体外背侧脊髓中间神经元图谱揭示 Wnt 信号作为祖细胞扩增的关键调节因子。
In vitro atlas of dorsal spinal interneurons reveals Wnt signaling as a critical regulator of progenitor expansion.
机构信息
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cell Rep. 2022 Jul 19;40(3):111119. doi: 10.1016/j.celrep.2022.111119.
Restoring sensation after injury or disease requires a reproducible method for generating large quantities of bona fide somatosensory interneurons. Toward this goal, we assess the mechanisms by which dorsal spinal interneurons (dIs; dI1-dI6) can be derived from mouse embryonic stem cells (mESCs). Using two developmentally relevant growth factors, retinoic acid (RA) and bone morphogenetic protein (BMP) 4, we recapitulate the complete in vivo program of dI differentiation through a neuromesodermal intermediate. Transcriptional profiling reveals that mESC-derived dIs strikingly resemble endogenous dIs, with the correct molecular and functional signatures. We further demonstrate that RA specifies dI4-dI6 fates through a default multipotential state, while the addition of BMP4 induces dI1-dI3 fates and activates Wnt signaling to enhance progenitor proliferation. Constitutively activating Wnt signaling permits the dramatic expansion of neural progenitor cultures. These cultures retain the capacity to differentiate into diverse populations of dIs, thereby providing a method of increasing neuronal yield.
在损伤或疾病后恢复感觉需要一种可重复的方法来产生大量真正的感觉中间神经元。为此，我们评估了从小鼠胚胎干细胞（mESCs）中衍生出背侧脊髓中间神经元（dI；dI1-dI6）的机制。使用两种发育相关的生长因子，视黄酸（RA）和骨形态发生蛋白 4（BMP4），我们通过神经中胚层中间产物重现了 dI 分化的完整体内程序。转录谱分析表明，mESC 衍生的 dI 与内源性 dI 非常相似，具有正确的分子和功能特征。我们进一步证明，RA 通过默认多能状态指定 dI4-dI6 命运，而添加 BMP4 诱导 dI1-dI3 命运并激活 Wnt 信号以增强祖细胞增殖。持续激活 Wnt 信号允许神经祖细胞培养物的显著扩增。这些培养物保持分化为不同群体的 dI 的能力，从而提供了增加神经元产量的方法。
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