A RHO Small GTPase Regulator ABR Secures Mitotic Fidelity in Human Embryonic Stem Cells.

Masatoshi Ohgushi,Maki Minaguchi,Yoshiki Sasai,Mototsugu Eiraku

doi:10.1016/j.stemcr.2017.05.003

Masatoshi Ohgushi, Maki Minaguchi + Show 2 more

Open Access

https://doi.org/10.1016/j.stemcr.2017.05.003

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Abstract

SummaryPluripotent stem cells can undergo repeated self-renewal while retaining genetic integrity, but they occasionally acquire aneuploidy during long-term culture, which is a practical obstacle for medical applications of human pluripotent stem cells. In this study, we explored the biological roles of ABR, a regulator of RHO family small GTPases, and found that it has pivotal roles during mitotic processes in human embryonic stem cells (hESCs). Although ABR has been shown to be involved in dissociation-induced hESC apoptosis, it does not appear to have direct effects on cell survival unless cell-cell contact is impaired. Instead, we found that it is important for faithful hESC division. Mechanistically, ABR depletion compromised centrosome dynamics and predisposed the cell to chromosome misalignment and missegregation, which raised the frequency of aneuploidy. These results provide insights into the mechanisms that support the genetic integrity of self-renewing hESCs.

Highlights

The faithful inheritance of genetic material during repetitive cell division is fundamental for animal development and tissue regeneration in multicellular organisms
We previously reported that the aberrant activation of the RHO-ROCK pathway was responsible for dissociationinduced human embryonic stem cells (hESCs) apoptosis (Watanabe et al, 2007; Ohgushi et al, 2010)
We succeeded in reducing ABR protein to an undetectable level after dox addition (Figure 1A), and we refer to these genetically engineered cells as tet-shABR hESCs

Summary

Introduction

The faithful inheritance of genetic material during repetitive cell division is fundamental for animal development and tissue regeneration in multicellular organisms. Several quality control mechanisms survey the organism for genetic normality and activate programs for error correction or elimination of abnormal cells. These mechanisms could suppress aneuploidy, a genetic aberration that arises from missegregation of whole chromosomes during mitosis. If aneuploid cells override these barriers and continue proliferating, they can acquire cancerous properties. It is well recognized that chromosomal instability, the condition in which aneuploidy occurs at a high rate, underlies genetic abnormalities found in many types of tumor cells. Aneuploidy is commonly observed in a wide range of tumor tissues and cancer-derived cell lines (reviewed in Santaguida and Amon, 2015)

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