CD95 Ligand Is a Proliferative and Antiapoptotic Signal in Quiescent Hepatic Stellate Cells

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

“…In quiescent HSC, CD95L also induces EGFR tyrosine phosphorylation and the activation of the receptor tyrosine kinase activity, but in contrast to hepatocytes, CD95L induces an EGF-dependent EGFR activation (94) . This is due to a c-Src-dependent activation of EGF shedding by matrix metalloproteinase 9 (MMP9), leading to ligand-dependent EGFR activation (94) . CD95L-induced EGFR activation then couples to an Erk-mediated HSC proliferation, as indicated by an increase in bromodeoxyuridine (BrdU) incorporation and in cell number.…”

“…In rat hepatocytes, hyperosmotic cell shrinkage triggers ligand-independent and Src family kinase Yes-dependent CD95 activation and subsequent CD95 trafficking to the plasma membrane, thereby sensitizing hepatocytes toward CD95 ligand (CD95L)-induced apoptosis or even executing apoptosis when the hyperosmotic challenge is strong enough (10,73,86) . In contrast, in HSCs, proapoptotic stimuli such as CD95L lead to a c-Src-mediated EGFR activation and subsequent cell proliferation (94) .…”

“…Quiescent HSCs, i.e., cells that have been in culture for 24 -48 h only and do not express detectable amounts of α -smooth muscle actin, represent a hepatic stem/progenitor cell compartment in their niche (92,93) and are fairly resistant toward apoptotic cell death (94,95) . In quiescent HSC, CD95L also induces EGFR tyrosine phosphorylation and the activation of the receptor tyrosine kinase activity, but in contrast to hepatocytes, CD95L induces an EGF-dependent EGFR activation (94) .…”

“…CD95L-induced EGFR activation then couples to an Erk-mediated HSC proliferation, as indicated by an increase in bromodeoxyuridine (BrdU) incorporation and in cell number. In addition to CD95L-induced EGFR activation and stimulation of cell proliferation, CD95L also triggers apoptosis resistance through CD95 tyrosine nitration in quiescent HSC (94) . This may be important in a hostile cytokine milieu during liver injury, which allows quiescent HSC to fulfill their role as resident liver stem cells (92,93) .…”

The niche of stellate cells within rat liver #

“…10,11 Similar to hematopoietic stem cells, quiescent HSCs are resistant against CD95-mediated apoptosis and proliferate in response to CD95 ligand. [12][13][14][15] Thus, there is growing evidence that stellate cells are stem/progenitor cells of the vertebrate liver.…”