In vitro atlas of dorsal spinal interneurons reveals Wnt signaling as a critical regulator of progenitor expansion.
In vitro atlas of dorsal spinal interneurons reveals Wnt signaling as a critical regulator of progenitor expansion.
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DOI：
10.1016/j.celrep.2022.111119
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发表时间：
2022-07-19
期刊：
影响因子：
8.8
通讯作者：
Butler, Samantha J.
中科院分区：
文献类型：
--
作者：
Gupta, Sandeep;Kawaguchi, Riki;Heinrichs, Eric;Gallardo, Salena;Castellanos, Stephanie;Mandric, Igor;Novitch, Bennett G.;Butler, Samantha J.
在受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体感中间神经元。为了实现这一目标，我们评估了从小鼠胚胎干细胞(MESCs)分化出脊髓背侧中间神经元(dis；dI1-dI6)的机制。使用两种发育相关的生长因子，维甲酸(RA)和骨形态发生蛋白(BMP)4，我们概述了通过神经中胚层中间体进行Di分化的完整体内程序。转录图谱显示，mESC来源的dis与内源性dis惊人地相似，具有正确的分子和功能特征。我们进一步证明，RA通过默认的多势状态来指定dI4-dI6的命运，而BMP4的加入诱导了dI1-DI3的命运并激活了Wnt信号来促进祖细胞的增殖。结构性地激活Wnt信号允许神经前体细胞培养的戏剧性扩张。这些培养保留了分化成不同的Di群体的能力，从而提供了一种增加神经元产量的方法。Gupta等人开发从小鼠胚胎干细胞(MESCs)中获得完整的真正脊髓感觉中间神经元的方案。他们进一步确定了导致神经元间多样性的关键细胞状态，并将Wnt信号确定为在体外扩增脊髓祖细胞以大量产生感觉间神经元用于治疗的靶点。
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. Gupta et al. develop protocols to derive a full complement of bona fide spinal sensory interneurons from mouse embryonic stem cells (mESCs). They further identify key cellular states that contribute to the interneuron diversity and identify Wnt signaling as a target to expand spinal progenitors in vitro for producing sensory interneurons in large quantities for therapeutic applications.
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