Induction of experimental cell division to generate cells with reduced chromosome ploidy

Nuria Marti Gutierrez, Aleksei Mikhalchenko, Maria Shishimorova, Daniel Frana, Crystal Van Dyken, Ying Li, Hong Ma, Amy Koski, Dan Liang, Sang-Goo Lee, Daniel Eyberg, Zahra Safaei, Eunju Kang, Yeonmi Lee, Thomas O’Leary, David Lee, Sacha Krieg, Diana Wu, Elizabeth Rubin, Paula Amato () and Shoukhrat Mitalipov ()
Additional contact information
Nuria Marti Gutierrez: Oregon Health & Science University
Aleksei Mikhalchenko: Oregon Health & Science University
Maria Shishimorova: Oregon Health & Science University
Daniel Frana: Oregon Health & Science University
Crystal Van Dyken: Oregon Health & Science University
Ying Li: Oregon Health & Science University
Hong Ma: Oregon Health & Science University
Amy Koski: Oregon Health & Science University
Dan Liang: Oregon Health & Science University
Sang-Goo Lee: Oregon Health & Science University
Daniel Eyberg: Oregon Health & Science University
Zahra Safaei: Oregon Health & Science University
Eunju Kang: CHA University
Yeonmi Lee: CHA University
Thomas O’Leary: Oregon Health & Science University
David Lee: Oregon Health & Science University
Sacha Krieg: Oregon Health & Science University
Diana Wu: Oregon Health & Science University
Elizabeth Rubin: Oregon Health & Science University
Paula Amato: Oregon Health & Science University
Shoukhrat Mitalipov: Oregon Health & Science University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Somatic cell nuclear transfer (SCNT) enables the direct reprogramming of somatic cells into functional oocytes, albeit with a diploid genome. To address ploidy reduction, we investigated an experimental reductive cell division process, termed mitomeiosis, wherein non-replicated (2n2c) somatic genomes are prematurely forced to divide following transplantation into the metaphase cytoplasm of enucleated human oocytes. However, despite fertilization with sperm, SCNT oocytes remained arrested at the metaphase stage, indicating activation failure. Artificial activation using a selective cyclin-dependent kinase inhibitor successfully bypassed this arrest, inducing the segregation of somatic chromosomes into a zygotic pronucleus and a polar body. Comprehensive chromosome tracing via sequencing revealed that homologous chromosome segregation occurred randomly and without crossover recombination. Nonetheless, an average of 23 somatic chromosomes were retained within the zygote, demonstrating the feasibility of experimentally halving the diploid chromosome set. Fertilized human SCNT oocytes progressed through normal embryonic cell divisions, ultimately developing into embryos with integrated somatic and sperm-derived chromosomes. While our study demonstrates the potential of mitomeiosis for in vitro gametogenesis, at this stage it remains just a proof of concept and further research is required to ensure efficacy and safety before future clinical applications.

Date: 2025
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DOI: 10.1038/s41467-025-63454-7

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