Title | NFIA is a gliogenic switch enabling rapid derivation of functional human astrocytes from pluripotent stem cells. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Tchieu J, Calder EL, Guttikonda SR, Gutzwiller EM, Aromolaran KA, Steinbeck JA, Goldstein PA, Studer L |
Journal | Nat Biotechnol |
Volume | 37 |
Issue | 3 |
Pagination | 267-275 |
Date Published | 2019 03 |
ISSN | 1546-1696 |
Keywords | Animals, Astrocytes, Cell Differentiation, Gene Expression Regulation, Developmental, Humans, Mice, Neural Stem Cells, Neurogenesis, Neuroglia, Neurons, NFI Transcription Factors, Pluripotent Stem Cells, Promoter Regions, Genetic |
Abstract | The mechanistic basis of gliogenesis, which occurs late in human development, is poorly understood. Here we identify nuclear factor IA (NFIA) as a molecular switch inducing human glial competency. Transient expression of NFIA is sufficient to trigger glial competency of human pluripotent stem cell-derived neural stem cells within 5 days and to convert these cells into astrocytes in the presence of glial-promoting factors, as compared to 3-6 months using current protocols. NFIA-induced astrocytes promote synaptogenesis, exhibit neuroprotective properties, display calcium transients in response to appropriate stimuli and engraft in the adult mouse brain. Differentiation involves rapid but reversible chromatin remodeling, glial fibrillary acidic protein (GFAP) promoter demethylation and a striking lengthening of the G1 cell cycle phase. Genetic or pharmacological manipulation of G1 length partially mimics NFIA function. We used the approach to generate astrocytes with region-specific or reactive features. Our study defines key mechanisms of the gliogenic switch and enables the rapid production of human astrocytes for disease modeling and regenerative medicine. |
DOI | 10.1038/s41587-019-0035-0 |
Alternate Journal | Nat. Biotechnol. |
PubMed ID | 30804533 |
PubMed Central ID | PMC6591152 |
Grant List | R01 AG056298 / AG / NIA NIH HHS / United States R01 AG054720 / AG / NIA NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States F30 MH115616 / MH / NIMH NIH HHS / United States R21 NS084334 / NS / NINDS NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
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