A research group led by Professor Yasusei Kudo from the Department of Oral Bioscience, Graduate School of Biomedical Sciences, Associate Professor Takaaki Tsunematsu and Professor Naozumi Ishimaru (currently at Institute of Science Tokyo) from the Department of Oral Pathology at Tokushima University, in collaboration with Keio University, the University of Edinburgh (UK), the University of Verona (Italy), and New York University (USA), has announced the discovery of a new mechanism for maintaining the undifferentiated state of pluripotent stem cells and found that the chromosomal passenger complex (CPC) that controls cell division is essential for maintaining this state. This finding is expected to have applications in medical fields such as cancer treatment and was published in the online edition of the international academic journal Science Signaling on February 19.
Pluripotent stem cells, such as iPS cells and ES cells, have the ability to differentiate into various cell types and are expected to be applied in regenerative medicine, disease research, and drug discovery research. However, many aspects of how the undifferentiated state is maintained remain unclear.
In this study, the research group used human embryonic carcinoma cells as a model for pluripotent stem cells and discovered that the CPC, a protein complex that controls the movement and arrangement of chromosomes during cell division, is essential for maintaining pluripotency. The CPC consists of four proteins—Aurora-B kinase, Survivin, Borealin, and INCENP—and is highly conserved from yeast to humans. It is normally degraded by an enzyme called the APC/CCdh1 ubiquitin ligase complex after cell division is completed.
In contrast, the group found that in somatic cells, the function of the APC/CCdh1 ubiquitin ligase complex is suppressed, and the CPC is stably activated. It was also shown that the CPC is involved in maintaining the undifferentiated state beyond its role in cell division. When CPC function was inhibited, hEC cells spontaneously differentiated and progressed from an undifferentiated state to differentiation. Additionally, it was shown that epithelial-to-mesenchymal transition is involved in stem cell fate determination upon CPC inactivation.
Aurora-B kinase is activated in cancer, and inhibitors are being developed as new anticancer drugs. Cancer tissues contain cancer stem cells with treatment resistance, which cause recurrence. A new treatment strategy is anticipated wherein Aurora-B inhibitors induce differentiation of cancer stem cells, enhancing therapeutic effects when used in combination with conventional anticancer drugs.
Kudo commented: "Through this research, we have revealed a new mechanism in which the CPC, which plays an important role in cell division, is involved in maintaining the undifferentiated state of pluripotent stem cells. Controlling stem cell differentiation is an important issue directly linked to regenerative medicine and drug discovery, so the findings of this study provide foundational knowledge. For future development, we expect to further elucidate the role of the CPC in iPS cells and cancer stem cells, with applications in regenerative medicine and new cancer treatments."
Journal Information
Publication: Science Signaling
Title: Sustained chromosomal passenger complex activity preserves the pluripotency of human embryonic carcinoma cells
DOI: 10.1126/scisignal.adg4626
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.