Human post-mortem organotypic brain slice cultures: a tool to study pathomechanisms and test therapies.
Gene therapy
Human post-mortem brain
Leukodystrophy
Organotypic brain slice culture
White matter
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
31 May 2024
31 May 2024
Historique:
received:
13
02
2024
accepted:
16
04
2024
medline:
1
6
2024
pubmed:
1
6
2024
entrez:
1
6
2024
Statut:
epublish
Résumé
Human brain experimental models recapitulating age- and disease-related characteristics are lacking. There is urgent need for human-specific tools that model the complex molecular and cellular interplay between different cell types to assess underlying disease mechanisms and test therapies. Here we present an adapted ex vivo organotypic slice culture method using human post-mortem brain tissue cultured at an air-liquid interface to also study brain white matter. We assessed whether these human post-mortem brain slices recapitulate the in vivo neuropathology and if they are suitable for pathophysiological, experimental and pre-clinical treatment development purposes, specifically regarding leukodystrophies. Human post-mortem brain tissue and cerebrospinal fluid were obtained from control, psychiatric and leukodystrophy donors. Slices were cultured up to six weeks, in culture medium with or without human cerebrospinal fluid. Human post-mortem organotypic brain slice cultures remained viable for at least six weeks ex vivo and maintained tissue structure and diversity of (neural) cell types. Supplementation with cerebrospinal fluid could improve slice recovery. Patient-derived organotypic slice cultures recapitulated and maintained known in vivo neuropathology. The cultures also showed physiologic multicellular responses to lysolecithin-induced demyelination ex vivo, indicating their suitability to study intrinsic repair mechanisms upon injury. The slice cultures were applicable for various experimental studies, as multi-electrode neuronal recordings. Finally, the cultures showed successful cell-type dependent transduction with gene therapy vectors. These human post-mortem organotypic brain slice cultures represent an adapted ex vivo model suitable for multifaceted studies of brain disease mechanisms, boosting translation from human ex vivo to in vivo. This model also allows for assessing potential treatment options, including gene therapy applications. Human post-mortem brain slice cultures are thus a valuable tool in preclinical research to study the pathomechanisms of a wide variety of brain diseases in living human tissue.
Identifiants
pubmed: 38822428
doi: 10.1186/s40478-024-01784-1
pii: 10.1186/s40478-024-01784-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
83Subventions
Organisme : ZonMw
ID : TOP 91217006
Pays : Netherlands
Organisme : VWM Families Foundation
ID : VWM Families Foundation
Organisme : Progressive MS alliance challenge award
ID : PA2001-26033
Organisme : Dutch National MS Foundation
ID : OZ2021-008
Informations de copyright
© 2024. The Author(s).
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