Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives
Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives
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定义人神经中胚层祖细胞衍生物中后腹侧脊髓身份的信号决定因素
作者：
Matthew Wind;Antigoni Gogolou;Ichcha Manipur;Ilaria Granata;L. Butler;P. Andrews;Ivana Barbaric;K. Ning;M. Guarracino;M. Placzek;Anestis Tsakiridis
摘要运动神经元（MN）的前后轴特性决定了它们的功能和对神经变性的脆弱性。因此，它是旨在从人多能干细胞（hPSC）产生MN用于再生医学/疾病建模应用的策略设计中的关键参数。然而，在体外生成对应于胸/腰骶脊髓的后部MN一直具有挑战性。虽然诱导类似于神经中胚层祖细胞（NMPs），真正的前体脊髓的细胞，提供了一个有前途的解决方案，从这些细胞的后MNs的逐步规范没有很好地定义。在这里，我们确定了引导人类神经基质蛋白样细胞向胸腹侧脊髓神经外胚层转变的信号。我们发现，结合WNT-FGF活动驱动后背前/早期神经状态，而抑制TGFβ-BMP信号通路促进腹侧身份和神经承诺。基于这些结果，我们定义了一个优化的协议，用于生成胸部MN，可以有效地整合在鸡胚的神经管。我们希望我们的研究结果将有助于比较不同轴向身份的hPSC衍生的脊髓细胞。总结：描述了一种有效的策略，用于在体外产生以前难以产生的后脊髓祖细胞和MN表现出胸轴，特别是，节前柱状身份。
ABSTRACT The anteroposterior axial identity of motor neurons (MNs) determines their functionality and vulnerability to neurodegeneration. Thus, it is a crucial parameter in the design of strategies aiming to produce MNs from human pluripotent stem cells (hPSCs) for regenerative medicine/disease modelling applications. However, the in vitro generation of posterior MNs corresponding to the thoracic/lumbosacral spinal cord has been challenging. Although the induction of cells resembling neuromesodermal progenitors (NMPs), the bona fide precursors of the spinal cord, offers a promising solution, the progressive specification of posterior MNs from these cells is not well defined. Here, we determine the signals guiding the transition of human NMP-like cells toward thoracic ventral spinal cord neurectoderm. We show that combined WNT-FGF activities drive a posterior dorsal pre-/early neural state, whereas suppression of TGFβ-BMP signalling pathways promotes a ventral identity and neural commitment. Based on these results, we define an optimised protocol for the generation of thoracic MNs that can efficiently integrate within the neural tube of chick embryos. We expect that our findings will facilitate the comparison of hPSC-derived spinal cord cells of distinct axial identities. Summary: An efficient strategy is described for the in vitro generation of previously hard-to-produce posterior spinal cord progenitors and MNs exhibiting a thoracic axial and, in particular, preganglionic columnar identity.
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影响因子：
15.9
作者：
Lu, Paul;Ceto, Steven;Tuszynski, Mark H.
通讯作者：
Tuszynski, Mark H.
使用微流体梯度的图案化人类神经管模型。
影响因子：
64.8
作者：
Xue,Xufeng;Kim,YungSu;Ponce-Arias,Alfredo-Isaac;O'Laughlin,Richard;Yan,RobinZhexuan;Kobayashi,Norio;Tshuva,RamiYair;Tsai,Yu-Hwai;Sun,Shiyu;Zheng,Yi;Liu,Yue;Wong,FrederickCK;Surani,Azim;Spence,JasonR;Song,Hongjun;Ming,G
通讯作者：
Ming,G
影响因子：
11.6
作者：
Rugman, AM;Verbeke, A
通讯作者：
Verbeke, A
影响因子：
23.9
作者：
Peljto M;Dasen JS;Mazzoni EO;Jessell TM;Wichterle H
通讯作者：
Wichterle H
影响因子：
23.9
作者：
Zhang X;Huang CT;Chen J;Pankratz MT;Xi J;Li J;Yang Y;Lavaute TM;Li XJ;Ayala M;Bondarenko GI;Du ZW;Jin Y;Golos TG;Zhang SC
通讯作者：
Zhang SC