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Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis

Nature Materials volume 16, pages 1252–1261 (2017)Cite this article

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Abstract

The role of pathological angiogenesis on liver fibrogenesis is still unknown. Here, we developed fibrotic microniches (FμNs) that recapitulate the interaction of liver sinusoid endothelial cells (LSECs) and hepatic stellate cells (HSCs). We investigated how the mechanical properties of their substrates affect the formation of capillary-like structures and how they relate to the progression of angiogenesis during liver fibrosis. Differences in cell response in the FμNs were synonymous of the early and late stages of liver fibrosis. The stiffness of the early-stage FμNs was significantly elevated due to condensation of collagen fibrils induced by angiogenesis, and led to activation of HSCs by LSECs. We utilized these FμNs to understand the response to anti-angiogenic drugs, and it was evident that these drugs were effective only for early-stage liver fibrosis in vitro and in an in vivo mouse model of liver fibrosis. Late-stage liver fibrosis was not reversed following treatment with anti-angiogenic drugs but rather with inhibitors of collagen condensation. Our work reveals stage-specific angiogenesis-induced liver fibrogenesis via a previously unrevealed mechanotransduction mechanism which may offer precise intervention strategies targeting stage-specific disease progression.

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Figure 1: Establishment of the mechanotransduction-modulated fibrotic microniches (FμNs).
Figure 2: Characterization of the biomimetic FμNs.
Figure 3: Condensed collagen fibres as mechanical transducer to activate HSCs both in vitro and in vivo.
Figure 4: Collagen fibres function as mechanical transducer to activate HSCs through the DDR2-JAK2/PI3K/AKT-MYOCD pathway.
Figure 5: Anti-angiogenesis treatment in early-stage liver fibrosis.
Figure 6: Treatment of late-stage liver fibrosis by targeting vasculature and condensed collagen fibres.

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Acknowledgements

We would like to acknowledge the sequencing core facility, NIKON Biological Imaging Center, Animal Core Facility and Center of Biomedical Analysis at Tsinghua University for technical assistance. This work is financially supported by the National Natural Science Foundation of China (81522022) and National Key R&D Program of China (2017YFA0104901).

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Author notes

  1. Longwei Liu and Zhifeng You: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China

    Longwei Liu, Zhifeng You, Hongsheng Yu, Lyu Zhou, Hui Zhao, Xiaojun Yan, Bingjie Wang, Lu Zhu & Yanan Du

  2. School of Life Sciences, Tsinghua University, Beijing 100084, China

    Longwei Liu, Lyu Zhou, Hui Zhao & Bingjie Wang

  3. Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China

    Dulei Li, Tie Xia & Yan Shi

  4. Sequencing core facility, Tsinghua University, Beijing 100084, China

    Yuzhou Xu

  5. Department of Dermatology, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China

    Chenyu Huang

  6. Tianjin Second People’s Hospital and Tianjin Institute of Hepatology, Tianjin 300192, China

    Wei Hou

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Contributions

L.L., Z.Y. and Y.D. conceived and designed the experiments; L.L. conducted the in vitro FμN experiments with help from H.Z., L.Zhu and B.W.; H.Y., B.W. and L.Zhou helped to establish the hydrogel system and performed the AFM experiments, while Y.S. and T.X. provided technical support; D.L. helped in flow analysis; Z.Y. and L.L. designed and performed the mouse experiments and data processing; Bioinformatics analysis was performed by L.L. and Y.X.; W.H. and C.H. provided clinical consultation; L.L., Z.Y. and Y.D. wrote the manuscript, which W.H., C.H., H.Y., X.Y. helped to revise; Y.D. is the principal investigator of the supporting grants.

Corresponding author

Correspondence to Yanan Du.

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Liu, L., You, Z., Yu, H. et al. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nature Mater 16, 1252–1261 (2017). https://doi.org/10.1038/nmat5024

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