Impaired non‐canonical transforming growth factor‐β signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4‐deficient murine cardiac fibroblasts

Akboua, Hanane; Eghbalzadeh, Kaveh; Keser, Ugur; Wahlers, Thorsten; Paunel-Görgülü, Adnana

doi:10.1111/jcmm.16915

Cited by 6 publications

(4 citation statements)

References 47 publications

(85 reference statements)

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“…In contrast to these studies, we were not able to identify a direct inhibitory action of PBMCsec on canonical TGFβ/Smad signaling [82]. However, TGFβ has been shown to also induce fibrosis via non-canonical (non-SMAD) signaling pathways [83], and blocking noncanonical signaling prevents pro-fibrotic phenotypes [84]. Possible non-canonical pathways might include glycogen synthase kinase-3β (GSK-3β) [85], a pathway we previously found to be regulated upon non-SMAD TGFβ-mediated abolishment of myoFB differentiation [7].…”

Section: Discussioncontrasting

confidence: 66%

The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring

et al. 2023

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Hypertrophic scars can cause pain, movement restrictions, and reduction in the quality of life. Despite numerous options to treat hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Factors secreted by peripheral blood mononuclear cells (PBMCsec) have been previously described for their beneficial effects on tissue regeneration. In this study, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single-cell resolution (scRNAseq). Mouse wounds and scars, and human mature scars were treated with PBMCsec intradermally and topically. The topical and intradermal application of PBMCsec regulated the expression of various genes involved in pro-fibrotic processes and tissue remodeling. We identified elastin as a common linchpin of anti-fibrotic action in both mouse and human scars. In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast differentiation and attenuates abundant elastin expression with non-canonical signaling inhibition. Furthermore, the TGFβ-induced breakdown of elastic fibers was strongly inhibited by the addition of PBMCsec. In conclusion, we conducted an extensive study with multiple experimental approaches and ample scRNAseq data demonstrating the anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings. These findings point at PBMCsec as a novel therapeutic option to treat skin scarring.

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Section: Discussioncontrasting

confidence: 66%

The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring

et al. 2023

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“…In contrast to these studies, we were not able to identify a direct inhibitory action of PBMCsec on canonical TGFβ/Smad signaling (80). However, TGFβ has been shown to also induce fibrosis via non-canonical (non-SMAD) signaling pathways (81), and blocking non-canonical signaling prevents profibrotic phenotypes (82). Possible non-canonical pathways might include glycogen synthase kinase-3β (GSK-3β) (82), a pathway we previously found regulated upon non-SMAD TGFβ-mediated abolishment of myoFB-differentiation (7).…”

Section: Discussionmentioning

confidence: 99%

“…However, TGFβ has been shown to also induce fibrosis via non-canonical (non-SMAD) signaling pathways (81), and blocking non-canonical signaling prevents profibrotic phenotypes (82). Possible non-canonical pathways might include glycogen synthase kinase-3β (GSK-3β) (82), a pathway we previously found regulated upon non-SMAD TGFβ-mediated abolishment of myoFB-differentiation (7). Hitherto, only few secreted molecules inhibiting non-canonical TGF-signaling have been described.…”

Section: Discussionmentioning

confidence: 99%

The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring

Vorstandlechner

Copic

Klas

et al. 2022

Preprint

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Background Hypertrophic scars can cause pain, movement restrictions, and reduction of quality of life. Despite numerous options to tackle hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Secreted factors from peripheral blood mononuclear cells (PBMCsec) were previously described for their beneficial effects in tissue regeneration. Here, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single cell resolution (scRNAseq). Methods Mouse wounds and scars were treated with PBMCsec either intradermally or topically. Human mature scars were treated with PBMCsec ex vivo in explant cultures. All experimental settings were analyzed by single cell RNA sequencing (scRNAseq). A variety of bioinformatics approaches were used to decipher gene regulation in the scRNAseq data sets. Components of the extracellular matrix (ECM) were investigated in situ by immunofluorescence. The effect of PBMCsec on myofibroblast differentiation and elastin expression was investigated by stimulating human primary fibroblasts with TGFβ. Findings Topical and intradermal application of PBMCsec regulated the expression of a variety of genes involved in pro-fibrotic processes and tissue remodeling. Our bioinformatics approach identified elastin as a common linchpin of antifibrotic action in both, the mouse and human experimental setting. In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast-differentiation and attenuates abundant elastin expression through non-canonical signaling inhibition. Furthermore, TGFβ-induced breakdown of elastic fibers was strongly inhibited by addition of PBMCsec. Interpretation Together, we showed anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings, suggesting PBMCsec as a novel therapeutic option to treat skin scarring.

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“…RNA was reverse transcribed using High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Real-time PCR was performed using Power SYBR Green PCR Master Mix (Applied Biosystems) and specific primers for IL-6 , IL-12 , IL-1 β, MMP-2, MMP-9 ( 28 ), iNOS , Ym-1 , SPHK1 , LIGHT , FIZZ/RELM -α, MerTK ( 29 ), TNF -α ( 30 ), TGF -β ( 31 ) and CCL2 ( 32 ). All samples were run in triplicates.…”

Section: Methodsmentioning

confidence: 99%

Peptidylarginine deiminase 4 deficiency in bone marrow cells prevents plaque progression without decreasing atherogenic inflammation in apolipoprotein E-knockout mice

Paunel-Görgülü

Conforti²,

Mierau³

et al. 2022

Front. Cardiovasc. Med.

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IntroductionDespite multiple studies in the past, the role of peptidylarginine deiminase 4 (PAD4) in atherosclerosis is currently insufficiently understood. In this regard, PAD4 deletion or inhibition of enzymatic activity was previously reported to ameliorate disease progression and inflammation. Besides, strong influence of neutrophil extracellular traps (NETs) on atherosclerosis burden has been proposed. Here, we studied the role of PAD4 for atherogenesis and plaque progression in a mouse model of atherosclerosis.Methods and resultsLethally irradiated ApoE–/– mice were reconstituted with ApoE–/–/Pad4–/– bone marrow cells and fed a high-fat diet (HFD) for 4 and 10 weeks, respectively. PAD4 deficiency did not prevent the development of atherosclerotic lesions after 4 weeks of HFD. However, after 10 weeks of HFD, mice with bone marrow cells-restricted PAD4 deficiency displayed significantly reduced lesion size, impaired lipid incorporation, decreased necrotic core area and less collagen when compared to ApoE–/– bone marrow-transplanted mice as demonstrated by histological staining. Moreover, flow cytometric analysis and quantitative real-time PCR revealed different macrophage subsets in atherosclerotic lesions and higher inflammatory response in these mice, as reflected by increased content of M1-like macrophages and upregulated aortic expression of the pro-inflammatory genes CCL2 and iNOS. Notably, diminished oxLDL uptake by in vitro-polarized M1-like macrophages was evidenced when compared to M2-like cells.ConclusionThese results suggest that pharmacological inhibition of PAD4 may impede lipid accumulation and lesion progression despite no beneficial effects on vascular inflammation.

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Impaired non‐canonical transforming growth factor‐β signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4‐deficient murine cardiac fibroblasts

Cited by 6 publications

References 47 publications

The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring

The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring

The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring

Peptidylarginine deiminase 4 deficiency in bone marrow cells prevents plaque progression without decreasing atherogenic inflammation in apolipoprotein E-knockout mice

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