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1.
Sci Rep ; 11(1): 8242, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859268

RESUMO

We identified a human embryonic stem cell subline that fails to respond to the differentiation cues needed to obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed that the subline has hyperactivation of the WNT and BMP4 signalling. Modulation of these pathways with small molecules confirmed them as the cause of the differentiation impairment. While activation of WNT and BMP4 in control cells resulted in a loss of endoderm differentiation and induction of extra-embryonic mesoderm markers, inhibition of these pathways in the subline restored its ability to differentiate. Karyotyping and exome sequencing analysis did not identify any changes in the genome that could account for the pathway deregulation. These findings add to the increasing evidence that different responses of stem cell lines to differentiation protocols are based on genetic and epigenetic factors, inherent to the line or acquired during cell culture.


Assuntos
Proteína Morfogenética Óssea 4/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias Humanas/fisiologia , Proteínas Wnt/genética , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Endoderma/citologia , Endoderma/fisiologia , Membranas Extraembrionárias/citologia , Membranas Extraembrionárias/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Mesoderma/citologia , Mesoderma/fisiologia , Transdução de Sinais/genética , Transcriptoma , Proteínas Wnt/metabolismo
2.
Stem Cell Reports ; 13(1): 163-176, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31178415

RESUMO

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-ß- 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.


Assuntos
Diferenciação Celular/genética , Cromossomos Humanos Par 20/genética , Células-Tronco Pluripotentes/citologia , Fator de Crescimento Transformador beta/metabolismo , Aberrações Cromossômicas , Cromossomos Humanos Par 20/química , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Amplificação de Genes , Humanos , Placa Neural/citologia , Células-Tronco Pluripotentes/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
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