Gain of 20q11.21 in Human Pluripotent Stem Cells Impairs TGF-β-Dependent Neuroectodermal Commitment.

Christina Markouli, Edouard Couvreu De Deckersberg, Marius Regin, Ha Nguyen Thi, Filippo Zambelli, Alexander Scott Keller, Dominika Dziedzicka, Joery De Kock, Laurentijn Tilleman, Filip Van Nieuwerburgh, Lorenzo Franceschini, Karen Sermon, Mieke Geens, Claudia Spits

Onderzoeksoutput: Article

12 Citaten (Scopus)

Samenvatting

Gain of 20q11.21 is one of the most common recurrent genomic aberrations in human pluripotent stem cells. Although it is known that overexpression of the antiapoptotic gene Bcl-xL confers a survival advantage to the abnormal cells, their differentiation capacity has not been fully investigated. RNA sequencing of mutant and control hESC lines, and a line transgenically overexpressing Bcl-xL, shows that overexpression of Bcl-xL is sufficient to cause most transcriptional changes induced by the gain of 20q11.21. Moreover, the differentially expressed genes in mutant and Bcl-xL overexpressing lines are enriched for genes involved in TGF-β- and SMAD-mediated signaling, and neuron differentiation. Finally, we show that this altered signaling has a dramatic negative effect on neuroectodermal differentiation, while the cells maintain their ability to differentiate to mesendoderm derivatives. These findings stress the importance of thorough genetic testing of the lines before their use in research or the clinic. In this article Spits and colleagues show that Bcl-xL overexpression is the main driver of the distinct transcriptomic profile of human embryonic stem cells with a gain of 20q11.21. The cells have an abnormal TGF-β- and SMAD-mediated signaling, which impairs commitment to neuroectoderm while differentiation to the other lineages remains unaffected.

Originele taal-2English
Pagina's (van-tot)163-176
Aantal pagina's14
TijdschriftStem Cell Reports
Volume13
Nummer van het tijdschrift1
DOI's
StatusPublished - 9 jul 2019

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