A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis

Xi, Ying; LaCanna, Ryan; Ma, Hsiao-Yen; N’Diaye, Elsa-Noah; Gierke, Sarah; Caplazi, Patrick; Sagolla, Meredith; Huang, Zhiyu; Lucio, Laura; Arlantico, Alexander; Jeet, Surinder; Brightbill, Hans; Emson, Claire; Wong, Aaron K.; Morshead, Katrina B.; DePianto, Daryle J.; Roose‐Girma, Merone; Yu, Charles; Tam, Lucinda; Jia, Guiquan; Ramalingam, Thirumalai R.; Marsters, Scot A.; Ashkenazi, Avi; Kim, Si Hyun; Wu, Shuang; Wolters, Paul J.; Feldstein, Ariel E.; Heiden, Jason A. Vander; Ding, Ning

doi:10.1016/j.cmet.2022.07.009

Cited by 19 publications

(18 citation statements)

References 93 publications

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“…As expected, PFD attenuated serum-induced MRTFA nuclear translocation in a dose-dependent manner without compromising the overall MRTFA protein level ( figure 3a and c). In addition, we did not observe any significant impact of PFD on fibrillar collagen gene expression and lung fibroblast viability ( supplementary figures S2 and S3 ) and, consistently, a recent report suggested that MRTF signalling is not required for these two processes in fibroblasts [ 55 ]. The IC 50 for PFD on MRTF nuclear translocation is ∼100 and ∼150 µM for each fibroblast line, with the maximal inhibition reaching >90% ( figure 3b , d and e).…”

Section: Resultssupporting

confidence: 87%

Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone

Ma¹,

Heiden²,

Uttarwar³

et al. 2022

Eur Respir J

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease characterized by aberrant fibroblast/myofibroblast accumulation and excessive collagen matrix deposition in the alveolar areas of lungs. As the first approved IPF medication, pirfenidone (PFD) significantly decelerates lung function decline while its underlying anti-fibrotic mechanism remains elusive. In this study, using transcriptomic and immunofluorescence analyses of primary human IPF tissues, we showed that myocardin related transcription factor (MRTF) signaling is activated in myofibroblasts accumulated in IPF lungs. Furthermore, we showed that PFD inhibits MRTF activation in primary human lung fibroblasts at the clinically achievable concentrations (half-maximal inhibitory concentration (IC50)=50–150 µM, maximal inhibition>90%, maximal concentration of PFD in patients<100 µM). Mechanistically, PFD appears to exert its inhibitory effects by promoting the interaction between MRTF and actin indirectly. Finally, PFD-treated IPF lungs exhibit significantly less MRTF activation in FF areas than naïve IPF lungs. Our results suggest MRTF signaling as a direct target for PFD and implicate that some of the anti-fibrotic effects of PFD may be due to MRTF inhibition in lung fibroblasts.

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Section: Resultssupporting

confidence: 87%

Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone

Ma¹,

Heiden²,

Uttarwar³

et al. 2022

Eur Respir J

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“…Recent studies indicate that only 1/3 of patients with NAFL/NASH progress into fibrosis, raising the possibility of the unique determinants of fibrosis progression in addition to the underlying causes of liver injury. Consistent with the findings from a transcriptomic screening, prominent nuclear localization of myocardin‐related transcription factor (MRTF) was observed in fibrotic livers, colocalizing with actin alpha 2 (ACTA2), suggesting that MRTF‐cytoskeleton activation could be a molecular marker of hepatic fibrosis (Xi et al 2022). However, we are not totally convinced about the nuclear localization of MRTF and its increase with fibrosis progression (Fig.…”

Section: Ccn4/wisp1 Stimulates Pancreatic β‐Cells But Promotes Liver ...supporting

confidence: 63%

“…To be noted, in Fig. 6G‐H in Xi et al (2022), the suppression in ACTA2 staining upon anti‐CCN4 treatment for 16 weeks was not all that obvious.…”

Section: Ccn4/wisp1 Stimulates Pancreatic β‐Cells But Promotes Liver ...mentioning

confidence: 84%

Recent progress on the role of cellular communication network factors (CCN) 3, 4 and 6 in regulating adiposity, liver fibrosis and pancreatic islets

Xega

Alami

Liu

2023

J. Cell Commun. Signal.

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CCN/WISP (cellular communication network factors, or Wnt-inducted secreted proteins) family of proteins consists of six extracellular matrix (ECM)-associated proteins that regulate development, cell adhesion and proliferation, ECM remodeling, inflammation, and tumorigenesis. In the last two decades, metabolic regulation by these matricellular proteins has been studied extensively, several excellent reviews have covered the roles of CCN1, -2 and − 5. In this brief review, we will focus on those lesser-known members and more recent discoveries, together with other recent articles presenting a more complete picture of the current state of knowledge. We have found that CCN2, -4, and − 5 promote pancreatic islet function, while CCN3 plays a unique and negative role. CCN3 and − 4 are pro-adiposity leading to insulin resistance, but CCN5 and − 6 are anti-adiposity. While CCN2 and − 4 promote tissue fibrosis and inflammation, all other four members are clearly anti-fibrotic. As for cellular signaling, they are known to interact with integrins, other cell membrane proteins and ECM thereby regulate Akt/protein kinase B, myocardin-related transcription factor (MRTF), and focal adhesion kinase. Yet, a cohesive mechanism of action to comprehensively explain those major functions is still lacking.

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“…Activation of the WISP1-MRIF signaling pathway induces HSC migration and promotes liver fibrosis progression. Notably, an anti-WISP1 antibody significantly ameliorated liver fibrosis in NASH mice[ 92 ].…”

Section: Approaches Targeting Hsc Activation To Prevent Nash-related ...mentioning

confidence: 99%

Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

Wang¹,

Zhang²,

Guan³

2023

World J Gastroenterol

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Nonalcoholic fatty liver disease (NAFLD), a leading chronic disease worldwide, affects approximately a quarter of the global population. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple steatosis. NASH is also identified as the most rapidly growing cause of hepatocellular carcinoma. Although in the past decade, several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase, farnesoid X receptor signaling, peroxisome proliferator-activated receptor signaling, hepatocellular injury, and inflammatory signaling, proven pharmaceutical agents to treat NASH are still lacking. Thus, continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the field. In the current review, we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling pathways. We also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.

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A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis

Cited by 19 publications

References 93 publications

Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone

Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone

Recent progress on the role of cellular communication network factors (CCN) 3, 4 and 6 in regulating adiposity, liver fibrosis and pancreatic islets

Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

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