Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases

Li, Xiaohe; Fang, Yinshan; Jiang, Dechun; Dong, Yingying; Liu, Yingying; Zhang, Si; Guo, Jiasen; Qi, Chao; Zhao, Can; Jiang, Fangxin; Jin, Yueyue; Geng, Jing; Yang, Cheng; Zhang, Hongkai; Wei, Bin; Liang, Jiurong; Wang, Chen; Dai, Huaping; Zhou, Honggang; Jiang, Dianhua; Ning, Wen

doi:10.1016/j.ymthe.2020.09.031

Cited by 29 publications

(17 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During the development of RA, FSTL1 overexpression promotes cell proliferation, migration, and invasiveness of the extracellular matrix of SF through increased expression of TLR4 and NF κ B [ 10 , 11 ]. Antagonism against FSTL1 exerts an effective antifibrotic effect and reduces the severity of arthritis [ 12 ]. Therefore, elucidating the transcription factors (TFs) and gene regulatory networks regulating FSTL1 will likely lead to the development of novel therapeutic approaches for RA.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Transcriptome Analysis Reveals the Importance of IRF1/FSTL1 in Synovial Fibroblast Subsets for the Development of Rheumatoid Arthritis

Wang

Gong

2022

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

Objectives. This study aimed to investigate the potential role of synovial fibroblasts (SFs) in the development of rheumatoid arthritis (RA) to identify potential molecular targets and provide a theoretical basis for the treatment of RA. Methods. GSE109449, a fibroblast transcriptome dataset of synovial tissue from RA and osteoarthritis (OA), were obtained from the GEO database. After standard cell quality control, this single-cell transcriptome data was used to perform routine single-cell analysis processes. After completing dimensionality reduction, clustering, and cell subset identification of fibroblasts, the SCENIC analysis helped calculate the significant gene regulatory networks in fibroblasts and their subsets. From these computed gene regulatory networks, the regulon in which follistatin-like protein 1 (FSTL1) resides was extracted and used to analyze the transcriptional regulatory status of fibroblasts. Finally, the gene set enrichment analysis (GSEA) was used to calculate the respective enriched gene sets of IRF1 and FSTL1. Results. Three SF subgroups were identified from the single-cell transcriptome analysis; SF subset 3 was more abundant in RA than in OA ( p < 0.001 ). From the SCENIC analysis, we obtained 269 regulons and the corresponding gene regulatory networks in SF from the RA datasets. Next, we screened and obtained a regulon-containing FSTL1, where IRF1 was the major transcription factor. The top five regulons in SF subset 3 were TWIST1, MECOM, KLF6, MAFB, and RUNX1. Among the 3 SF subsets, IRF1 regulon was ranked the highest in SF subset 3. Differential analysis of pseudobulk RNA-seq showed that IRF1 was up-regulated in RA compared to OA. Between the three SF subgroups, IRF1 and FSTL1 expression was more up-regulated in SF subset 3 compared to the other two subgroups. Conclusions. IRF1 was found to regulate the invasiveness of SFs by regulating FSTL1, which may influence the disease progression of RA.

show abstract

Section: Introductionmentioning

confidence: 99%

Single-Cell Transcriptome Analysis Reveals the Importance of IRF1/FSTL1 in Synovial Fibroblast Subsets for the Development of Rheumatoid Arthritis

Wang

Gong

2022

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

show abstract

“…If there has a therapeutic strategy that can balance this pathological change? Previous studies have suggested that FSTL1 attenuated pathological injury of multiple organs by alleviating fibrosis, particularly in cardiac dysfunction ( Jiang et al, 2020 ; Hu et al, 2020 ; Li et al, 2021 ; Z.; Chen Z. et al, 2019 ; Yang et al, 2020 ). Our current findings are consistent with these aforementioned research findings that the upregulation of FSTL1 in DM compared with the control group, which was further increased in T2DM with MI.…”

Section: Discussionmentioning

confidence: 99%

FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice

Yang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.

show abstract

“…The inhibition of FSTL1 expression or activity protected against lung injury and fibrosis [253,254]. Recently, FSTL1 neutralizing antibodies were shown to exhibit potent anti-inflammatory actions, attenuate bleomycin-induced IPF and dermal fibrosis in vivo, and downregulate TGF-β1-driven fibrosis in human skin ex vivo [255].…”

Section: Immunomodulating Biomolecules For Fibrosis Attenuationmentioning

confidence: 99%

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

et al. 2021

View full text Add to dashboard Cite

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

show abstract

Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases

Cited by 29 publications

References 63 publications

Single-Cell Transcriptome Analysis Reveals the Importance of IRF1/FSTL1 in Synovial Fibroblast Subsets for the Development of Rheumatoid Arthritis

Single-Cell Transcriptome Analysis Reveals the Importance of IRF1/FSTL1 in Synovial Fibroblast Subsets for the Development of Rheumatoid Arthritis

FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

Contact Info

Product

Resources

About