Gabriella S Darmasaputra, Cindy C Geerlings, Susana M Chuva de Sousa Lopes, Hans Clevers, Matilde Galli
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引用次数: 0
摘要
双核多倍体细胞在许多动物组织中都很常见,它们是通过内异生产生的,内异生是一种非规范细胞周期,细胞进入 M 期但不进行细胞分裂。在啮齿类动物中,细胞分裂的不同步骤已被证明在内生 M 期受到抑制,但目前还不清楚人类细胞是如何进行内生的。在本研究中,我们利用胎儿衍生的人类肝细胞器官组织(Hep-Orgs)来研究人类肝细胞如何启动和执行内膜形成。我们发现,处于内膜有丝分裂 M 期的细胞具有正常的有丝分裂时间,但在细胞分裂过程中会失去与中体的膜锚定,这与四种皮质锚定蛋白 RacGAP1、Anillin、SEPT9 和柠檬激酶(CIT-K)的缺失有关。此外,减少 WNT 活性会增加 Hep-Orgs 中双核细胞的比例,这种效应依赖于非典型 E2F 蛋白 E2F7 和 E2F8。综上所述,我们阐明了人类 Hep-Orgs 中的肝细胞是如何发生内异症的,从而为哺乳动物的内异症机制提供了新的见解。
Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase.
Binucleated polyploid cells are common in many animal tissues, where they arise by endomitosis, a non-canonical cell cycle in which cells enter M phase but do not undergo cytokinesis. Different steps of cytokinesis have been shown to be inhibited during endomitosis M phase in rodents, but it is currently unknown how human cells undergo endomitosis. In this study, we use fetal-derived human hepatocyte organoids (Hep-Orgs) to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, which is associated with the loss of four cortical anchoring proteins, RacGAP1, Anillin, SEPT9, and citron kinase (CIT-K). Moreover, reduction of WNT activity increases the percentage of binucleated cells in Hep-Orgs, an effect that is dependent on the atypical E2F proteins, E2F7 and E2F8. Together, we have elucidated how hepatocytes undergo endomitosis in human Hep-Orgs, providing new insights into the mechanisms of endomitosis in mammals.
期刊介绍:
The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.