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.
