Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression

Abstract

Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this ‘proof of concept’ study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.

NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

“…Accordingly, we found hyper-expression of p16 Ink4a in liver sections of this patient compared to a control liver samples (Fig. 4A), findings that were consistent with the previously reported association of senescence with liver steatosis and cirrhosis (17)(18)(19)(20).…”

“…Accordingly, we found hyper-expression of p16 Ink4a in liver sections of this patient compared to a control liver samples (Fig. 4A), findings that were consistent with the previously reported association of senescence with liver steatosis and cirrhosis (17)(18)(19)(20). We also evaluated the abundance of senescent-associated proteins in a patient with a biallelic DPP9 rare variants with hypomorphic or lacking alleles that failed to repress NLRP1.…”

Telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma in 63,272 individuals from the general population

“…[30] It has been hypothesized that short telomeres impair the liver's regenerative capacity, prompting fibrosis formation, [30] potentially through HSC activation by senescent hepatocytes. [34] To the best of our knowledge, an association between telomere length and incident HCC in the general population has not been reported before. We found that the risk of HCC was elevated in those with telomere length both above and below the median, but only significantly in the latter.…”

“…In humans, Rattan et al 29 found that shorter telomeres were associated with fibrosis in the elderly, while Calado et al 33 reported that liver disease frequently occurs in families with mutations in genes encoding the telomerase enzyme, and that telomerase enzyme mutations were more prevalent in sporadic cirrhosis cases than in healthy controls 30 . It has been hypothesized that short telomeres impair the liver’s regenerative capacity, prompting fibrosis formation, 30 potentially through HSC activation by senescent hepatocytes 34 …”

Increased cell senescence in human metabolic disorders

“…However, in response to chronic tissue damage, continuous rounds of hepatocyte death and HSC proliferation allow the production of senescent cells to outpace their clearance, contributing to persistent inflammation and advancing fibrosis ( 73 , 83 ). Furthermore, the accumulation of senescent hepatocytes and their SASP factors leads to an increase in the number of activated HSCs and, as a result, fibrosis progression with cirrhosis and HCC risk ( 84 , 85 ). Indeed, even though HSCs may have a dual function in either protecting or promoting HCC ( 86 ), it has been demonstrated that nontumoral HSCs in NASH-related HCC expressed higher levels of senescence and SASP markers than nontumoral HSCs in other types of HCCs.…”