The human body function requires crosstalk between different tissues. An essential crosstalk is in the neuromusculoskeletal (NMS) axis involving neural, muscular, and skeletal tissues, which is challenging to model using human cells. Here, we describe the generation of three-dimensional, NMS tri-tissue organoids (hNMSOs) from human pluripotent stem cells through a co-development strategy. Staining, single-nucleus RNA sequencing, and spatial transcriptome profiling revealed the co-emergence and self-organization of neural, muscular, and skeletal lineages within individual organoids, and the neural domains of hNMSOs obtained a ventral-specific identity and produced motor neurons innervating skeletal muscles. The neural, muscular, and skeletal regions of hNMSOs exhibited maturation and established functional connections during development. Notably, structural, functional, and transcriptomic analyses revealed that skeletal support in hNMSOs benefited human muscular development. Modeling with hNMSOs also unveiled the neuromuscular alterations following pathological skeletal degeneration. Together, our study provides an accessible experimental model for future studies of human NMS crosstalk and abnormality.

中文翻译：

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从人类多能干细胞中产生自组织神经肌肉骨骼三组织类器官


人体功能需要不同组织之间的串扰。一个重要的串扰位于神经肌肉骨骼 （NMS） 轴上，涉及神经、肌肉和骨骼组织，使用人类细胞进行建模具有挑战性。在这里，我们描述了通过共同开发策略从人类多能干细胞产生三维 NMS 三组织类器官 （hNMSO）。染色、单核 RNA 测序和空间转录组分析揭示了单个类器官内神经、肌肉和骨骼谱系的共同出现和自组织，hNMSO 的神经域获得了腹侧特异性身份并产生了支配骨骼肌的运动神经元。hNMSO 的神经、肌肉和骨骼区域在发育过程中表现出成熟并建立功能连接。值得注意的是，结构、功能和转录组学分析表明，hNMSO 中的骨骼支撑有利于人类肌肉发育。使用 hNMSO 建模还揭示了病理骨骼变性后的神经肌肉改变。总之，我们的研究为未来人类 NMS 串扰和异常的研究提供了一个可访问的实验模型。