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Telomerase-expressing distributed hepatocyte stem cells repopulate the liver during homeostasis and injury

ABSTRACT: Telomerase-expressing distributed hepatocyte stem cells repopulate the liver during homeostasis and injury

PROVIDER: PRJNA412544 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6116743_1.fastq.gz	Fastqsanger.gz
	SRR6116743_2.fastq.gz	Fastqsanger.gz
	SRR6116744_1.fastq.gz	Fastqsanger.gz
	SRR6116744_2.fastq.gz	Fastqsanger.gz
	SRR6116745_1.fastq.gz	Fastqsanger.gz

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Telomerase-expressing distributed hepatocyte stem cells repopulate the liver during homeostasis and injury

Project description:We identified a subset of hepatocytes with high Telomerase Reverse transcriptase (Tert) that functions as the repopulating stem cells in homeostasis and injury. We performed RNA-Seq to reveal the differences of these cells and the other hepatocytes.

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Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury.

Project description:Hepatocytes are replenished gradually during homeostasis and robustly after liver injury1, 2. In adults, new hepatocytes originate from the existing hepatocyte pool3-8, but the cellular source of renewing hepatocytes remains unclear. Telomerase is expressed in many stem cell populations, and mutations in telomerase pathway genes have been linked to liver diseases9-11. Here we identify a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury. Using lineage tracing from the telomerase reverse transcriptase (Tert) locus in mice, we demonstrate that rare hepatocytes with high telomerase expression (TERTHigh hepatocytes) are distributed throughout the liver lobule. During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver. In response to injury, the repopulating activity of TERTHigh hepatocytes is accelerated and their progeny cross zonal boundaries. RNA sequencing shows that metabolic genes are downregulated in TERTHigh hepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage. Genetic ablation of TERTHigh hepatocytes combined with chemical injury causes a marked increase in stellate cell activation and fibrosis. These results provide support for a 'distributed model' of hepatocyte renewal in which a subset of hepatocytes dispersed throughout the lobule clonally expands to maintain liver mass.

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Project description:Telomere homeostasis, crucial for various biological processes, relies on telomerase activity. We identified ZC3H15 as a novel telomerase-interacting protein. Its deletion unexpectedly increased telomerase activity but led to shortened telomeres and cellular senescence. ZC3H15 interacts with telomerase and itself, regulating telomerase activity in an RNA-dependent manner. Proximity labeling showed ZC3H15's interaction with proteins involved in organelle assembly and RNA processes. Loss of ZC3H15 sequestered TERC in the Cajal body, reducing telomerase recruitment to telomeres during S phase. These findings unveil ZC3H15's role in telomere dynamics and cellular senescence, suggesting its potential as a target for cancer therapy or anti-aging interventions.

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Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges [RNA-seq]

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