A p53-Dependent Checkpoint Induced upon DNA Damage Alters Cell Fate during hiPSC Differentiation
| Autor: | Julian E. Sale, Alastair Crisp, Cara B. Eldridge, Finian J. Allen, Rodrigo A. Grandy, Ludovic Vallier |
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| Přispěvatelé: | Allen, Finian [0000-0002-9823-562X], Vallier, Ludovic [0000-0002-3848-2602], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
p53
0301 basic medicine Mesoderm Transcription Genetic DNA damage Induced Pluripotent Stem Cells Germ layer Biology Cell fate determination Biochemistry hiPSC 03 medical and health sciences checkpoint 0302 clinical medicine Tissue engineering Report Genetics medicine Humans Cell Lineage Endoderm DNA-damage response Cell Differentiation differentiation Cell Cycle Checkpoints Cell Biology Cell biology 030104 developmental biology medicine.anatomical_structure hESC Apoptosis definitive endoderm Tumor Suppressor Protein p53 030217 neurology & neurosurgery DNA Damage Developmental Biology Definitive endoderm |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2020.08.003 |
| Popis: | Summary The ability of human induced pluripotent stem cells (hiPSCs) to differentiate in vitro to each of the three germ layer lineages has made them an important model of early human development and a tool for tissue engineering. However, the factors that disturb the intricate transcriptional choreography of differentiation remain incompletely understood. Here, we uncover a critical time window during which DNA damage significantly reduces the efficiency and fidelity with which hiPSCs differentiate to definitive endoderm. DNA damage prevents the normal reduction of p53 levels as cells pass through the epithelial-to-mesenchymal transition, diverting the transcriptional program toward mesoderm without induction of an apoptotic response. In contrast, TP53-deficient cells differentiate to endoderm with high efficiency after DNA damage, suggesting that p53 enforces a “differentiation checkpoint” in early endoderm differentiation that alters cell fate in response to DNA damage. Highlights • DNA damage impairs the efficiency and fidelity of human stem cell differentiation • p53 is reduced transiently during the commitment to definitive endoderm • Preventing p53 reduction diverts cells away from endoderm without apoptosis • p53-deficient cells differentiate to endoderm efficiently in the face of DNA damage Eldridge et al. demonstrate a temporal window during which the differentiation of human iPSCs to definitive endoderm is sensitive to low levels of DNA damage, causing diversion of the differentiation program toward a more mesodermal fate. This effect is almost entirely dependent on p53, with both the efficiency and the fidelity of endoderm differentiation being restored in damaged p53-deficient cells. |
| Databáze: | OpenAIRE |
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