The isochromosome 20q abnormality of pluripotent cells interrupts germ layer differentiation

Vitillo, Loriana; Anjum, Fabiha; Hewitt, Zoë; Stavish, Dylan; Laing, Owen; Baker, Duncan; Barbaric, Ivana; Coffey, Peter

doi:10.1016/j.stemcr.2023.01.007

Cited by 10 publications

(8 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another documented feature of genetically variant cells is altered differentiation propensity, which can in turn impact the efficiency and the number of produced cell types required for basic research and disease modelling. For example, previous work has shown that the amplification of chromosome 17q in hPSCs leads to altered neuronal differentiation 13 , while we recently demonstrated that the presence of isochromosome 20q impairs spontaneous differentiation of hPSCs 14 .…”

Section: Introductionmentioning

confidence: 76%

Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype

Wing,

Price,

Stavish

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Human pluripotent stem cell (hPSC)-derived cardiomyocytes have emerged as powerful tools for disease modelling and cell therapy. The production of cardiomyocytes from hPSCs typically requires expanding large numbers of hPSCs and maintaining them in culture for extended periods of time. This in turn predisposes hPSCs to the acquisition of non-random genetic changes, including recurrent gains of chromosome 1q. Here, we show that gain of chromosome 1q in hPSCs affects both the efficiency of differentiation to cardiomyocytes and phenotype of the differentiated cells. Mechanistically, we show that aberrant activation of the Wnt signalling pathway underpins the skewed differentiation of variant 1q hPSCs. Collectively, our data demonstrates that the presence of genetically variant cells in cultures is a significant concern for production of hPSC-derived cardiomyocytes for research or clinical applications. Further, our results suggest new approaches for removing genetically variant cells for future clinical applications.

show abstract

Section: Introductionmentioning

confidence: 76%

Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype

Wing,

Price,

Stavish

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Work from our group and others is beginning to generate a detailed picture showing how these genetic abnormalities affect differentiation in a cell lineage-specific manner. For instance, 20q11.21 gain impairs neuroectoderm commitment without affecting mesendoderm induction ( Jo et al., 2020 ; Markouli et al., 2019 ), and recently, it has been shown that cells with an isochromosome 20q are not able to survive retinal pigmented epithelial cell differentiation and display overall disruptions in the ability to correctly differentiate ( Vitillo et al., 2023 ). In this work, we show that 18q loss specifically impairs neuroectoderm commitment and appears to delay cardiac differentiation.…”

Section: Discussionmentioning

confidence: 99%

SALL3 mediates the loss of neuroectodermal differentiation potential in human embryonic stem cells with chromosome 18q loss

Lei,

Al Delbany,

Krivec

et al. 2024

Stem Cell Reports

View full text Add to dashboard Cite

“…Also, while entering the mesendodermal lineage equally efficiently as hESC wt , hESC 1q generate hepatoblasts and cardiac progenitors that have gene-expression profiles suggestive of a poor cell maturation. It is interesting to note that hESC with a gain of 20q11.21 22,23 , an isochromosome 20 51 and with a loss of 18q 52 all display an abnormal response to the neuroectoderm differentiation signaling cues. This common response suggests a particular vulnerability of the neuroectodermal lineage to genetic abnormalities, with potentially common signaling pathways disrupting the differentiation process.…”

Section: Discussionmentioning

confidence: 99%

Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

Krivec,

Couvreu de Deckersberg,

Lei

et al. 2023

Preprint

View full text Add to dashboard Cite

Gains of 1q are a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains of 1q impact the differentiation capacity to derivates of the three germ layers, leading to miss-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation and by poorer expression of lineage specific markers in hepatoblasts and cardiac progenitors. Competition assays show that the cells retain their selective advantage during differentiation, which is mediated by a higher expression of MDM4, a gene located in the common region of gain. MDM4 drives the winner phenotype of the mutant cells in both the undifferentiated and differentiating state by reducing the cells sensitivity to DNA-damage through decreased p53-mediated apoptosis. Finally, we find that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.

show abstract

The isochromosome 20q abnormality of pluripotent cells interrupts germ layer differentiation

Cited by 10 publications

References 47 publications

Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype

Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype

SALL3 mediates the loss of neuroectodermal differentiation potential in human embryonic stem cells with chromosome 18q loss

Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

Contact Info

Product

Resources

About