Aging impairs hepatic stellate cell functions

Hepatic stellate cells are liver-resident mesenchymal stem cells residing in a quiescent state on a basement membrane-like structure in the space of Disse, which represents their perivascular niche. One component of this niche is the laminin-α5 (LAMA5) chain, which constitutes heterotrimeric laminin-521 (LN-521) together with the LAMB2 and LAMC1 chains. LN-521 sustains quiescence and hepatocyte growth factor (HGF) expression in stellate cells. During aging, hepatic stellate cells acquire a senescence-associated secretory phenotype characterized by increased expression of inflammatory factors and reduced expression of growth factors such as HGF. Mechanical forces are reduced in sinusoids of the aged liver by declined hepatic blood flow of about 50 % as reported earlier. Exposure of isolated stellate cells to fluid shear stress triggers HGF release in an integrin-α5/β1 (ITGA5/ITGB1) dependent manner and increases Itga5, Lamb2, and Lamc1 expression. These laminin chains, ITGA5, ITGB1, and HGF decrease in the aged rat liver. Interestingly, CRISPR/Cas9-mediated knockout of ITGA5 and ITGB1 significantly lowered HGF release by stellate cells. Thus, ITGA5/ITGB1 heterodimer is important for the sensing of mechanical stimuli by stellate cells, a process that is disturbed by aging. In conclusion, the reduction of extracellular matrix proteins such as LN-521 in the whole liver and lowered expression of ITGA5 and HGF in stellate cells is most likely induced by the regression of mechanical forces in the aged liver. Impaired integrin-mediated anchorage and quiescence of stellate cells indicate disturbed integrity of their niche in the space of Disse during aging, which results in alleviation of stellate cell functions such as HGF synthesis and release. Age-related alterations in stellate cells offer explanations for the declined regenerative potential of the aged liver since stellate cells are important sources of trophic factors involved in liver maintenance and repair.

Publikationsverlauf

Artikel online veröffentlicht:
04. Januar 2021