Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

Takahiro Nishio; Yukinori Koyama; Xiao Liu; Sara B. Rosenthal; Gen Yamamoto; Hiroaki Fuji; Jacopo Baglieri; Na Li; Laura N. Brenner; Keiko Iwaisako; Kojiro Taura; James S. Hagood; Nicholas F. LaRusso; Tapan K. Bera; Ira Pastan; David A. Brenner; Tatiana Kisseleva

doi:10.1073/pnas.2101270118

Immunotherapy-based targeting of MSLN⁺ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

Takahiro Nishio, Yukinori Koyama, Xiao Liu, Sara B. Rosenthal, Gen Yamamoto, Hiroaki Fuji, Jacopo Baglieri, Na Li, Laura N. Brenner, Keiko Iwaisako, Kojiro Taura, James S. Hagood, Nicholas F. LaRusso, Tapan K. Bera, Ira Pastan, David A. Brenner, Tatiana Kisseleva

Gastroenterology and Hepatology

Research output: Contribution to journal › Article › peer-review

Abstract

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln⁻/⁻ mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1⁻/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN⁺ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

Original language	English (US)
Article number	e2101270118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	29
DOIs	https://doi.org/10.1073/pnas.2101270118
State	Published - Jul 20 2021

Keywords

Activated portal fibroblasts
Cholestatic fibrosis
Mesothelin

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2101270118

Cite this

Nishio, T., Koyama, Y., Liu, X., Rosenthal, S. B., Yamamoto, G., Fuji, H., Baglieri, J., Li, N., Brenner, L. N., Iwaisako, K., Taura, K., Hagood, J. S., LaRusso, N. F., Bera, T. K., Pastan, I., Brenner, D. A., & Kisseleva, T. (2021). Immunotherapy-based targeting of MSLN⁺ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. Proceedings of the National Academy of Sciences of the United States of America, 118(29), [e2101270118]. https://doi.org/10.1073/pnas.2101270118

Immunotherapy-based targeting of MSLN⁺ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. / Nishio, Takahiro; Koyama, Yukinori; Liu, Xiao et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 29, e2101270118, 20.07.2021.

Research output: Contribution to journal › Article › peer-review

Nishio, T, Koyama, Y, Liu, X, Rosenthal, SB, Yamamoto, G, Fuji, H, Baglieri, J, Li, N, Brenner, LN, Iwaisako, K, Taura, K, Hagood, JS, LaRusso, NF, Bera, TK, Pastan, I, Brenner, DA & Kisseleva, T 2021, 'Immunotherapy-based targeting of MSLN⁺ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 29, e2101270118. https://doi.org/10.1073/pnas.2101270118

@article{12a52356383b4582b9f4b464bd707754,

title = "Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis",

abstract = "We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.",

keywords = "Activated portal fibroblasts, Cholestatic fibrosis, Mesothelin",

author = "Takahiro Nishio and Yukinori Koyama and Xiao Liu and Rosenthal, {Sara B.} and Gen Yamamoto and Hiroaki Fuji and Jacopo Baglieri and Na Li and Brenner, {Laura N.} and Keiko Iwaisako and Kojiro Taura and Hagood, {James S.} and LaRusso, {Nicholas F.} and Bera, {Tapan K.} and Ira Pastan and Brenner, {David A.} and Tatiana Kisseleva",

note = "Funding Information: ACKNOWLEDGMENTS. We thank Ms. Karin Diggle for excellent technical assistance and Drs. Simon S. Wong, Thomas Whisenant, Katrin Hochrath, and Mojgan Hosseini (University of California San Diego) for help with experiments. This work was supported by NIH R01DK101737, U01AA022614, and R01DK099205, R01DK111866 (to T.K.), R01DK101737 (to D.A.B.), R01DK09920 (to D.A.B.), P50AA011999 (to T.K. and D.A.B.), and AI043477 (to D.A.B.). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",

year = "2021",

month = jul,

day = "20",

doi = "10.1073/pnas.2101270118",

language = "English (US)",

volume = "118",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "29",

}

TY - JOUR

T1 - Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

AU - Nishio, Takahiro

AU - Koyama, Yukinori

AU - Liu, Xiao

AU - Rosenthal, Sara B.

AU - Yamamoto, Gen

AU - Fuji, Hiroaki

AU - Baglieri, Jacopo

AU - Li, Na

AU - Brenner, Laura N.

AU - Iwaisako, Keiko

AU - Taura, Kojiro

AU - Hagood, James S.

AU - LaRusso, Nicholas F.

AU - Bera, Tapan K.

AU - Pastan, Ira

AU - Brenner, David A.

AU - Kisseleva, Tatiana

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Ms. Karin Diggle for excellent technical assistance and Drs. Simon S. Wong, Thomas Whisenant, Katrin Hochrath, and Mojgan Hosseini (University of California San Diego) for help with experiments. This work was supported by NIH R01DK101737, U01AA022614, and R01DK099205, R01DK111866 (to T.K.), R01DK101737 (to D.A.B.), R01DK09920 (to D.A.B.), P50AA011999 (to T.K. and D.A.B.), and AI043477 (to D.A.B.). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.

PY - 2021/7/20

Y1 - 2021/7/20

N2 - We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

AB - We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

KW - Activated portal fibroblasts

KW - Cholestatic fibrosis

KW - Mesothelin

UR - http://www.scopus.com/inward/record.url?scp=85110046803&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85110046803&partnerID=8YFLogxK

U2 - 10.1073/pnas.2101270118

DO - 10.1073/pnas.2101270118

M3 - Article

C2 - 34253615

AN - SCOPUS:85110046803

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 29

M1 - e2101270118

ER -