Activation of Hepatic Stellate Cells Requires Dissociation of E-Cadherin–Containing Adherens Junctions with Hepatocytes

Hayato Urushima, Hideto Yuasa, Tsutomu Matsubara, Noriyuki Kuroda, Yaiko Hara, Kouji Inoue, Kenjiro Wake, Tetsuji Sato, Scott L. Friedman, Kazuo Ikeda

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Hepatic stellate cells (HSCs) are resident mesenchymal cells in the space of Disse interposed between liver sinusoidal endothelial cells and hepatocytes. Thorn-like microprojections, or spines, project out from the cell surface of HSCs, crossing the space of Disse, to establish adherens junctions with neighboring hepatocytes. Although HSC activation is initiated largely from stimulation by adjacent cells, isolated HSCs also activate spontaneously in primary culture on plastic. Therefore, other unknown HSC-initiating factors apart from paracrine stimuli may promote activation. The dissociation of adherens junctions between HSCs and hepatocytes as an activating signal for HSCs was explored, establishing epithelial cadherin (E-cadherin) as an adhesion molecule linking hepatocytes and HSCs. In vivo, following carbon tetrachloride–induced liver injury, HSCs lost their spines and dissociated from adherens junctions in the early stages of injury, and were subsequently activated along with an increase in YAP/TAZ expression. After abrogation of liver injury, HSCs reconstructed their spines and adherens junctions. In vitro, reconstitution of E-cadherin–containing adherens junctions by forced E-cadherin expression quiesced HSCs and suppressed TAZ expression. Additionally, increase of TAZ expression leading to the activation of HSCs by autocrine stimulation of transforming growth factor-β, was revealed as a mechanism of spontaneous activation. Thus, we have uncovered a critical event required for HSC activation through enhanced TAZ-mediated mechanotransduction after the loss of adherens junctions between HSCs and hepatocytes.

Original languageEnglish
Pages (from-to)438-453
Number of pages16
JournalAmerican Journal of Pathology
Issue number3
StatePublished - Mar 2021


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