Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents

Subcortical white matter stroke (WMS) accounts for up to 30% of all stroke events. WMS damages primarily astrocytes, axons, oligodendrocytes, and myelin. We hypothesized that a therapeutic intervention targeting astrocytes would be ideally suited for brain repair after WMS. We characterize the cellu...

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Bibliographic Details
Published in:Science translational medicine 2021-04, Vol.13 (590)
Main Authors: Llorente, Irene L, Xie, Yuan, Mazzitelli, Jose A, Hatanaka, Emily A, Cinkornpumin, Jessica, Miller, David R, Lin, Ying, Lowry, William E, Carmichael, S Thomas
Format: Article
Language:English
Subjects:
Animals
Astrocytes
Axon guidance
Axon sprouting
Cell Differentiation
Cognitive ability
Deferoxamine
Dementia disorders
Dementia, Vascular
Glial stem cells
Humans
Hydroxylase
Hypoxia
Mice
Myelin
Myelin Sheath
Myelination
Neural stem cells
Oligodendrocytes
Oligodendroglia
Phenotypes
Pluripotency
Progenitor cells
Prolyl hydroxylase
Rodentia
Stem cell transplantation
Stroke
Stroke - therapy
Substantia alba
Vascular dementia
White Matter
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Summary:Subcortical white matter stroke (WMS) accounts for up to 30% of all stroke events. WMS damages primarily astrocytes, axons, oligodendrocytes, and myelin. We hypothesized that a therapeutic intervention targeting astrocytes would be ideally suited for brain repair after WMS. We characterize the cellular properties and in vivo tissue repair activity of glial enriched progenitor (GEP) cells differentiated from human-induced pluripotent stem cells, termed hiPSC-derived GEPs (hiPSC-GEPs). hiPSC-GEPs are derived from hiPSC-neural progenitor cells via an experimental manipulation of hypoxia inducible factor activity by brief treatment with a prolyl hydroxylase inhibitor, deferoxamine. This treatment permanently biases these cells to further differentiate toward an astrocyte fate. hiPSC-GEPs transplanted into the brain in the subacute period after WMS in mice migrated widely, matured into astrocytes with a prorepair phenotype, induced endogenous oligodendrocyte precursor proliferation and remyelination, and promoted axonal sprouting. hiPSC-GEPs enhanced motor and cognitive recovery compared to other hiPSC-differentiated cell types. This approach establishes an hiPSC-derived product with easy scale-up capabilities that might be effective for treating WMS.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.aaz6747