Microenvironmental regulation of the sinusoidal endothelial cell phenotype in vitro

Abstract

Liver sinusoidal endothelial cells (LSECs) differ, both structurally and functionally, from endothelial cells (ECs) lining blood vessels of other tissues. For example, in contrast to other ECs, LSECs possess fenestrations, have low detectable levels of platelet endothelial cell adhesion molecule 1 expression, and in rat tissue, they distinctively express a cell surface marker recognized by the SE-1 antibody. These unique phenotypic characteristics seen in hepatic tissue are lost over time upon culture in vitro; therefore, this study sought to systematically examine the effects of microenvironmental stimuli-namely, extracellular matrix and neighboring cells, on the LSEC phenotype in vitro. In probing the role of the underlying extracellular matrix, we identified collagen I and collagen III as well as mixtures of collagen I/collagen IV/fibronectin as having a positive effect on LSEC survival. Furthermore, using a stable hepatocellular model (hepatocyte-fibroblast) we were able to prolong the expression of both SE-1 and phenotypic functions of LSEC such as factor VIII activity and AcLOL uptake in cocultured LSECs through the production of short-range paracrine signals. In the course of these experiments, we identified the antigen recognized by SE-1 as CD32b. Conclusion: Collectively, this study has identified several microenvironmental regulators of liver sinusoidal endothelial cells that prolong their phenotypic functions for up to 2 weeks in culture, enabling the development of better in vitro models of liver physiology and disease. (HEPATOLOGY 2009;50:920-928.)

Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation

“…The liver is a prominent source of cytokines (11), and, as such, the hepatic extracellular matrix is a repository of cytokines, chemokines, and growth factors that can be released when required to be used by proximal cells, contributing to cellular programming (27,28). In transplant, a unique situation occurs in which the cytokine profile of the donor allograft combines with that of the recipient, as cytokines produced in the donor allograft are likely to be flushed into the patient's circulating blood during reperfusion.…”

Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

“…To fulfill their clearance functions, LSECs express 3 major types of scavenger receptors: (a) the macrophage mannose receptor binding denatured collagen (3) and collagen peptides preventing gelatin formation in the circulation, tissue plasminogen activator regulating fibrinolytic activity, and lysosomal enzymes that are recruited for further use in LSEC (4); (b) the Fcγ receptors FcγRII in the human system (5) and FcγRIIB2 in the rat (6,7); and (c) the major LSEC hyaluronan (HA) scavenger receptor. Upon identification and cloning of the stabilin family of fasciclin-like HA receptor homologs by our group (8), the identity of the LSEC HA scavenger receptor was established as stabilin-2 on the basis of HA affinity purification and sequencing (9).…”

Designing a Multicellular Organotypic 3D Liver Model with a Detachable, Nanoscale Polymeric Space of Disse

“…1,11 There is a growing recognition that hepatic cell cultures should mimic the in vivo structure of the liver. 12,13 In the liver, hepatic parenchymal cells are separated from NPCs by an interfacial region known as the Space of Disse. 1 This proteinenriched interface exhibits a thickness in the 0.5-1 mm range and plays a critical role in the transfer of signaling molecules and nutrients between hepatic cells.…”