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Human iPSC-derived neural stem cells display a radial glia-like signature in vitro and favorable long-term safety in transplanted mice

ABSTRACT: Human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NSCs) are a promising source of cell therapy approaches to treat neurodegenerative and demyelinating disorders. Despite ongoing efforts to characterize hiPSC-derived cells in vitro and in vivo, we lack comprehensive genome- and transcriptome-wide studies addressing hiPSC-NSC identity and safety, which are critical for establishing accepted criteria for prospective clinical applications. Here, we evaluated the transcriptional and epigenetic signatures of hiPSCs and differentiated hiPSC-NSC progeny, finding that the hiPSC-to-NSC transition results in a complete loss of pluripotency and the acquisition of a radial glia-associated transcriptional and gene regulatory signatures. Importantly, hiPSC-NSCs share with somatic human fetal NSCs (hfNSCs) the main transcriptional and epigenetic patterns associated with NSC-specific biology. In vivo, long-term observation (up to 10 months) of mice intracerebrally transplanted as neonates with hiPSC-NSCs showed robust engraftment and widespread distribution of hiPSC-NSCs in the host brain parenchyma. Engrafted hiPSC-NSCs displayed multilineage potential and preferentially generated glial cells. No hyperproliferation, tumor formation, or expression of pluripotency markers was observed. Finally, we identified a novel candidate transcription factor involved in the astroglial commitment of hiPSC-NSCs. Overall, these comprehensive in vitro and in vivo analyses clarify the cell identity and safety profile of hiPSC-NSCs, supporting their continuing development as an alternative to somatic hfNSCs in treating neurodegenerative and demyelinating disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE238206 | GEO | 2024/07/01

REPOSITORIES: GEO

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Project description:Stem cell functions require activation of stem cell-intrinsic transcriptional programs as well as intimate extracellular interactions with a niche microenvironment. How the core pluripotency transcriptional machinery controls residency of stem cells in the niche microenvironment is unknown. Here we show that the helix loop helix transcriptional regulators Id (Inhibitors of DNA binding) are the master regulators that coordinate stem cell activities with anchorage of neural stem cells (NSCs) to the embryonic and postnatal niche. Conditional inactivation of Id genes (Id1, Id2 and Id3) in the mouse NSC compartment triggered detachment of embryonic and post-natal NSCs from the ventricular and vascular niche respectively, followed by premature differentiation. Through an unbiased interrogation of the gene modules directly targeted by deletion of Id genes in NSCs, we discovered that Id proteins repress the bHLH-mediated activation of Rap1GAP, thus serving to maintain the GTPase activity of RAP1, a key mediator of cell adhesion. Preventing the elevation of Rap1GAP efficiently countered the consequences of Id loss on NSC-niche interaction and stem cell identity. Thus, by preserving anchorage to the extracellular environment of NSCs, Id activity synchronizes NSC functions to residency in the specialized niche. We generated Id-cTKO mice carrying a Cre-recombinase-oestrogen-receptor-T2 (Cre-ER) allele targeted to the ubiquitously expressed ROSA26 locus (Id-cTKO-Rosa-Cre-ER). In this system, 4-hydroxytamoxifen (4-OHT) releases the Cre recombinase inhibition and allows recombination of genomic loxP sites. Indeed, efficient deletion of Id1 and Id2 with complete loss of Id protein expression was detectable after treatment of NSCs with 4-OHT for 72 h. Total RNA was extracted from triplicate samples of Id-cTKO-Rosa-Cre-ER NSCs treated for different times (6 h, 12 h, 18 h, 24 h, 48 h, 96 h, 144 h) with 4-OHT or control vehicle and used for analysis on Illumina MouseWG-6 expression BeadChip. The raw array data was normalized using the Bioconductor package Lumi using quantile normalization.

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Human iPSC-derived neural stem cells display a radial glia-like signature in vitro and favorable long-term safety in transplanted mice

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