Role of Differentiation of Liver Sinusoidal Endothelial Cells in Progression and Regression of Hepatic Fibrosis in Rats

Abstract

BACKGROUND & AIMS Capillarization, characterized by loss of differentiation of liver sinusoidal endothelial cell (LSEC), precedes the onset of hepatic fibrosis. We investigated whether restoring differentiation to LSEC in liver affects their interactions with hepatic stellate cells (HSCs) and thereby promotes quiescence of HSCs and regression of fibrosis. METHODS Rat LSECs were cultured with inhibitors and/or agonists and examined by scanning electron microscopy for fenestrae in sieve plates. Cirrhosis was induced in rats using thioacetamide, followed by administration of BAY 60-2770, an activator of soluble guanylate cyclase (sGC). Fibrosis was assessed by Sirius red staining; expression of α-smooth muscle actin was measured by immunoblot analysis. RESULTS Maintenance of LSEC differentiation requires vascular endothelial growth factor-A stimulation of nitric oxide (NO)-dependent signaling (via sGC and cGMP) and NO-independent signaling. In rats with thioacetamide-induced cirrhosis, BAY 60-2770 accelerated the complete reversal of capillarization (restored differentiation of LSEC) without directly affecting activation of HSC or fibrosis. Restoration of differentiation to LSEC led to quiescence of HSC and regression of fibrosis, in the absence of further exposure to BAY 60-2770. Activation of sGC with BAY 60-2770, prevented progression of cirrhosis, despite continued administration of thioacetamide. CONCLUSIONS Differentiation of LSEC has an important role in activation of HSC and the fibrotic process in rats.

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

“…S9A). After CCl 4 injury, WT mice demonstrated prominent aggregates of macrophages, which were not seen in the stabilin-1 −/− animals ( Fig. 2 A-C).…”

“…S4 A and B). In response to liver injury from either CCl 4 or MCD diet, we detected a subset of stabilin-1 + F4/80 + intrahepatic macrophages Analysis of chronic human liver disease demonstrated that CD31 + sinusoidal endothelial cells expressed stabilin-1, whereas CD68 + Kupffer cells within the sinusoids did not (SI Appendix, Fig. S4 E and F).…”

“…To further confirm the role of macrophage stabilin-1 in fibrosis resolution, we undertook experiments similar in design to those described by Ramachandran et al (25). This consisted of a 4-wk model of CCl 4 liver injury performed in MACRO stab-1 −/− and WT mice followed by adoptive transfer of WT myeloid cell elements or vehicle control at 24 and 72 h after the final injection of CCl 4 followed by an analysis of fibrogenesis at 120 h. Transcription of fibrogenic markers and collagen III expression in liver tissue showed no differences between WT mice receiving myeloid cells or vehicle without cells (SI Appendix, Fig. S12 A, D, and F), whereas in the MACRO stab-1 −/− , there was a trend of reduced transcription in nearly all fibrogenic markers in mice receiving WT myeloid cells (SI Appendix, Fig.…”

“…In addition to HSCs, other nonparenchymal cells contribute to the regulation of liver fibrosis. Hepatic sinusoidal endothelial cells (HSECs), which lie in close proximity to HSCs, play an important role in maintaining HSC quiescence (4), and macrophages play a critical role in fibrosis progression, tissue remodelling, and resolution (5).…”

Differential Roles of Angiogenesis in the Induction of Fibrogenesis and the Resolution of Fibrosis in Liver

“…LSEC with normal fenestration and function prevents HSC activation and promotes reversion to the quiescent state of HSC, but capillarized LSEC with defenestration and malfunction does not. 47) LSEC fenestration is maintained by VEGF secreted by hepatocytes or HSCs and VEGF downstream signaling produces nitric oxide (NO), which acts through the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G pathway. [48][49][50] Restoration of LSEC through reversal of capillarization by pharmacological therapy to activate the VEGF-NO-related signaling pathway accelerates HSC quiescence and regression of fibrosis.…”