Reconstituting human somitogenesis in vitro
Reconstituting human somitogenesis in vitro
The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms, but remains largely elusive in humans due to ethical and technical limitations. Despite recent advances with pluripotent stem cell (PSC)-based approaches1–5, a system that robustly recapitulates human somitogenesis in both space and time remains missing. Here, we introduce a PSC-derived mesoderm-based 3D model of human segmentation and somitogenesis, which we termed Axioloids, that captures accurately the oscillatory dynamics of the segmentation clock as well as the morphological and molecular characteristics of segmentation and sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior-posterior FGF/WNT signaling gradients and Retinoic Acid (RA) signaling components. We identify an unexpected critical role of RA signaling in the stabilization of forming segments, indicating distinct, but also synergistic effects of RA and extracellular matrix (ECM) on the formation and epithelialization of somites. Importantly, comparative analysis demonstrates striking similarities of Axioloids to the human embryo, further validated by the presence of the HOX code in Axioloids. Lastly, we demonstrate the utility of our Axioloid system to study the pathogenesis of human congenital spine diseases, by using patient-like iPSC cells with mutations in HES7 and MESP2, which revealed disease-associated phenotypes including loss of epithelial somite formation and abnormal rostrocaudal patterning. These results suggest that Axioloids represent a promising novel platform to study axial development and disease in humans.
Yoshioka-Kobayashi Kumiko、Thompson Jamie L.、Kerwin Janet、Lisgo Steven、Tsujimura Taro、Zhang Yi、Hamidi Sofiane、Sunadome Kazunori、Munira Sirajam、Moris Naomi、Alev Cantas、Mieda Ai、Kurokawa Yuzuru、Yamanaka Yoshihiro、Martinez-Arias Alfonso、Yamamoto Takuya
Institute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityThe Francis Crick InstituteHDBR, Newcastle UniversityHDBR, Newcastle UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityThe Francis Crick InstituteInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversityInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto UniversitySystems Bioengineering, DCEXS, Universidad Pompeu FabraInstitute for the Advanced Study of Human Biology (ASHBi), Kyoto University||Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University||Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP)
基础医学生物科学研究方法、生物科学研究技术分子生物学
Yoshioka-Kobayashi Kumiko,Thompson Jamie L.,Kerwin Janet,Lisgo Steven,Tsujimura Taro,Zhang Yi,Hamidi Sofiane,Sunadome Kazunori,Munira Sirajam,Moris Naomi,Alev Cantas,Mieda Ai,Kurokawa Yuzuru,Yamanaka Yoshihiro,Martinez-Arias Alfonso,Yamamoto Takuya.Reconstituting human somitogenesis in vitro[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.06.03.494621.点此复制
评论