SENP1 regulates the transformation of lung resident mesenchymal stem cells and is associated with idiopathic pulmonary fibrosis progression

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Abstract

Background

Lung resident mesenchymal stem cells (LR-MSCs) play an important role in idiopathic pulmonary fibrosis (IPF) by transforming into myofibroblasts, thereby losing their repair ability. Evidence suggests that key proteins of multiple signaling pathways are involved in myofibroblast differentiation of LR-MSCs, such as β-Catenin and GLI family zinc finger 1 (GLI1). These proteins are regulated by SUMO (small ubiquitin-like modifier) modification, which is a post-translational modification that promotes protein degradation, while Sumo specific protein 1 (SENP1)-mediated deSUMOylation produces the opposite biological effects. Therefore, we speculated that SENP1 might be a potential target for treating pulmonary fibrosis by preventing the myofibroblast differentiation of LR-MSCs.

Methods

LR-MSCs were isolated from mice by using immunomagnetic beads. The extracted LR-MSCs were identified by flow cytometric analysis and multilineage differentiation assays. Lentivirus packaged shRNA silenced the expression of SENP1 in vitro and vivo. The silencing efficacy of SENP1 was verified by real-time quantitative PCR. The effect of down-regulated SENP1 on the myofibroblast differentiation of LR-MSCs was assessed by Immunofluorescence and Western blot. Immunoprecipitation was used to clarify that SENP1 was a key target for regulating the activity of multiple signaling pathways in the direction of LR-MSCs differentiation. LR-MSCs resident in the lung was analyzed with in vivo imaging system. HE and Masson staining was used to evaluate the therapeutic effect of LR-MSCs with SENP1 down-regulation on the lung of BLM mice.

Results

In this study, we found that the myofibroblast differentiation of LR-MSCs in IPF lung tissue was accompanied by enhanced SENP1-mediated deSUMOylation. The expression of SENP1 increased in LR-MSCs transition of bleomycin (BLM)-induced lung fibrosis. Interfering with expression of SENP1 inhibited the transformation of LR-MSCs into myofibroblasts in vitro and in vivo and restored their therapeutic effect in BLM lung fibrosis. In addition, activation of the WNT/β-Catenin and Hedgehog/GLI signaling pathways depends on SENP1-mediated deSUMOylation.

Conclusions

SENP1 might be a potential target to restore the repair function of LR-MSCs and treat pulmonary fibrosis.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12964-022-00921-4.

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Most cited references 28

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Multilineage potential of adult human mesenchymal stem cells.

M. Pittenger, A M Mackay, S C Beck … (1999)

Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

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Mesenchymal Stem Cells in Fibrotic Disease

Rafael Kramann, Rebekka K Schneider, Xiaokun Li … (2017)

Fibrosis is associated with organ failure and high mortality and is commonly characterized by aberrant myofibroblast accumulation. Investigating the cellular origin of myofibroblasts in various diseases is thus a promising strategy for developing targeted anti-fibrotic treatments. Recent studies using genetic lineage tracing technology have implicated diverse organ-resident perivascular mesenchymal stem cell (MSC)-like cells and bone marrow-MSCs in myofibroblast generation during fibrosis development. In this Review, we give an overview of the emerging role of MSCs and MSC-like cells in myofibroblast-mediated fibrotic disease in the kidney, lung, heart, liver, skin, and bone marrow.

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Idiopathic pulmonary fibrosis: Disease mechanisms and drug development

Paolo Spagnolo, Jonathan Kropski, Mark G. Jones … (2021)

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.

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Author and article information

Contributors

Yang Yang: yangydoc@163.com

Zuojun Xu: xuzjdoc@163.com

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 14 July 2022

Publication date PMC-release: 14 July 2022

Publication date Collection: 2022

Volume: 20

Electronic Location Identifier: 104

Affiliations

[1 ]GRID grid.410646.1, ISNI 0000 0004 1808 0950, Department of Respiratory and Critical Medicine, , Sichuan Provincial People’s Hospital, Sichuan Academy of Medical Sciences, ; No. 32, Section 2, West 1st ring road, Qingyang District, Chengdu, 610072 Sichuan China

[2 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Department of Respiratory and Critical Medicine, Peking Union Medical College Hospital, , Chinese Academy of Medical Sciences and Peking Union Medical College, ; No. 1 Shuai Fu Yuan Street, Dong Cheng District, Beijing, 100730 China

[3 ]GRID grid.470124.4, State Key Laboratory of Respiratory Disease, National Clinical Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, , The First Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, Guangdong China

Article

Publisher ID: 921

DOI: 10.1186/s12964-022-00921-4

PMC ID: 9281027

PubMed ID: 35836260

SO-VID: 54cd692f-17f7-4f2d-91c7-ce7365b7a465

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 14 March 2022

Date accepted : 15 June 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82070067

Award Recipient : Zuojun Xu

Funded by: FundRef http://dx.doi.org/10.13039/501100012166, National Key Research and Development Program of China;

Award ID: 2016YFC0905700

Award Recipient : Zuojun Xu

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ScienceOpen disciplines: Cell biology

Keywords: idiopathic pulmonary fibrosis,myofibroblasts,lung resident mesenchymal stem cells,senp1

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: idiopathic pulmonary fibrosis, myofibroblasts, lung resident mesenchymal stem cells, senp1

SENP1 regulates the transformation of lung resident mesenchymal stem cells and is associated with idiopathic pulmonary fibrosis progression

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Related collections

Stress signalling in stem cells

Most cited references 28

Multilineage potential of adult human mesenchymal stem cells.

Mesenchymal Stem Cells in Fibrotic Disease

Idiopathic pulmonary fibrosis: Disease mechanisms and drug development

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