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Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing

Cell Research volume 33, pages 516–532 (2023)Cite this article

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Abstract

Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.

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Fig. 1: THBD is upregulated in senescent cells and aged tissues.
Fig. 2: THBD signaling is critical for senescent cell survival.
Fig. 3: THBD signaling axis is upregulated in senescent cells and aged tissues.
Fig. 4: THBD signaling persists in recycling endocytic vesicles.
Fig. 5: THBD stabilizes the THBD signaling complex in endocytic vesicles by suppressing proteasome- and lysosome-associated degradation processes.
Fig. 6: THBD suppresses NEDD4L-mediated THBD signaling complex degradation.
Fig. 7: THBD signaling antagonism attenuates liver fibrosis through senescent cell clearance.

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Data availability

The RNA transcriptional profiling data involved in this study has been uploaded to NCBI GEO datasets (GSE228941).

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Acknowledgements

We thank Dr. Tso-Pan Yao and Dr. Nina Tsvetanova for their valuable insight and discussion on endosomal dynamics and signaling. We also thank Drs. Rui Chen, Handan Xiang, Yi Ding, and Omar Lopez for their extensive discussion and valuable input on the senescent field.

Funding

This work was supported by grants from National Institutes of Health (R01CA244564 to X.F.W., R01DK077794 to A.M.D.), Duke Eye Center EM Facility Core (P30EY005722 to V.Y.A.), NIH Pathway to Independence Award (K99EY033763 to T.R.L.), Florence McAlister Professorship of Medicine (A.M.D.).

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Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA

    Christopher C. Pan, Kun Xiang, Lianmei Tan, Yaosi Liang, Tao Yin, Calvin Wang, De Huang, Ergang Wang, Mengyang Chong, Peter B. Alexander, Vadim Y. Arshavsky & Xiao-Fan Wang

  2. Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA

    Raquel Maeso-Díaz, Kuo Du, Seh Hoon Oh & Anna Mae Diehl

  3. Division of Ophthalmology, Department of Medicine, Duke University, Durham, NC, USA

    Tylor R. Lewis & Vadim Y. Arshavsky

  4. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA

    Liuyang Wang

  5. Department of Physiology, Morehouse School of Medicine, Atlanta, GA, USA

    Fengrui Yang & Xuebiao Yao

  6. Department of Immunology, Duke University, Durham, NC, USA

    Bryan Jian Wei Lim & Qi-Jing Li

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Contributions

C.C.P., P.B.A., and X.F.W. conceived the study. C.C.P., R.M.D., T.R.L., L.T., Y.L., L.W., F.Y., T.Y., C.W., K.D., D.H., S.H.O., X.Y., V.Y.A., Q.J.L., and X.F.W. contributed to the methodology. C.C.P., R.M.D., T.R.L., K.X., L.T., Y.L., L.W., F.Y., T.Y., C.W., K.D., D.H., S.H.O., E.W., B.L., and M.C. performed the experiments and analyzed the data. X.F.W. and A.M.D. acquired the funding. X.F.W. supervised the study. C.C.P., P.B.A., and X.F.W. drafted the manuscript. C.C.P., R.M.D., K.D., T.R.L., P.B.A., and X.F.W. reviewed and edited the manuscript.

Corresponding author

Correspondence to Xiao-Fan Wang.

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The authors declare no competing interests.

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Pan, C.C., Maeso-Díaz, R., Lewis, T.R. et al. Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing. Cell Res 33, 516–532 (2023). https://doi.org/10.1038/s41422-023-00820-4

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  • DOI: https://doi.org/10.1038/s41422-023-00820-4

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