Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge, UK.
Nat Commun. 2022 May 23;13(1):2844. doi: 10.1038/s41467-022-29839-8.
The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Following the initial expansion of the progenitor cell pool, these cells generate neurons of all the cortical layers and then astrocytes and oligodendrocytes. Yet, the regulatory pathways that control the expansion and maintenance of the progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of cerebral cortex developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-β1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate into lower- and upper-layer cortical neurons in vitro and in vivo. The identification of mechanisms that drive the neuroepithelial stem cell self-renewal and differentiation and preserve this potential in vitro is key to developing regenerative and cell-based therapeutic approaches to treat neurological conditions.
大脑皮层由背侧前脑神经上皮祖细胞发育而来。在祖细胞池最初扩张之后，这些细胞产生所有皮层层的神经元，然后产生星形胶质细胞和少突胶质细胞。然而，目前尚不清楚控制祖细胞池扩增和维持的调节途径。在这里，我们定义了六个基本的通路组成部分，它们可以在体外调节皮质特异性人神经上皮干细胞（cNESCs）的增殖，而不会丧失大脑皮层发育潜能。我们表明，FGF 的激活和 BMP 和 ACTIVIN A 信号的抑制对于长期 cNESC 增殖是必需的。我们还证明，当 GSK3、AKT 和核 CATENIN-β1 活性较低时，cNESCs 保留了背侧端脑特异性潜能。值得注意的是，这六个通路组成部分的调节支持了 cNESCs 的克隆扩增。此外，cNESCs 在体外和体内分化为低和上层皮层神经元。鉴定驱动神经上皮干细胞自我更新和分化并在体外保留这种潜能的机制是开发用于治疗神经疾病的再生和基于细胞的治疗方法的关键。
