Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation

Anjum, Fatima; Wang, Ying; Uchida, Yutaka; Norden, Pieter R.; Liu, Ting; Culver, Austin; Dietz, William H.; Culver, Ford; Millay, Meredith; Mukouyama, Yoh‐suke; Kume, Tsutomu

doi:10.1172/jci80465

Cited by 75 publications

(83 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Non-immune normal goat, rabbit, syrian hamster and rat IgGs and isotype controls (detailed in the S1 Table) were employed as negative controls for the respective antigen-specific labeling. Similar procedures for mouse cardiac cell isolation and antibodies for the detection of podoplanin, LYVE-1, F4/80 or PDGFRα by flow-cytometry, were recently reported by other groups [22, 23]. Samples were acquired with BD FACSCantoII (BD Biosciences) and analyzed using FlowJo software (Tree Star Inc.).…”

Section: Methodsmentioning

confidence: 99%

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

et al. 2017

View full text Add to dashboard Cite

Cardiac lymphatic vasculature undergoes substantial expansion in response to myocardial infarction (MI). However, there is limited information on the cellular mechanisms mediating post-MI lymphangiogenesis and accompanying fibrosis in the infarcted adult heart. Using a mouse model of permanent coronary artery ligation, we examined spatiotemporal changes in the expression of lymphendothelial and mesenchymal markers in the acutely and chronically infarcted myocardium. We found that at the time of wound granulation, a three-fold increase in the frequency of podoplanin-labeled cells occurred in the infarcted hearts compared to non-operated and sham-operated counterparts. Podoplanin immunoreactivity detected LYVE-1-positive lymphatic vessels, as well as masses of LYVE-1-negative cells dispersed between myocytes, predominantly in the vicinity of the infarcted region. Podoplanin-carrying populations displayed a mesenchymal progenitor marker PDGFRα, and intermittently expressed Prox-1, a master regulator of the lymphatic endothelial fate. At the stages of scar formation and maturation, concomitantly with the enlargement of lymphatic network in the injured myocardium, the podoplanin-rich LYVE-1-negative multicellular assemblies were apparent in the fibrotic area, aligned with extracellular matrix deposits, or located in immediate proximity to activated blood vessels with high VEGFR-2 content. Of note, these podoplanin-containing cells acquired the expression of PDGFRβ or a hematoendothelial epitope CD34. Although Prox-1 labeling was abundant in the area affected by MI, the podoplanin-presenting cells were not consistently Prox-1-positive. The concordance of podoplanin with VEGFR-3 similarly varied. Thus, our data reveal previously unknown phenotypic and structural heterogeneity within the podoplanin-positive cell compartment in the infarcted heart, and suggest an alternate ability of podoplanin-presenting cardiac cells to generate lymphatic endothelium and pro-fibrotic cells, contributing to scar development.

show abstract

Section: Methodsmentioning

confidence: 99%

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

et al. 2017

View full text Add to dashboard Cite

show abstract

“…11,15,18 In addition, FOXC1 has recently been identified as a primary open-angle glaucoma (POAG) susceptibility locus 19 and an essential regulator of lymphangiogenesis. 20 FOXC1 encodes a forkhead transcription factor encoded by a single exon, whereas PITX2 is a member of a paired class of homeodomain transcription factors and encodes four alternative transcripts (PITX2A, B, C and D). Both are expressed during embryonic development and regulate downstream genes important for cell differentiation and migration via DNA binding.…”

Section: Introductionmentioning

confidence: 99%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

View full text Add to dashboard Cite

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P = 0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0 ± 13.0 years) compared with PITX2 carriers (18.0 ± 10.6 years, P = 0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P = 0.03) but became comparable at 25 years old (71.4% vs 57.7%, P = 0.38). These findings have important implications for the genetic counselling of families affected by AxenfeldRieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

show abstract

“…6c-e) and FOXC2 and HOXD8 regulon activity (Fig. 4g)54,55 . Lymphatics populated the portal region of healthy livers(Fig.…”

mentioning

confidence: 99%

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Ramachandran

Dobie

Wilson-Kanamori

et al. 2019

Preprint

View full text Add to dashboard Cite

Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 primary human single cells, yielding molecular definitions for the major non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2 + CD9 + macrophage subpopulation with a fibrogenic phenotype, that has a distinct differentiation trajectory from circulating monocytes. In the endothelial compartment, we show that newly-defined ACKR1 + and PLVAP + endothelial cells expand in cirrhosis and are topographically located in the fibrotic septae. Multi-lineage ligand-receptor modelling of specific interactions between the novel scar-associated macrophages, endothelial cells and collagen-producing myofibroblasts in the fibrotic niche, reveals intra-scar activity of several major pathways which promote hepatic fibrosis. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis. MainLiver cirrhosis is a major global healthcare burden. Recent estimates suggest that 844 million people worldwide have chronic liver disease, with a mortality rate of two million deaths per year and a rising incidence 1 . In health, the liver serves a myriad of functions including detoxification, metabolism, bile production and immune surveillance. Chronic liver disease, the result of iterative liver injury secondary to any cause, results in progressive fibrosis, disrupted hepatic architecture, vascular changes and aberrant regeneration, defining characteristics of liver cirrhosis 2 . Importantly, the degree of liver fibrosis predicts adverse patient outcomes, including the development of cirrhosis-related complications, hepatocellular carcinoma and death 3 . Hence, there is a clear therapeutic imperative to develop effective anti-fibrotic approaches for patients with chronic liver disease 4-7 .Liver fibrosis involves a complex, orchestrated interplay between multiple nonparenchymal cell (NPC) lineages including immune, endothelial and mesenchymal cells spatially located within areas of scarring, termed the fibrotic niche. Despite rapid progress in our understanding of the cellular interactions underlying liver fibrogenesis accrued using rodent models, there remains a significant 'translational gap' between putative targets and effective patient therapies 4,5 . This is in part due to the very limited definition of the functional heterogeneity and interactome of cell lineages that contribute to the fibrotic niche of human liver cirrhosis, which is imperfectly recapitulated by rodent models 4,6 .Single-cell RNA sequencing (scRNA-seq) has the potential to deliver a step change in both our understanding of healthy tissue homeostasis as well as disease pathogenesis, allowing the interr...

show abstract

Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation

Cited by 75 publications

References 73 publications

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Contact Info

Product

Resources

About