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. 2021 Jul 23;11(8):1095. doi: 10.3390/biom11081095

Figure 2.

Figure 2

Canonical and non-canonical pathways implicated in fibroblast–myofibroblast differentiation. Three of the best described pathways involved in myofibroblast phenotypic acquisition are the TGF-β1/Smad; HA/CD44/EGFR; and Wnt/β-catenin pathways: (A) TGF-β1 is released from the LAP complex and binds to TGFβRII dimers, enabling association with and the activation of TGFβRI. Smad2 and Smad3 are subsequently phosphorylated and co-associate with Smad4 to initiate the transcription of pro-fibrotic genes; (B) TGF-β1 induced the upregulation of HAS2 synthesised linear HA and hyaladherin crosslinkers, such as TSG-6 and HC5, resulting in HA interactions with CD44s and the thickening of a crosslinked HA pericellular coat. HA interactions with CD44s induce clustering of CD44s within lipid rafts, wherein the co-receptor EGFR is activated and initiates biphasic signalling via ERK1/2 and CaMKII. Early signalling was suggested to promote differentiation-associated gene expression, whereas late signalling was suggested to promote proliferation-associated gene expression; and (C) the Wnt ligand binding to the transmembrane Frazzled receptor (FZD), in the absence of DKK1, which induces localisation with and the activation of LRP5 and LRP6. The Wnt/FZD/LRP signalling drives the dishevelled-mediated attenuation of the β-catenin inhibitory complex (CK-1/Axin/APC/GSK-3), facilitating the accumulation of β-catenin and its translocation to the nucleus, wherein it associates with co-transcription factors, TLF and LEF, to induce pro-fibrotic gene expression.