Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease

Zhang, Yun; Shen, Lijing; Dreißigacker, Katja; Zhu, Honglin; Trinh-Minh, Thuong; Meng, Xianjun; Tran-Manh, Cuong; Dees, Clara; Matei, Alexandru-Emil; Chen, Chih‐Wei; Ditschkowski, Markus; Krauß, Stefan; Winkler, Julia; Wolff, Daniel; Ziemer, Mirjana; Beilhack, Andreas; Karrer, Sigrid; Herr, Wolfgang; Mackensen, Andréas; Schett, Georg; Spriewald, Bernd; Distler, Jörg H W

doi:10.1182/blood.2020008720

Cited by 13 publications

(8 citation statements)

References 67 publications

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“…also demonstrated that the TME contains anti-tumor components ( 51 ). Although it is well known that the Wnt signaling pathway promotes tumor progression ( 52 , 53 ), Green et al. proved that Wnt3a derived from CAFs can both promote and inhibit the growth of breast tumors ( 54 ).…”

Section: Origin and Heterogeneity Of Cafsmentioning

confidence: 99%

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Chen

Wei

et al. 2021

Front. Immunol.

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Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

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Section: Origin and Heterogeneity Of Cafsmentioning

confidence: 99%

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Chen

Wei

et al. 2021

Front. Immunol.

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“…This PDF file includes: Materials and Methods Figs. S1 to S22 Tables S1 to S3 references (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) Other Supplementary Material for this manuscript includes the following: data files S1 and S2 arriVe checklist Mdar reproducibility checklist…”

Section: Supplementary Materialsmentioning

confidence: 99%

Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis

Liang,

Dickel,

Györfi

et al. 2024

Sci. Transl. Med.

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Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated ( ENHO ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin 34–76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19 , an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin 34–76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin 34–76 -induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.

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“…In fibrosis, the canonical Wnt pathway is crucial for the stimulation of fibroblasts and the release of collagen. Wnt signaling accelerated the release of extracellular matrix components, promoted fibrosis, and triggered myofibroblast development from resting fibroblasts [ 107 ]. It should be noted that Wnt activation-induced fibrotic illness was more significant than the impacts of other fibrotic pathways.…”

Section: Role Of Wnt Pathway In Fibrosismentioning

confidence: 99%

Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation

Antar

Ashour

Marawan

et al. 2023

IJMS

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Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. The fibrosis process is associated with chronic inflammation, metabolic homeostasis, and transforming growth factor-β1 (TGF-β1) signaling, where the balance between the oxidant and antioxidant systems appears to be a key modulator in managing these processes. Virtually every organ system, including the lungs, heart, kidney, and liver, can be affected by fibrosis, which is characterized as an excessive accumulation of connective tissue components. Organ malfunction is frequently caused by fibrotic tissue remodeling, which is also frequently linked to high morbidity and mortality. Up to 45% of all fatalities in the industrialized world are caused by fibrosis, which can damage any organ. Long believed to be persistently progressing and irreversible, fibrosis has now been revealed to be a very dynamic process by preclinical models and clinical studies in a variety of organ systems. The pathways from tissue damage to inflammation, fibrosis, and/or malfunction are the main topics of this review. Furthermore, the fibrosis of different organs with their effects was discussed. Finally, we highlight many of the principal mechanisms of fibrosis. These pathways could be considered as promising targets for the development of potential therapies for a variety of important human diseases.

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Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease

Cited by 13 publications

References 67 publications

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis

Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation

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