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Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy
Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978300/ https://www.ncbi.nlm.nih.gov/pubmed/33754025 http://dx.doi.org/10.7150/thno.52102 |
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author | Zhang, Bo Meng, Fanzheng Liu, Yao Yuan, Yubin Wang, Jizhou Wu, Dehai Cui, Yifeng Zhang, Shugeng Guo, Hongrui Liang, Shuhang Wang, Wei Klos, Matthew Morgenstern, Sherry Liu, Yufeng Sun, Linmao Ma, Kun Liu, Xirui Wang, Yan Han, Jihua Yang, Guangchao Zheng, Chenyang Li, Xianying Zhou, Shuo Ji, Changyong Bai, Qingquan Wang, Jiabei Liu, Lianxin |
author_facet | Zhang, Bo Meng, Fanzheng Liu, Yao Yuan, Yubin Wang, Jizhou Wu, Dehai Cui, Yifeng Zhang, Shugeng Guo, Hongrui Liang, Shuhang Wang, Wei Klos, Matthew Morgenstern, Sherry Liu, Yufeng Sun, Linmao Ma, Kun Liu, Xirui Wang, Yan Han, Jihua Yang, Guangchao Zheng, Chenyang Li, Xianying Zhou, Shuo Ji, Changyong Bai, Qingquan Wang, Jiabei Liu, Lianxin |
author_sort | Zhang, Bo |
collection | PubMed |
description | Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFβ1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFβ1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFβ1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFβ1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFβ1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFβ1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFβ1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFβ1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFβ1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis. |
format | Online Article Text |
id | pubmed-7978300 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-79783002021-03-21 Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy Zhang, Bo Meng, Fanzheng Liu, Yao Yuan, Yubin Wang, Jizhou Wu, Dehai Cui, Yifeng Zhang, Shugeng Guo, Hongrui Liang, Shuhang Wang, Wei Klos, Matthew Morgenstern, Sherry Liu, Yufeng Sun, Linmao Ma, Kun Liu, Xirui Wang, Yan Han, Jihua Yang, Guangchao Zheng, Chenyang Li, Xianying Zhou, Shuo Ji, Changyong Bai, Qingquan Wang, Jiabei Liu, Lianxin Theranostics Research Paper Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFβ1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFβ1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFβ1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFβ1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFβ1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFβ1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFβ1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFβ1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFβ1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis. Ivyspring International Publisher 2021-03-04 /pmc/articles/PMC7978300/ /pubmed/33754025 http://dx.doi.org/10.7150/thno.52102 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Zhang, Bo Meng, Fanzheng Liu, Yao Yuan, Yubin Wang, Jizhou Wu, Dehai Cui, Yifeng Zhang, Shugeng Guo, Hongrui Liang, Shuhang Wang, Wei Klos, Matthew Morgenstern, Sherry Liu, Yufeng Sun, Linmao Ma, Kun Liu, Xirui Wang, Yan Han, Jihua Yang, Guangchao Zheng, Chenyang Li, Xianying Zhou, Shuo Ji, Changyong Bai, Qingquan Wang, Jiabei Liu, Lianxin Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
title | Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
title_full | Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
title_fullStr | Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
title_full_unstemmed | Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
title_short | Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
title_sort | inhibition of tgfβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978300/ https://www.ncbi.nlm.nih.gov/pubmed/33754025 http://dx.doi.org/10.7150/thno.52102 |
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