Laboratorio di Biologia, Scuola Normale Superiore, Pisa, 56126, Italy.
Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Pisa, 56124, Italy.
Development. 2022 Oct 15;149(20). doi: 10.1242/dev.200353. Epub 2022 Sep 9.
Using the timely re-activation of WNT signalling in neuralizing human induced pluripotent stem cells (hiPSCs), we have produced neural progenitor cells with a gene expression profile typical of human embryonic dentate gyrus (DG) cells. Notably, in addition to continuous WNT signalling, a specific laminin isoform is crucial to prolonging the neural stem state and to extending progenitor cell proliferation for over 200 days in vitro. Laminin 511 is indeed specifically required to support proliferation and to inhibit differentiation of hippocampal progenitor cells for extended time periods when compared with a number of different laminin isoforms assayed. Global gene expression profiles of these cells suggest that a niche of laminin 511 and WNT signalling is sufficient to maintain their capability to undergo typical hippocampal neurogenesis. Moreover, laminin 511 signalling sustains the expression of a set of genes responsible for the maintenance of a hippocampal neurogenic niche. Finally, xenograft of human DG progenitors into the DG of adult immunosuppressed host mice produces efficient integration of neurons that innervate CA3 layer cells spanning the same area of endogenous hippocampal neuron synapses.
通过及时重新激活 WNT 信号在神经诱导多能干细胞（hiPSCs）中，我们产生了具有典型人胚胎齿状回（DG）细胞基因表达谱的神经祖细胞。值得注意的是，除了持续的 WNT 信号外，特定的层粘连蛋白异构体对于延长神经干细胞状态和延长体外祖细胞增殖超过 200 天至关重要。与测试的许多不同层粘连蛋白异构体相比，层粘连蛋白 511 确实需要特异性支持增殖并抑制海马祖细胞的分化，以延长时间。这些细胞的全基因组表达谱表明，层粘连蛋白 511 和 WNT 信号的小生境足以维持其进行典型海马神经发生的能力。此外，层粘连蛋白 511 信号维持一组负责维持海马神经发生小生境的基因的表达。最后，将人 DG 祖细胞异种移植到成年免疫抑制宿主小鼠的 DG 中，可有效地整合神经元，这些神经元支配 CA3 层细胞，跨越内源性海马神经元突触的相同区域。
