YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts

Abstract

Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblast-rich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP1) is activated by tissue stiffness and the profibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP1 regulates the differentiation of dermal fibroblasts into highly contractile myofibroblasts and that YAP1 governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP1 in transforming growth factor-β1-stimulated dermal fibroblasts decreased the formation of contractile smooth muscle α-actin stress fibers and the deposition of collagen type I, which are hallmark features of myofibroblasts. Translating our findings to a clinically relevant model, we found that YAP1 deficiency in Dupuytren disease myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP1-deficient Dupuytren myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP1 levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly co-localized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP1 is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1-induced myofibroblast differentiation and primary Dupuytren myofibroblasts.

YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis

“…Interestingly, the effects of YAP silencing were not as profound as those of verteporfin, suggesting that verteporfin may also mediate its effects through other non-YAP-dependent mechanisms. Indeed, although prior studies have mostly focused on the profibrotic activity of YAP, 36,37 it is possible, for example, that verteporfin-induced reductions in TAZ may also have important effects.…”

“…This effect is consistent with prior evidence of physical interactions between YAP/TAZ and Smad2/3 in the nucleus, [14][15][16] and it is in line with reports from our group and others indicating that YAP and TAZ exhibit profibrotic activity. [35][36][37] Indeed, Speight et al 24 previously showed a role for TAZ in controlling a-SMA expression in injured epithelium as part of epithelial-myofibroblast transition. 35 Similarly, recent reports have showed that a stiff environment promotes YAP/TAZdependent activation of fibroblasts and hepatic stellate cells, promoting matrix synthesis independent of TGF-b, possibly through the induction of CTGF and PAI1.…”

Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions

“…Recent evidence has shown that TGF-β-induced myofibroblastic (i.e., CAF) activation is dependent on Rho activity and nuclear translocation of Yes-associated protein-1 (YAP1). This TGF-β-mediated process is known to transcriptionally regulate proteins involved in proliferation and apoptosis which ultimately culminates in altered ECM production [121]. In fact, YAP has been shown to play a role in both ECM remodeling and in cellular responses to altered ECMs.…”

Connective Tissue Degeneration: Mechanisms of Palmar Fascia Degeneration (Dupuytren’s Disease)

“…Novel players have been implicated in the pathogenesis of DD such as Wilm’s tumour protein-1 (WT1) [31•] and YAP [32•]. YAP1, a member of the Hippo pathway, which has recently been shown to promote differentiation of fibroblasts into myofibroblasts, potentially acts downstream of TGFβ [32•].…”

“…YAP1, a member of the Hippo pathway, which has recently been shown to promote differentiation of fibroblasts into myofibroblasts, potentially acts downstream of TGFβ [32•].…”