scholarly journals Fgf10/Fgfr2b Signaling Orchestrates the Symphony of Molecular, Cellular, and Physical Processes Required for Harmonious Airway Branching Morphogenesis

2021 ◽  
Vol 8 ◽  
Author(s):  
Matthew R. Jones ◽  
Lei Chong ◽  
Saverio Bellusci
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Spatial Scales ◽  
Branching Morphogenesis ◽  
Physical Factors ◽  
Matrix Remodeling ◽  
Fibroblast Growth ◽  
Regulatory Pathways ◽  
Airway Branching

Airway branching morphogenesis depends on the intricate orchestration of numerous biological and physical factors connected across different spatial scales. One of the key regulatory pathways controlling airway branching is fibroblast growth factor 10 (Fgf10) signaling via its epithelial fibroblast growth factor receptor 2b (Fgfr2b). Fine reviews have been published on the molecular mechanisms, in general, involved in branching morphogenesis, including those mechanisms, in particular, connected to Fgf10/Fgfr2b signaling. However, a comprehensive review looking at all the major biological and physical factors involved in branching, at the different scales at which branching operates, and the known role of Fgf10/Fgfr2b therein, is missing. In the current review, we attempt to summarize the existing literature on airway branching morphogenesis by taking a broad approach. We focus on the biophysical and mechanical forces directly shaping epithelial bud initiation, branch elongation, and branch tip bifurcation. We then shift focus to more passive means by which branching proceeds, via extracellular matrix remodeling and the influence of the other pulmonary arborized networks: the vasculature and nerves. We end the review by briefly discussing work in computational modeling of airway branching. Throughout, we emphasize the known or speculative effects of Fgfr2b signaling at each point of discussion. It is our aim to promote an understanding of branching morphogenesis that captures the multi-scalar biological and physical nature of the phenomenon, and the interdisciplinary approach to its study.

scholarly journals Targeting fibroblast growth factor receptors to combat aggressive ependymoma

2021 ◽  
Author(s):  
Daniela Lötsch ◽  
Dominik Kirchhofer ◽  
Bernhard Englinger ◽  
Li Jiang ◽  
Konstantin Okonechnikov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Growth Factor Receptors ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Cell Models ◽  
Fibroblast Growth Factor Receptors

AbstractEpendymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

scholarly journals BASIC FIBROBLAST GROWTH FACTOR AND ADIPONECTIN IN ADOLESCENCE WITH JUVENILE IDIOPATHIC ARTHRITIS TREATED WITH METHOTREXATE

2020 ◽  
Vol 4 ◽  
pp. 70-76
Author(s):  
Liudmyla Parkhomenko ◽  
Larysa Strashok ◽  
Olga Pavlova
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Fibroblast Growth ◽  
Cellular Mechanisms ◽  
Reactive Protein ◽  
Study Results ◽  
Methotrexate Dose

Methotrexate has been applied clinically for juvenile idiopathic arthritis (JIA) treatment for decades. It is recommended for use globally, according all modern guidelines. Despite the fact that fibrosis molecular mechanisms as well as methotrexate (MTX) elimination and fibrosis indexes were studied a lot there is still not enough information for adolescence. Adiponectin, fibroblast growth factor and fibrosis indexes in adolescents with JIA treated with methotrexate were studied in this work. The aim was to study dynamics of molecular-cellular mechanisms activation of fibrotic processes development in the liver in adolescents with juvenile idiopathic arthritis treated with methotrexate. Materials and methods: A total of 68 children with juvenile idiopathic arthritis, were enrolled in the study. 25 boys (36.8 %) and 43 girls (63.2 %) were examined. Children were divided into three groups in accordance with the methotrexate dose. The following data were analyzed: ESR (mm/hour), C-reactive protein (mg/l), Hemolytic activity (CU), circulating immune complexes, (g/l), ALT (U/l), AST (U/l), Adiponectin (mcg/ml), BFGF (pg/ml), APRI index, FIB-4 Score. Results: According to our results when patients start using MTX they have significantly positive effect. Therefore, when analyzing all parameters liver pathologies may occur before MTX use. When MTX used, its proinflammation and antifibrotic effects lead to normalization of all organs and systems, as well as joints and liver. Also, long-term MTX use can lead to adverse effects. Conclusions: So, it is important to control possible liver disorders in adolescence treated with MTX. According to our study results we find out that there are decreasing of liver damage parameters in patients which started using MTX.

Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung

Development ◽  
1997 ◽  
Vol 124 (23) ◽  
pp. 4867-4878 ◽  
Author(s):  
S. Bellusci ◽  
J. Grindley ◽  
H. Emoto ◽  
N. Itoh ◽  
B.L. Hogan
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Development ◽  
Expression Patterns ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Fibroblast Growth ◽  
Embryonic Mouse ◽  
Fibroblast Growth Factor 10

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48–60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.

scholarly journals Evidence for Overlapping and Distinct Biological Activities and Transcriptional Targets Triggered by Fibroblast Growth Factor Receptor 2b Signaling between Mid- and Early Pseudoglandular Stages of Mouse Lung Development

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1274
Author(s):  
Matthew R. Jones ◽  
Arun Lingampally ◽  
Jin Wu ◽  
Jamschid Sedighi ◽  
Negah Ahmadvand ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Development ◽  
Fibroblast Growth Factor Receptor ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Branching Morphogenesis ◽  
Soluble Form ◽  
Alveolar Type ◽  
Fibroblast Growth

Branching morphogenesis is the basic developmental mode common to organs such as the lungs that undergo a process of ramification from a rudimentary tree. However, the precise molecular and cellular bases underlying the formation of branching organs are still unclear. As inactivation of fibroblast growth factor receptor 2b (Fgfr2b) signaling during early development leads to lung agenesis, thereby preventing the analysis of this pathway at later developmental stages, we used transgenic mice to induce expression of a soluble form of Fgfr2b to inactivate Fgfr2b ligands at embryonic day (E) 14.5, corresponding to the mid-pseudoglandular stage of lung development. We identified an Fgfr2b signaling signature comprised of 46 genes enriched in the epithelium, some of which were common to, but most of them distinct from, the previously identified Fgfr2b signaling signature at E12.5. Our results indicate that Fgfr2b signaling at E14.5 controls mostly proliferation and alveolar type 2 cell (AT2) differentiation. In addition, inhibition of Fgfr2b signaling at E14.5 leads to morphological and cellular impairment at E18.5, with defective alveolar lineage formation. Further studies will have to be conducted to elucidate the role of Fgfr2b signaling at successive stages (canalicular/saccular/alveolar) of lung development as well as during homeostasis and regeneration and repair after injury.

scholarly journals The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3117-3131 ◽  
Author(s):  
Marina Simian ◽  
Yohei Hirai ◽  
Marc Navre ◽  
Zena Werb ◽  
Andre Lochter ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factors ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Fibroblast Growth Factor ◽  
Mammary Epithelial Cell ◽  
Three Dimensional ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Fibroblast Growth

The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth factor 7, fibroblast growth factor 2 and hepatocyte growth factor was strongly reduced by inhibitors of MMPs, indicating the requirement of MMPs for three-dimensional growth involved in morphogenesis. Recombinant stromelysin 1/MMP3 alone was sufficient to drive branching in the absence of growth factors in the organoids. Plasmin also stimulated branching; however, plasmin-dependent branching was abolished by both inhibitors of plasmin and MMPs, suggesting that plasmin activates MMPs. To differentiate between signals for proliferation and morphogenesis, we used a cloned mammary epithelial cell line that lacks epimorphin, an essential mammary morphogen. Both epimorphin and MMPs were required for morphogenesis, but neither was required for epithelial cell proliferation. These results provide direct evidence for a crucial role of MMPs in branching in mammary epithelium and suggest that, in addition to epimorphin, MMP activity is a minimum requirement for branching morphogenesis in the mammary gland.

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