Ikeda Yuki, Tani Shoichiro, Moriishi Takeshi, Kuroda Aiko, Matsuo Yuki, Saeki Naoya, Inui-Yamamoto Chizuko, Abe Makoto, Maeda Takashi, Rowe David W, Chung Ung-Il, Hojo Hironori, Matsushita Yuki, Sawase Takashi, Ohba Shinsuke
Department of Tissue and Developmental Biology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
Regen Ther. 2023 Oct 10;24:536-546. doi: 10.1016/j.reth.2023.09.017. eCollection 2023 Dec.
Vertebrates form their skeletal tissues from three distinct origins (the neural crest, paraxial mesoderm, and lateral plate mesoderm) through two distinct modes of ossification (intramembranous and endochondral ossification). Since the paraxial mesoderm generates both intramembranous and endochondral bones, it is thought to give rise to both osteoprogenitors and osteo-chondroprogenitors. However, it remains unclear what directs the paraxial mesoderm-derived cells toward these different fates in distinct skeletal elements during human skeletal development. To answer this question, we need experimental systems that recapitulate paraxial mesoderm-mediated intramembranous and endochondral ossification processes. In this study, we aimed to develop a human pluripotent stem cell (hPSC)-based system that models the human intramembranous ossification process. We found that spheroid culture of the hPSC-derived paraxial mesoderm derivatives generates osteoprogenitors or osteo-chondroprogenitors depending on stimuli. The former induced intramembranous ossification, and the latter endochondral ossification, in mouse renal capsules. Transcriptional profiling supported the notion that bone signatures were enriched in the intramembranous bone-like tissues. Thus, we developed a system that recapitulates intramembranous ossification, and that enables the induction of two distinct modes of ossification by controlling the cell fate of the hPSC-derived paraxial mesoderm derivatives.
脊椎动物通过两种不同的骨化方式（膜内骨化和软骨内骨化），从三个不同的起源（神经嵴、轴旁中胚层和侧板中胚层）形成其骨骼组织。由于轴旁中胚层产生膜内骨和软骨内骨，因此人们认为它既能产生骨祖细胞，也能产生骨 - 软骨祖细胞。然而，在人类骨骼发育过程中，是什么引导轴旁中胚层来源的细胞在不同的骨骼元件中走向这些不同的命运，仍不清楚。为了回答这个问题，我们需要能够重现轴旁中胚层介导的膜内骨化和软骨内骨化过程的实验系统。在本研究中，我们旨在开发一种基于人类多能干细胞（hPSC）的系统，该系统可模拟人类膜内骨化过程。我们发现，hPSC来源的轴旁中胚层衍生物的球体培养根据刺激产生骨祖细胞或骨 - 软骨祖细胞。前者在小鼠肾囊中诱导膜内骨化，后者诱导软骨内骨化。转录谱分析支持了在膜内骨样组织中富集骨特征的观点。因此，我们开发了一种能够重现膜内骨化的系统，并且通过控制hPSC来源的轴旁中胚层衍生物的细胞命运，能够诱导两种不同的骨化方式。
