Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury

Abstract

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 incompletely understood. Telomerase is expressed in many stem cell populations, and telomerase pathway gene mutations are 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 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 injury responses, the repopulating activity of TERTHigh hepatocytes is accelerated and their progeny cross zonal boundaries. RNA-seq reveals that metabolic genes are down regulated 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.

Bioprinting of Multiscaled Hepatic Lobules within a Highly Vascularized Construct

“…[ 52 ] Lin et al have shown that a subset of hepatocytes expressed high levels of telomerase and are expressed in many stem cell populations, which aids in the repopulation of liver cells during hemostasis and injury. [ 53 ] Huch et al have reported that LGR5+ adult bile duct‐derived biopotent progenitor cells from human liver can be converted into functional hepatocytes in vitro and upon transplantation in vivo. [ 52 ] Further, liver organoid technology is strongly dependent upon endogenous cell organization, self‐assembly or self‐organization, with xenogeneic components, such as Matrigel.…”

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

“…We used qRT–PCR to examine the levels of mRNAs encoding proteins involved in liver proliferation and found an increase in mRNAs encoding β‐catenin ( Ctnnb1 ) and GSK3β ( Gsk3b ) (Fig E). Unlike most cells in adult organs, a sub‐population of liver cells expresses Tert , which encodes the catalytic subunit of telomerase, and these cells are responsible for liver maintenance and renewal (Lin et al , ). We found that Tert abundance was significantly increased in the 30‐week‐old Mrps12 ep / ep liver (Fig E), providing an explanation for the increased cellular proliferation we observed in these mice.…”

Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture

“…They divide under the influence of WNT/RSPO3 signals secreted by CV endothelial cells (Wang et al, 2015). Separately, rare Telomerase-expressing hepatocytes scattered throughout the liver lobule also proliferate and generate small clones after long-term lineage tracing (Lin et al, 2018). However, taken as a whole, hepatocytes generally renew themselves slowly by comparison to fast-cycling tissues such as the small intestines, which renews itself every 3-5 days (Clevers et al., 2014).…”