Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits.
Animals
Astrocytes
/ pathology
Cell Differentiation
Corpus Callosum
/ diagnostic imaging
Disease Models, Animal
Induced Pluripotent Stem Cells
/ physiology
Magnetic Resonance Imaging
Male
Mice, Inbred C57BL
Motor Activity
Multiple Sclerosis
/ pathology
Neural Stem Cells
/ physiology
Oligodendroglia
/ pathology
Remyelination
Cuprizone
Diffusion tensor imaging
Magnetic resonance imaging
Magnetization transfer ratio
Multiple sclerosis
Neural stem cells
Remyelination
Reprogramming
Stem cell therapeutics
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
09 06 2020
09 06 2020
Historique:
received:
28
05
2020
accepted:
30
05
2020
entrez:
11
6
2020
pubmed:
11
6
2020
medline:
29
5
2021
Statut:
epublish
Résumé
Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.
Identifiants
pubmed: 32517808
doi: 10.1186/s40478-020-00960-3
pii: 10.1186/s40478-020-00960-3
pmc: PMC7285785
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
84Subventions
Organisme : Wellcome Trust
ID : RRZA/057 RG79423
Pays : United Kingdom
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