NFIA is a gliogenic switch enabling rapid derivation of functional human astrocytes from pluripotent stem cells
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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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hiPSC-derived astrocytes can be generated with a fast protocol in 2D layers or integrated in 3D systems such as spheroids and organoids.
“hiPSC-derived astrocytes, which can be generated with a fast protocol in 2D layers104 or integrated in 3D systems such as spheroids and organoids105–108”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [104]
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- Authors
- Tchieu, J., Calder, E. L., Guttikonda, S. R., Gutzwiller, E. M., Aromolaran, K. A., Steinbeck, J. A., Goldstein, P. A., & Studer, L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Tchieu, Jason
- Studer, Lorenz
- Venue
- Nature Biotechnology
- Published
- 2019-02-25
- Volume
- 37
- Issue
- 3
- Pages
- 267-275
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC6591152
- OpenAlex
- W2917543658
- Cited by
- 231
- References
- 64
- Citations by year
- 2026: 24 · 2025: 47 · 2024: 40 · 2023: 28 · 2022: 26 · 2021: 33 · 2020: 24 · 2019: 9
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center
- National Institute on Aging (R01AG056298, R01AG054720)
- National Institute of Mental Health (F30MH115616)
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (T32GM007739)
- National Institute of Neurological Disorders and Stroke (R21NS084334)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- NFIA, gliogenesis, astrocyte differentiation, pluripotent stem cells, neural stem cells, chromatin remodeling, synaptogenesis, neuroprotection, reactive astrocytes, disease modeling, regenerative medicine
- MeSH terms
- Animals, Astrocytes, Cell Differentiation, Humans, Neuroglia, Neurons, Promoter Regions, Genetic, Gene Expression Regulation, Developmental, Pluripotent Stem Cells, Mice, NFI Transcription Factors, Neurogenesis, Neural Stem Cells
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