TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways

Zhao, Zhenzhen; Zhang, Yumeng; Zhang, Chaoyang; Zhang, Jingting; Luo, Xueting; Qiu, Qinghua; Luo, Da; Zhang, Jingfa

doi:10.1038/s12276-022-00778-0

Cited by 38 publications

(29 citation statements)

References 48 publications

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“…Increased fibrosis can be mediated by an increase in fibroblast number or activation. Pericytes also secrete ECM and have been described to be a source of myofibroblasts following kidney injury 37 , in subretinal fibrosis 38 , or in cancer 39 . To study whether the deletion of Rgs5 in pericytes would induce fibroblast expansion in the heart, we analysed the area covered by fibroblasts by staining PDGFRα, which is a well established marker for fibroblasts and not present in pericytes 40 .…”

Section: Resultsmentioning

confidence: 99%

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Tamiato,

Tombor,

Fischer

et al. 2023

Preprint

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BackgroundPericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although ageing is one of the main risk factors for cardiovascular disease, the consequences of ageing on cardiac pericytes are unknown.MethodsIn this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of Regulator of G protein signalling 5 (RGS5) loss of function and finally have performed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 deletion in pericytes on the neighbouring fibroblasts.ResultsAgeing reduced the pericyte area and capillary coverage in the murine heart. Single nucleus RNA sequencing analysis further revealed that the expression ofRgs5was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, fibrosis, and induced morphological changes and a pro-fibrotic gene expression signature in pericytes characterized by the expression of different extracellular matrix components and growth factors e.g.TGFB2andPDGFB.Indeed, culturing fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation as evidenced by the increased expression of α smooth muscle actin in a TGFβ2-dependent mechanism.ConclusionsOur results have identified RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.

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Section: Resultsmentioning

confidence: 99%

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Tamiato,

Tombor,

Fischer

et al. 2023

Preprint

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“…Zhao et al. reported that inhibition of mTOR exerted synergistic effects on inhibiting α‐SMA expression and cell proliferation [43, 44]. Therefore, we suspected that α‐SMA‐positive DPSCs modulated mitochondrial function by modulating the mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 96%

“…It has been reported that many signaling pathways are involved in modulating mitochondrial function, including the Akt/mTOR/nuclear factor kappa B (NF-κB) signaling pathway [40], the PI3K/Akt/mTOR signaling pathway [41], and the extracellular signal-regulated kinase (ERK) signaling pathway [42]. Zhao et al reported that inhibition of mTOR exerted synergistic effects on inhibiting α-SMA expression and cell proliferation [43,44]. Therefore, we suspected that α-SMA-positive DPSCs modulated mitochondrial function by modulating the mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Role of alpha smooth muscle actin in odontogenic differentiation of dental pulp stem cells

Ma,

Shen,

et al. 2023

European J Oral Sciences

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Pulpotomy is an effective treatment for retaining vital pulp after pulp exposure caused by caries removal and/or trauma. The expression of alpha smooth muscle actin (α‐SMA) is increased during the wound‐healing process, and α‐SMA‐positive fibroblasts accelerate tissue repair. However, it remains largely unknown whether α‐SMA‐positive fibroblasts influence pulpal repair. In this study, we established an experimental rat pulpotomy model and found that the expression of α‐SMA was increased in dental pulp after pulpotomy relative to that in normal dental pulp. In vitro results showed that the expression of α‐SMA was increased during the induction of odontogenic differentiation in dental pulp stem cells (DPSCs) compared with untreated DPSCs. Moreover, α‐SMA overexpression promoted the odontogenic differentiation of DPSCs via increasing mitochondrial function. Mechanistically, α‐SMA overexpression activated the mammalian target of rapamycin (mTOR) signaling pathway. Inhibition of the mTOR signaling pathway by rapamycin decreased the mitochondrial function in α‐SMA‐overexpressing DPSCs and suppressed the odontogenic differentiation of DPSCs. Furthermore, we found that α‐SMA overexpression increased the secretion of transforming growth factor beta‐1 (TGF‐β1). In sum, our present study demonstrates a novel mechanism by which α‐SMA promotes odontogenic differentiation of DPSCs by increasing mitochondrial respiratory activity via the mTOR signaling pathway.

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“…Thus, TGF-β stimulation triggers the differentiation of pericytes into scar-forming myofibroblasts in a process referred to as pericyte-to-myofibroblast transition (PMT) which is essential to wound healing. However, excess PMT is believed to be a significant contributor to fibrosis ( Wu et al, 2013 ; Yamaguchi et al, 2020 ; Zhao et al, 2022 ). Multiple studies have explored the effect of TGF-β on the differentiation of pericytes into myofibroblasts, thusly gaining a more motile phenotype and contributing to the increased population of myofibroblasts at the site of inflammation ( Johnson et al, 2015 ).…”

Section: Pericyte Responses To the Microenvironmentmentioning

confidence: 99%

“…Multiple studies have explored the effect of TGF-β on the differentiation of pericytes into myofibroblasts, thusly gaining a more motile phenotype and contributing to the increased population of myofibroblasts at the site of inflammation ( Johnson et al, 2015 ). TGF-β-induced subretinal PMT has been shown to act in Smad2/3 and Akt/mTOR pathways ( Wu et al, 2013 ; Zhao et al, 2022 ). Thus, TGF-β signalling is important to pericyte function but may be dysregulated and contribute to lung fibrosis.…”

Section: Pericyte Responses To the Microenvironmentmentioning

confidence: 99%

Pericytes: The lung-forgotten cell type

Garrison

Bignold

et al. 2023

Front. Physiol.

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Pericytes are a heterogeneous population of mesenchymal cells located on the abluminal surface of microvessels, where they provide structural and biochemical support. Pericytes have been implicated in numerous lung diseases including pulmonary arterial hypertension (PAH) and allergic asthma due to their ability to differentiate into scar-forming myofibroblasts, leading to collagen deposition and matrix remodelling and thus driving tissue fibrosis. Pericyte-extracellular matrix interactions as well as other biochemical cues play crucial roles in these processes. In this review, we give an overview of lung pericytes, the key pro-fibrotic mediators they interact with, and detail recent advances in preclinical studies on how pericytes are disrupted and contribute to lung diseases including PAH, allergic asthma, and chronic obstructive pulmonary disease (COPD). Several recent studies using mouse models of PAH have demonstrated that pericytes contribute to these pathological events; efforts are currently underway to mitigate pericyte dysfunction in PAH by targeting the TGF-β, CXCR7, and CXCR4 signalling pathways. In allergic asthma, the dissociation of pericytes from the endothelium of blood vessels and their migration towards inflamed areas of the airway contribute to the characteristic airway remodelling observed in allergic asthma. Although several factors have been suggested to influence this migration such as TGF-β, IL-4, IL-13, and periostin, recent evidence points to the CXCL12/CXCR4 pathway as a potential therapeutic target. Pericytes might also play an essential role in lung dysfunction in response to ageing, as they are responsive to environmental risk factors such as cigarette smoke and air pollutants, which are the main drivers of COPD. However, there is currently no direct evidence delineating the contribution of pericytes to COPD pathology. Although there is a lack of human clinical data, the recent available evidence derived from in vitro and animal-based models shows that pericytes play important roles in the initiation and maintenance of chronic lung diseases and are amenable to pharmacological interventions. Therefore, further studies in this field are required to elucidate if targeting pericytes can treat lung diseases.

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TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways

Cited by 38 publications

References 48 publications

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Role of alpha smooth muscle actin in odontogenic differentiation of dental pulp stem cells

Pericytes: The lung-forgotten cell type

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