한빛사논문
Qian Zhu 1,8, Akanksha Mishra 1,8, Joy S. Park 1,8, Dongxin Liu 1, Derek T. Le 1, Sasha Z. Gonzalez 1, Morgan Anderson-Crannage 1, James M. Park 1, Gun-Hoo Park 1, Laura Tarbay 1, Kamron Daneshvar 1, Matthew Brandenburg 1, Christina Signoretti 1, Amy Zinski 1, Edward-James Gardner 1, Kelvin L. Zheng 1, Chiderah P. Abani 1, Carla Hu 1, Cameron P. Beaudreault 1, Xiao-Lei Zhang 1, Patric K. Stanton 1, Jun-Hyeong Cho 2, Libor Velíšek 1,3,4, Jana Velíšková 1,3,5, Saqlain Javed 6, Christopher S. Leonard 6, Hae-Young Kim 7, Sangmi Chung 1,9
1Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA
2Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, CA, USA
3Department of Neurology, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA
4Department of Pediatrics, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA
5Department of Obstetrics & Gynecology New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA
6Department of Physiology, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA
7Department of Public Health, New York Medical College, Valhalla, Mount Pleasant, NY, USA
8These authors contributed equally
9Lead contact
Corresponding author : Sangmi Chung
Abstract
Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy.
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