Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition.
cortical interneurons
human pluripotent stem cells
monosynaptic tracing
optogenetics
seizure
temporal lobe epilepsy
transplantation
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
15 03 2023
15 03 2023
Historique:
received:
02
06
2022
revised:
11
10
2022
accepted:
08
12
2022
pmc-release:
15
03
2024
pubmed:
11
1
2023
medline:
21
3
2023
entrez:
10
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36626901
pii: S0896-6273(22)01087-X
doi: 10.1016/j.neuron.2022.12.014
pmc: PMC10023356
mid: NIHMS1859644
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
807-823.e7Subventions
Organisme : NIMH NIH HHS
ID : R01 MH107884
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS121541
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS092786
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS118337
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH118339
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH113894
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS027881
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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