SPARC-YAP/TAZ inhibition prevents the fibroblasts-myofibroblasts transformation

Du, Jingxiao; Qian, Tianwei; Lü, Yi; Zhou, Wenkai; Xu, Xun; Zhang, Chaoyang; Zhang, Jingfa; Zhang, Zhihua

doi:10.1016/j.yexcr.2023.113649

Cited by 5 publications

(1 citation statement)

References 62 publications

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“…There was a decrease in the secretion of one of the well-described antifibrotic soluble factors, HGF, greater than that observed with TGFβ-1 stimulation alone. In accordance with these changes, the secretion of SPARC, a secreted protein acidic and rich in cysteine, increased significantly, for which stimulation of the YAP/TAZ signaling cascade with further translocation of non-phosphorylated YAP into the nucleus and activation of target genes YAP, TAZ, CTGF and CYR61, and the formation of myofibroblasts was shown [28]. There was also an increase in the secretion of fibulin-2, an ECM protein that is required for the activation of TGFβ-1 signaling and mediates the development of fibrosis [29].…”

Section: Discussionmentioning

confidence: 99%

Modeling the profibrotic microenvironmentin vitro: model validation

Grigorieva,

Basalova,

Dyachkova

et al. 2023

Preprint

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Establishing the molecular and cellular mechanisms of fibrosis requires the development of validated and reproducible models. The complexity ofin vivomodels challenges the monitoring of an individual cell fate, in some cases making it impossible. However, the set of factors affecting cells inin vitroculture systems differ significantly fromin vivoconditions, insufficiently reproducing living systems. Thus, to model profibrotic conditionsin vitro, usually the key profibrotic factor, transforming growth factor beta (TGFβ-1) is used as a single factor. TGFβ-1 stimulates the differentiation of fibroblasts into myofibroblasts, the main effector cells promoting the development and progression of fibrosis. However, except for soluble factors, the rigidity and composition of the extracellular matrix (ECM) play a critical role in the differentiation process. To develop the model of more complex profibrotic microenvironmentin vitro, we used a combination of factors: decellularized ECM synthesized by human dermal fibroblasts in the presence of ascorbic acid if cultured as cell sheets and recombinant TGFβ-1 as a supplement. When culturing human mesenchymal stromal cells derived from adipose tissue (MSCs) under described conditions, we observed differentiation of MSCs into myofibroblasts due to increased number of cells with stress fibrils with alpha-smooth muscle actin (αSMA), and increased expression of myofibroblast marker genes such as collagen I, EDA-fibronectin and αSMA. Importantly, secretome of MSCs changed in these profibrotic microenvironment: the secretion of the profibrotic proteins SPARC and fibulin-2 increased, while the secretion of the antifibrotic hepatocyte growth factor (HGF) decreased. Analysis of transciptomic pattern of regulatory microRNAs in MSCs revealed 49 miRNAs with increased expression and 3 miRNAs with decreased expression under profibrotic stimuli. Bioinformatics analysis confirmed that at least 184 gene targets of the differently expressed miRNAs genes were associated with fibrosis. To further validate the developed model of profibrotic microenvironment, we cultured human dermal fibroblasts in these conditions and observed increased expression of fibroblast activation protein (FAPa) after 12 hours of cultivation as well as increased level of αSMA and higher number of αSMA+ stress fibrils after 72 hours. The data obtained allow us to conclude that the conditions formed by the combination of profibrotic ECM and TGFβ-1 provide a complex profibrotic microenvironmentin vitro. Thus, this model can be applicable in studying the mechanism of fibrosis development, as well as for the development of antifibrotic therapy.

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Section: Discussionmentioning

confidence: 99%