227: 1q gain enables rescue of aneuploid hESCs during RPE differentiation

Couvreu de Deckersberg E et al., Nat Commun (2025) - This study shows that spontaneous RPE differentiation eliminates most aneuploid human pluripotent stem cells but permits expansion of cells with chromosome 1q gains when they are co-cultured with wild-type cells. Key terms: aneuploidy, 1q gain, RPE differentiation, co-culture, wild-type rescue.

Study Highlights:
Large-scale single-cell genomics revealed pervasive low-grade mosaicism in genetically balanced hPSC cultures, with 3–6% of cells carrying various aneuploidies. During undirected RPE differentiation most aneuploid lineages are purged, except for cells bearing gains of chromosome arm 1q which persist. 1q-gain cells only complete neural/RPE specification when co-cultured with wild-type cells that provide paracrine ligands and induce neuroectodermal regulons, enabling rescued differentiation trajectories. Rescued RPE1q cells show comparable RPE marker expression but display transcriptional signs of aneuploidy-related stress and can outcompete wild-type and other aneuploid cells, whereas 20q11.21 gains, iso20q and trisomy 20 generally fail to be rescued.

Conclusion:
Spontaneous RPE differentiation acts as a selective bottleneck removing most aneuploid cells but permits expansion of 1q-gain clones via wild-type co-culture rescue, underscoring the importance of genomic surveillance for hPSC-derived therapies

Music:
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First author:
Couvreu de Deckersberg E

Journal:
Nat Commun (2025)

DOI:
10.1038/s41467-025-66766-w

Reference:
Couvreu de Deckersberg E, Lei Y, Krivec N, Huyghebaert A, Duong MC, Janssens C, Regin M, Tsuiko O, Movahedi K, Verhulst S, van Grunsven LA, Sermon K, Al Delbany D, Spits C. 1q gain bypasses the selective barrier against aneuploidy in RPE differentiation via wild-type co-culture rescue. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66766-w

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-13.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content covering: baseline mosaicism in hPSCs, the selective bottleneck during RPE differentiation, the 1q-gain rescue via co-culture, the MDM4/p53 mechanism, signaling interactions with wild-type neighbors, and comparisons to other aneuploides; also covered limitations and safety considerations.
- transcript topics: hPSC mosaicism and common aneuploidies; undirected RPE differentiation bottleneck; 1q gain persistence and enrichment; wild-type co-culture rescue mechanism; MDM4/p53 axis and stress responses; signaling interactions between wt and 1q-gain cells

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Prevalence of low-grade mosaicism in hPSC cultures (3-6%).
- During undirected RPE differentiation, most aneuploidies are eliminated except 1q gains.
- 1q-gain c...