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- Title
Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents.
- 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
- Abstract
Astro-therapy for stroke: Astrocytes, axons, and myelin are subjected to major damage during subcortical white matter stroke (WMS), a debilitating disorder leading to cognitive and motor impairments. Previous studies have shown that immature astrocyte transplantation could promote remyelination in rodent models. Now, Llorente et al. used a model of WMS in mice to demonstrate that transplantation of glial enriched progenitor cells differentiated from human-induced pluripotent stem cells (hiPSC-GEPs) shortly after stroke matured into a mature astrocyte phenotype and had therapeutic effect on axonal damage, demyelination, and cognitive impairments more effectively than hiPSC-derived neuronal precursor cells. The results suggest that astrocyte precursors have therapeutic potential in stroke. 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.
- Subjects
OLIGODENDROGLIA; NEURAL stem cells; WHITE matter (Nerve tissue); VASCULAR dementia; PLURIPOTENT stem cells; PROGENITOR cells; COGNITION disorders
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 590, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aaz6747