Author ORCID Identifier

https://orcid.org/0000-0003-1942-4981

Date of Award

Summer 2024

Document Type

Thesis (Ph.D.)

Department or Program

Biochemistry and Cell Biology

First Advisor

Kristina M. Godek

Second Advisor

Duane A. Compton

Abstract

Mitosis is a fundamental process that ensures the equal distribution of replicated chromosomes, which carry an organism's genetic material, into two daughter cells. The fidelity of mitosis is paramount, as errors in chromosome segregation result in aberrant chromosome numbers, including gains or losses, a state termed aneuploidy. Aneuploidy impacts a broad range of human conditions, including being one of the major hurdles in early human development where it is the primary cause of miscarriages and birth defects. Strikingly, more than 70% of human preimplantation embryos are aneuploid with mitotic chromosome segregation errors being the most common source of aneuploidy. However, the causes and consequences of chromosome missegregation in early human development remain poorly understood. Similarly, human pluripotent stem cells (hPSCs) often become aneuploid during prolonged in vitro propagation. Thus, aneuploidy poses a great challenge to the use of hPSCs in regenerative medicine. My thesis work delves into these two aspects using hPSCs as a model system for human embryonic cells.

In Chapter 2, I aim to uncover the causes of chromosome segregation errors in hPSCs by comparing them to normal somatic cells. Using quantitative immunofluorescence and live-cell imaging, I demonstrate that hPSCs exhibit an intrinsically low mitotic fidelity, with lagging chromosomes in anaphase being the most common chromosome segregation error. In addition, I identify that persistent improper merotelic attachments underlie the high frequency of lagging chromosomes in hPSCs. Furthermore, I devise strategies to improve error correction and mitigate mitotic errors using small molecules in hPSCs. Notably, I demonstrate that a pluripotent developmental state confers a low fidelity of chromosome segregation. In Chapter 3, I contribute to work exploring the immediate consequences of chromosome missegregation in hPSCs. By inducing aneuploidy in hPSCs, we demonstrate their inherent tolerance to chromosome missegregation, as evidenced by continued proliferation without activating the p53-p21 response, contrasting with the response of normal somatic cells.

Overall, my research unveils remarkable and unexpected findings that mitotic fidelity is not conserved in normal human cells, and it depends on developmental state. Additionally, hPSCs inherently tolerate aneuploidy. My thesis provides valuable insights into early human development and stem cell biology.

Original Citation

Deng C, Ya A, Compton DA, Godek KM. A pluripotent developmental state confers a low fidelity of chromosome segregation. Stem Cell Reports. 2023 Feb 14;18(2):475-488. doi: 10.1016/j.stemcr.2022.12.008. Epub 2023 Jan 12. PMID: 36638786; PMCID: PMC9968987.

Ya A, Deng C, Godek KM. Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells. bioRxiv [Preprint]. 2024 May 10:2024.05.08.593217. doi: 10.1101/2024.05.08.593217. PMID: 38766106; PMCID: PMC11100710.

Available for download on Thursday, July 17, 2025

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