TY - JOUR
T1 - Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase
AU - Darmasaputra, Gabriella S
AU - Geerlings, Cindy C
AU - Chuva de Sousa Lopes, Susana M
AU - Clevers, Hans
AU - Galli, Matilde
N1 - © 2024 Darmasaputra et al.
PY - 2024/8/5
Y1 - 2024/8/5
N2 - 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.
AB - 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.
KW - Humans
KW - Cytokinesis
KW - Hepatocytes/metabolism
KW - Mitosis
KW - Organoids/cytology
KW - Polyploidy
U2 - 10.1083/jcb.202403020
DO - 10.1083/jcb.202403020
M3 - Article
C2 - 38727809
SN - 0021-9525
VL - 223
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 8
ER -