotion; Lumbar Vertebrae - pathology; Lumbar Vertebrae - physiopathology; Male; Motor Neurons - pathology; Motor Neurons - ultrastructure; Muscle Spasticity - complications; Muscle Spasticity - pathology; Muscle Spasticity - physiopathology; Neural Inhibition; Pluripotent Stem Cells - metabolism; Pluripotent Stem Cells - transplantation; Rats; Rats, Sprague-Dawley; somatosensory GABA neurons; spasticity; Spinal Cord - pathology; Spinal Cord - physiopathology; Spinal Cord Injuries - complications; Spinal Cord Injuries - pathology; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - therapy; spinal cord injury; stem cell transplantation; Synapses - metabolism; Synapses - ultrastructure
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108889

Spinal cord injury (SCI) often results in spasticity. There is currently no effective therapy for spasticity. Here, we describe a method to efficiently differentiate human pluripotent stem cells from spinal GABA neurons. After transplantation into the injured rat spinal cord, the DREADD (designer receptors exclusively activated by designer drug)-expressing spinal progenitors differentiate into GABA neurons, mitigating spasticity-like response of the rat hindlimbs and locomotion deficits in 3 months. Administering clozapine-N-oxide, which activates the grafted GABA neurons, further alleviates spasticity-like response, suggesting an integration of grafted GABA neurons into the local neural circuit. These results highlight the therapeutic potential of the spinal GABA neurons for SCI. [Display omitted] •Spinal GABA interneurons are efficiently generated from hPSCs•Human GABA neurons synapse with host spinal neurons•Cell transplantation mitigates spasticity in SCI rats•Therapeutic effect of GABA neurons depends on activity of grafted neurons Gong et al. develop a technology to guide human ESCs and iPSCs to a homogeneous population of functionally specialized spinal somatosensory neurons and to demonstrate the therapeutic potential of the cells for treating spasticity in SCI rats.