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

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 for 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, 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, 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 use 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.

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

“…This is different from cell fate specification and early differentiation steps, where individual master regulators trigger a highly coordinated cell intrinsic differentiation programme. For example, MyoD is able to induce myogenic programmes in a variety of cell types (Weintraub et al, 1989), and NFIA can trigger astrocyte differentiation of human NSCs (Tchieu et al, 2019). In contrast, our results suggest that maturation is controlled by a large number of transcription factors which induce astrocytic effector subprogrammes by both independent and cooperative activities.…”

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

“…In astrocytes and NPCs, the activity of GFAP gene in the cluster is under the regulation of different sets of TFs. TF-binding sites in GFAP gene promoter include AP-1 (Brenner, Messing, & Olsen, 2019), NFI (Tchieu et al, 2019), c-Jun (Gao et al, 2013), STAT3 (Urayama et al, 2013), peroxisome proliferator-activated receptor γ (PPAR-γ) (Rai et al, 2014) and many others (Ito et al, 2016). The products of these genes can be organized into several cascades in the transcriptional regulation of GFAP gene expression.…”

An update on human astrocytes and their role in development and disease

“…The most conventional approach, 3D generation and maintenance, has become the standard method on which the majority of subsequent protocols have been based, including significant portions of direct conversion methods (Juopperi et al, 2012;Krencik & Zhang, 2011;Mormone, D'Sousa, Alexeeva, Bederson, & Germano, 2014). Finally, direct conversion through TF expression significantly decreases the induction protocols length but stands as a relatively new and unexplored approach (Caiazzo et al, 2014;Canals et al, 2018;Li, Tao, et al, 2018;Li, Tian, et al, 2018;Tchieu et al, 2019).…”