The forkhead box F1 transcription factor inhibits collagen deposition and accumulation of myofibroblasts during liver fibrosis

Flood, Hannah M.; Bolte, Craig; Dasgupta, Nupur; Sharma, Akanksha; Zhang, Yufang; Gandhi, Chandrashekhar R.; Kalin, Tanya V.; Kalinichenko, Vladimir V.

doi:10.1242/bio.039800

Cited by 11 publications

(6 citation statements)

References 66 publications

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“…Together, this suggests that the phenotypes seen in Rhbdf2 −/− mice at later time points are not due to defects in hepatocytes but another cell population within the liver. We found an increase in areas densely populated with cells, consistent in appearance with fibrotic lesions (31,32), in Rhbdf2 −/− hematoxylin and eosin-stained liver tissue sections compared to Rhbdf2 +/− tissue (Fig. 4C).…”

Section: Lack Of Irhom2 Triggers Increased Presence Of Activated Hscs...supporting

confidence: 53%

iRhom2 inhibits bile duct obstruction–induced liver fibrosis

et al. 2019

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Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor–α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2−/−) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2−/− mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.

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Section: Lack Of Irhom2 Triggers Increased Presence Of Activated Hscs...supporting

confidence: 53%

iRhom2 inhibits bile duct obstruction–induced liver fibrosis

et al. 2019

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“…Dr. Kalinichenko’s lab analyzed human and mouse FOXF1 sequences and identified two highly conserved homologous regions containing potential transcription factor binding sites for the following families: basic leucine zipper CCAAT/enhancer binding protein β, winged helix/Forkhead Box A, zinc finger GATA, homeodomain Nkx2.5, and cut-homeodomain HNF-6 transcription factors 17 . Since Dr. Kalinichenko’s lab has well-documented evidence of the efficacy of this plasmid 16 , 18 , 19 , we have chosen to utilize this plasmid to overexpress FOXF1 in our LR-MSCs. Empty pShuttle A was used as control.…”

Section: Methodsmentioning

confidence: 99%

Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis

Cao

Walker

Braeuer

et al. 2020

Sci Rep

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Forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-associated transcription factor that demonstrates persistent expression into adulthood in mesenchymal stromal cells. However, its biologic function in human adult lung-resident mesenchymal stromal cells (LR-MSCs) remain to be elucidated. Here, we demonstrate that FOXF1 expression acts as a restraint on the migratory function of LR-MSCs via its role as a novel transcriptional repressor of autocrine motility-stimulating factor Autotaxin (ATX). Fibrotic human LR-MSCs demonstrated lower expression of FOXF1 mRNA and protein, compared to non-fibrotic controls. RNAi-mediated FOXF1 silencing in LR-MSCs was associated with upregulation of key genes regulating proliferation, migration, and inflammatory responses and significantly higher migration were confirmed in FOXF1-silenced LR-MSCs by Boyden chamber. ATX is a secreted lysophospholipase D largely responsible for extracellular lysophosphatidic acid (LPA) production, and was among the top ten upregulated genes upon Affymetrix analysis. FOXF1-silenced LR-MSCs demonstrated increased ATX activity, while mFoxf1 overexpression diminished ATX expression and activity. The FOXF1 silencing-induced increase in LR-MSC migration was abrogated by genetic and pharmacologic targeting of ATX and LPA1 receptor. Chromatin immunoprecipitation analyses identified three putative FOXF1 binding sites in the 1.5 kb ATX promoter which demonstrated transcriptional repression of ATX expression. Together these findings identify FOXF1 as a novel transcriptional repressor of ATX and demonstrate that loss of FOXF1 promotes LR-MSC migration via the ATX/LPA/LPA1 signaling axis.

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“…Deletion of FOX gene clusters in transgenic mouse models leads to spinal and vertebral abnormalities ( Stankiewicz et al , 2009 ). In addition, FOXF1 promotes tissue repair in other organs such as lungs and liver ( Bolte et al , 2017 ; Flood et al , 2019 ). In a previous study, the developmental transcription factor Brachyury was successful in reprogramming human NP cells from degenerate and painful IVDs to a healthy immature NP-like phenotype ( Tang et al , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Non-viral reprogramming of human nucleus pulposus cells with FOXF1 via extracellular vesicle delivery: an in vitro and in vivo study

Tang

Salazar-Puerta

Richards³

et al. 2021

eCM

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Intervertebral disc (IVD) degeneration is characterized by decreased cellularity and proteoglycan synthesis and increased inflammation, catabolism, and neural/vascular ingrowth. Regenerative methods for IVD degeneration are largely cell-therapy-based or involve viral vectors, which are associated with mutagenesis and undesired immune responses. The present study used bulk electroporation and engineered extracellular vesicles (EVs) to deliver forkhead-box F1 (FOXF1) mRNA to degenerate human nucleus pulposus (NP) cells as a minimally invasive therapeutic strategy for IVD regeneration. Bulk electroporation was used to investigate FOXF1 effects on human NP cells during a 4-week culture in 3D agarose constructs. Engineered EV delivery of FOXF1 into human IVD cells in monolayer was determined, with subsequent in vivo validation in a pilot mouse IVD puncture model. FOXF1 transfection significantly altered gene expression by upregulating healthy NP markers [FOXF1, keratin 19 (KRT19)], decreasing inflammatory cytokines [interleukin (IL)-1β, -6], catabolic enzymes [metalloproteinase 13 (MMP13)] and nerve growth factor (NGF), with significant increases in glycosaminoglycan accumulation in human NP cells. Engineered EVs loaded with FOXF1 demonstrated successful encapsulation of FOXF1 cargo and effective uptake by human NP cells cultured in monolayer. Injection of FOXF1-loaded EVs into the mouse IVD in vivo resulted in a significant upregulation of FOXF1 and Brachyury, compared to controls at 7 d post-injection, with no evidence of cytotoxicity. This is the first study to demonstrate non-viral delivery of FOXF1 and reprogramming of human NP cells in vitro and mouse IVD cells in vivo. This strategy represents a non-addictive approach for treating IVD degeneration and associated back pain.

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The forkhead box F1 transcription factor inhibits collagen deposition and accumulation of myofibroblasts during liver fibrosis

Cited by 11 publications

References 66 publications

iRhom2 inhibits bile duct obstruction–induced liver fibrosis

iRhom2 inhibits bile duct obstruction–induced liver fibrosis

Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis

Non-viral reprogramming of human nucleus pulposus cells with FOXF1 via extracellular vesicle delivery: an in vitro and in vivo study

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