Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Exp Mol Med. 2020 Aug;52(8):1166-1177. doi: 10.1038/s12276-020-0482-1. Epub 2020 Aug 13.
Pluripotent stem cells (PSCs) are attractive regenerative therapy tools for skeletal tissues. However, a deep understanding of skeletal development is required in order to model this development with PSCs, and for the application of PSCs in clinical settings. Skeletal tissues originate from three types of cell populations: the paraxial mesoderm, lateral plate mesoderm, and neural crest. The paraxial mesoderm gives rise to the sclerotome mainly through somitogenesis. In this process, key developmental processes, including initiation of the segmentation clock, formation of the determination front, and the mesenchymal-epithelial transition, are sequentially coordinated. The sclerotome further forms vertebral columns and contributes to various other tissues, such as tendons, vessels (including the dorsal aorta), and even meninges. To understand the molecular mechanisms underlying these developmental processes, extensive studies have been conducted. These studies have demonstrated that a gradient of activities involving multiple signaling pathways specify the embryonic axis and induce cell-type-specific master transcription factors in a spatiotemporal manner. Moreover, applying the knowledge of mesoderm development, researchers have attempted to recapitulate the in vivo development processes in in vitro settings, using mouse and human PSCs. In this review, we summarize the state-of-the-art understanding of mesoderm development and in vitro modeling of mesoderm development using PSCs. We also discuss future perspectives on the use of PSCs to generate skeletal tissues for basic research and clinical applications.
多能干细胞（PSCs）是一种有吸引力的骨骼组织再生治疗工具。然而，为了使用 PSCs 对骨骼发育进行建模，以及将 PSCs 应用于临床环境，需要深入了解骨骼发育。骨骼组织起源于三种细胞群体：轴旁中胚层、侧板中胚层和神经嵴。轴旁中胚层主要通过体节发生产生体节。在这个过程中，关键的发育过程，包括分段时钟的启动、决定前沿的形成以及间质上皮转化，被依次协调。体节进一步形成脊柱，并为各种其他组织做出贡献，如肌腱、血管（包括背主动脉），甚至脑膜。为了了解这些发育过程的分子机制，已经进行了广泛的研究。这些研究表明，涉及多个信号通路的活性梯度以时空方式特异性地指定胚胎轴，并诱导细胞类型特异性的主转录因子。此外，研究人员应用中胚层发育的知识，尝试使用小鼠和人类 PSCs 在体外环境中再现体内发育过程。在这篇综述中，我们总结了中胚层发育的最新理解和使用 PSCs 进行中胚层发育的体外建模。我们还讨论了使用 PSCs 生成骨骼组织用于基础研究和临床应用的未来展望。
