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Cited by 185Cellular Mechanics and InteractionsLiver physiology and pathologyTissue Engineering and Regenerative Medicine

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha

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Desai, Seema S., Tung, Jason C., Zhou, Vivian X., Grenert, James P., Malato, Yann, Rezvani, Milad, Español‐Suñer, Regina, Willenbring, Holger +2 more·2016·Hepatology
DOI 10.1002/hep.28450PMC PMC5224931
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Abstract

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver‐specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1‐6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte‐specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho‐associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion: Fibrotic levels of matrix stiffness significantly inhibit hepatocyte‐specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho‐associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (H epatology 2016;64:261–275)

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  • Hepatocytes respond to increase of stiffness by enhancing actin contractility, downregulating HNF4A protein and activating ERK, PI3K and YAP signalling.

    “Hepatocytes respond to increase of stiffness by enhancing actin contractility, downregulating HNF4A protein and activating extracellular signal‐regulated kinase (ERK), PI3K and YAP signalling [5, 22, 23].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [5]

    The Results sections on cytoskeletal tension and the HNF4α network report greater tension with increasing matrix stiffness and reduced HNF4α expression on stiff matrix, including at the protein level. The paper demonstrates FAK activation and discusses ERK as part of a mechanotransduction circuit, but does not show stiffness-induced ERK, PI3K, or YAP activation in hepatocytes (page numbers unavailable in our copy). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Crosslinking and deposition of extracellular matrix spread from the periphery toward the centre of the hepatic lobule, with a significant increase in rigidity at the borders, generating a heterogeneous response to stiffness in hepatic cells.

    “In addition, crosslinking and deposition of ECM spread from the periphery toward the centre of the hepatic lobule with a significant increase in rigidity at the borders, generating a heterogeneous response to stiffness in the hepatic cells [5].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [5]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Collagen deposits were detected in one- and two-month CCl4 models showing characteristic peripheral accumulation at the hepatic lobules.

    “Collagen deposits were detected in one‐ and two‐month models showing a characteristic peripheral accumulation at the hepatic lobules, as reported previously [5] (Fig. 1A and Fig. S1A).”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [5]

    The Results section on liver matrix stiffness (page unavailable) reports increased fibrillar collagen deposition in CCl4-treated mice. It describes central–central fibrosis in the mild CCl4 protocol and central–portal and portal–portal fibrosis in the severe protocol, but does not establish characteristic peripheral accumulation at hepatic lobules or identify the models as one and two months long. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • This may imply a significant role of the hepatocytes in the response to mechanical modifications during liver fibrosis through MRTcoF.

    “This may imply a significant role of the hepatocytes in the response to mechanical modifications during liver fibrosis through MRTcoF, as suggested previously [5, 6].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [5]

    The Results section on fibrotic matrix rigidity (page unavailable) reports activation of mechanotransduction in hepatocytes near fibrotic tracts, supporting a role for hepatocytes in responding to mechanical changes during fibrosis. The paper identifies integrin–FAK and Rho/ROCK signaling, but does not establish a response through MRTcoF. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Rho/ROCK signalling is an important mechanical response in PH.

    “It is known that Rho/ROCK signalling is an important mechanical response in PH [5, 22].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [5]

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Cited by

Sorted by citations

Authors
Desai, S. S., Tung, J. C., Zhou, V. X., Grenert, J. P., Malato, Y., Rezvani, M., Español‐Suñer, R., Willenbring, H., Weaver, V. M., & Chang, T. T.
Affiliations
University of California, San Francisco (US)
Corresponding author
Chang, Tammy T.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-03-09
Volume
64
Issue
1
Pages
261-275
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.28450
PMC
PMC5224931
OpenAlex
W2241161952
Cited by
185
References
4
Citations by year
2026: 10 · 2025: 14 · 2024: 22 · 2023: 23 · 2022: 25 · 2021: 14 · 2020: 33 · 2019: 21 · 2018: 8 · 2017: 9 · 2016: 6
FWCI
10.10
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (CIRM TR3-05542, NHLBI T32 HL007544)
  • National Heart, Lung, and Blood Institute (T32HL007544)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K08DK093708, P30DK026743)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
extracellular matrix stiffness, liver fibrosis, hepatocyte function, HNF4α, mechanotransduction, focal adhesion kinase, Rho/ROCK signaling, cytoskeletal tension, liver cirrhosis, hepatocyte dysfunction, gene expression regulation
MeSH terms
Animals, Cells, Cultured, Cytoskeleton, Extracellular Matrix, Liver Cirrhosis, Mice, Inbred C57BL, Gene Expression, Microscopy, Atomic Force, Hepatocytes, Mechanotransduction, Cellular, Hepatocyte Nuclear Factor 4, rho-Associated Kinases

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