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

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.

The Role of Lung Resident Mesenchymal Stromal Cells in the Pathogenesis and Repair of Chronic Lung Disease

“…In addition, ER stress has been identified within the IPF lung and has recently been linked to the differentiation of LR-MSCs to myofibroblasts, with the C/EBP homologous protein (CHOP) noted as being integral to this process. 63 …”

“… 39 Overexpression of the deSUMOylation enzyme SENP1 was observed in LR-MSCs differentiating into myofibroblasts. 63 Downregulation of SENP1 could reverse this differentiation by promoting SUMOylation of Wnt and HH proteins, and enhancing the degradation of β-catenin and GLI1. The findings from these studies link HH and Wnt signaling with the differentiation and fibrotic effects of LR-MSCs.…”

Mitochondrial Dysfunction in Lung Resident Mesenchymal Stem Cells from Idiopathic Pulmonary Fibrosis Patients

“…Although evidence has suggested that LRMPC actively contribute to IPF, evidence in animal models suggests that LRMSC could be involved in pulmonary fibrosis as a consequence of MSC exhaustion [ 16 ] and thereby limiting the regeneration of alveolar epithelium, and/or because they actively contribute to the dysregulated repair mechanism by differentiating into myofibroblasts [ 17 ]. Other studies conducted on LRMSC from lung damage animal models showed that LRMSC are able to differentiate into myofibroblasts through the activation of hedgehog and Wnt/B-catenin signaling [ 18 , 19 ] and suggested that they could be a major source of myofibroblasts, thereby actively contributing to pulmonary fibrosis progression [ 20 , 21 , 22 , 23 , 24 ]. In a study with human LRMSC involving IPF patients [ 25 ], the authors showed that IPF LRMSC displayed a higher expression of genes involved in inflammation, oxidative stress, hypoxia, and ECM pathway than control LRMSC and, in co-culture with control MSC or fibroblasts, induced a pathological phenotype on the surrounding cells.…”

The emerging roles of SUMOylation in pulmonary diseases

“…Previous studies have shown that SUMOylation and deSUMOylation play a role in the development of fibrosis in different organs, including the heart, liver, and kidney(Liu et al 2017 ; Zhao et al 2021 ; Wang et al 2018 ; Sun et al 2022 ). A recent study revealed that significantly higher expression of SUMO1, SUMO2, and UBC9 in total lung tissue of IPF patients compared to healthy individuals, accompanied by downregulation of SENP1(Yu et al 2022 ).…”

“…It has been determined that Lung-resident mesenchymal stem cells (LR-MSCs) may be a source of myofibroblasts, accelerating the development of IPF(Inui et al 2021 ; Yang et al 2021a ). Overexpression of SENP1 in LR-MSCs can stimulate the Wingless/Integrated (WNT)/β-catenin and Hedgehog/Glioma-associated oncogene homolog (GLI) signaling pathways by deSUMOylation of critical proteins, and encourage the transformation of LR-MSCs into myofibroblasts, exacerbating the development of pulmonary fibrosis(Sun et al 2022 ). As a result, SENP1 has emerged as a promising therapeutic target for the restoration of LR-MSC physiological functions and the treatment of pulmonary fibrosis.…”