Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis

Abstract

Telomere shortening limits the number of cell divisions of primary human cells and might affect the regenerative capacity of organ systems during aging and chronic disease. To test whether the telomere hypothesis applies to human cirrhosis, the telomere length was monitored in cirrhosis induced by a broad variety of different etiologies. Telomeres were significantly shorter in cirrhosis compared with noncirrhotic samples independent of the primary etiology and independent of the age of the patients. Quantitative fluorescence in situ hybridization showed that telomere shortening was restricted to hepatocytes whereas lymphocytes and stellate cells in areas of fibrosis had significantly longer telomere reserves. Hepatocyte-specific telomere shortening correlated with senescence-associated beta-galactosidase staining in 84% of the cirrhosis samples, specifically in hepatocytes, but not in stellate cells or lymphocytes. Hepatocyte telomere shortening and senescence correlated with progression of fibrosis in cirrhosis samples. This study demonstrates for the first time that cell type-specific telomere shortening and senescence are linked to progression of human cirrhosis. These findings give a novel explanation for the pathophysiology of cirrhosis, indicating that fibrotic scarring at the cirrhosis stage is a consequence of hepatocyte telomere shortening and senescence. The data imply that future therapies aiming to restore regenerative capacity during aging and chronic diseases will have to ensure efficient targeting of specific cell types within the affected organs.

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

“…[39][40][41] These findings indicate that hTERT activity in human hepatocytes is not sufficient to completely maintain telomeres at a stable length in chronically damaged liver. These data stand in line with the observation that human hematopoietic stem cells express low levels of telomerase but yet experience age-dependent telomere shortening.…”

Aging by epigenetics—A consequence of chromatin damage?

“…Because of senescence, most primary human cells have a finite proliferative lifespan, and evidence has been presented that senescence contributes to tissue aging in vivo, in part by limiting the self-renewal of tissues [61][62][63]. Specifically, senescent cells and/or molecular markers of the senescent phenotype have been reported to increase in some aging tissues [40,41,[64][65][66][67][68][69], and are linked to some age-associated tissue pathologies, such as osteoarthritis, atherosclerosis and liver cirrhosis [70][71][72]. Moreover, manipulation of the cell signals that initiate senescence, such as telomere length and expression of the proliferation inhibitor p16INK4a [66][67][68]70,[73][74][75][76][77][78][79][80], can modulate some aspects of organismal aging [70][71][72].…”

“…Specifically, senescent cells and/or molecular markers of the senescent phenotype have been reported to increase in some aging tissues [40,41,[64][65][66][67][68][69], and are linked to some age-associated tissue pathologies, such as osteoarthritis, atherosclerosis and liver cirrhosis [70][71][72]. Moreover, manipulation of the cell signals that initiate senescence, such as telomere length and expression of the proliferation inhibitor p16INK4a [66][67][68]70,[73][74][75][76][77][78][79][80], can modulate some aspects of organismal aging [70][71][72]. In addition to a likely role in tissue aging, cellular senescence is also a well-established tumor suppression process, by virtue of its ability to arrest proliferation and neoplastic progression of cells harboring oncogenic lesions [81][82][83][84][85][86][87].…”

Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state?

“…Given that telomere shortening and/or impaired telomerase activity have been linked to the development of progressive fibrosis in chronic liver injury [9][10][11][12], it is likely that enhanced telomerase activity serves a protective function. One means by which telomerase may confer protection during chronic liver injury is through the prevention of telomere shortening with its resultant replicative arrest and senescence.…”

“…This concept is supported by studies demonstrating that the telomeres of chronically diseased human livers are shorter than those of age-matched controls [9][10][11] Although relatively little work has been done examining the effects of liver injury on telomeres in experimental animals, the available data are intriguing. For example, mice with a targeted deletion of one of the components of telomerase demonstrate impaired hepatic regeneration and accelerated fibrogenesis in the context of liver injury [12].…”