Telomere Dysfunction Activates p53 and Represses HNF4α Expression Leading to Impaired Human Hepatocyte Development and Function.

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Michael MunroeLuis Francisco Zirnberger Batista

Abstract

Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo. Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mut...Continue Reading

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Citations

Jul 8, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Mark Antkowiak, Richard M Green
Apr 15, 2021·The Journal of Cell Biology·Alexandre T VessoniLuis F Z Batista
May 16, 2021·Seminars in Liver Disease·Nils HaepAlejandro Soto-Gutierrez

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Methods Mentioned

BETA
ELISA
Flow Cytometry
PCR
flow
light microscopy

Software Mentioned

Li
Image Studio
COR

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