Extrinsic factors facilitate neurogenesis in a human induced pluripotent stem cell-derived model of the dentate gyrus

ABSTRACT: Modeling development and maturation of the human hippocampus in culture is crucial to elucidate the physiological and pathological mechanisms of its neurogenesis. We established human hippocampal cell cultures by means of controlled neuralization of human induced pluripotent stem cells (hiPSCs). The timely re-activation of WNT signaling in hiPSCs, which were previously driven toward a dorsal telencephalic identity by the combined inhibition of WNT, BMP and TGF-β signaling, produced neural progenitors with a gene expression signature typical of human embryonic dentate gyrus (DG) cells. Key markers of neurogenesis resulted downstream of the NOTCH and WNT pathway and were upregulated in these progenitors. Notably, we found that, in addition to continuous WNT signaling, a specific laminin isoform is crucial to prolonging DG stem state and to extend DG progenitor proliferation for over 200 days in vitro. In fact, transition from laminin 511 to mouse laminin inhibited cell proliferation and promoted the differentiation of DG cells. Interestingly, global gene expression profiles of early and late progenitor cells and neurons suggest that a niche of laminin 511 and WNT signaling is sufficient to maintain a cell population enriched in DG progenitor cells and neurons. Finally, the xenograft of human DG progenitors into the DG of adult immunosuppressed host mice produced efficient integration of neurons, which innervated CA3 layer cells with an area covered by synapses similar to the area covered by endogenous hippocampal neuron synapses. Our observations indicate that neurons produced in the established culture niche resemble bona-fide human DG neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199355 | GEO | 2022/08/22

REPOSITORIES: GEO