NFIA is a gliogenic switch enabling rapid derivation of functional human astrocytes from pluripotent stem cells.

Nature Biotechnology
Jason TchieuLorenz Studer

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.

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Datasets Mentioned

BETA
GSE104232

Methods Mentioned

BETA
PCR
FACS
ELISA

Software Mentioned

Clampex
Bowtie2
HOMER
Clampfit
ImageJ
NFIA
HTSeq
ENSEMBL
STAR
MiniAnalysis

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