Negative Transpulmonary Pressure Disrupts Airway Morphogenesis by Suppressing Fgf10

Mechanical forces are increasingly recognized as important determinants of cell and tissue phenotype and also appear to play a critical role in organ development. During the fetal stages of lung morphogenesis, the pressure of the fluid within the lumen of the airways is higher than that within the chest cavity, resulting in a positive transpulmonary pressure. Several congenital defects decrease or reverse transpulmonary pressure across the developing airways and are associated with a reduced number of branches and a correspondingly underdeveloped lung that is insufficient for gas exchange after birth. The small size of the early pseudoglandular stage lung and its relative inaccessibility in utero have precluded experimental investigation of the effects of transpulmonary pressure on early branching morphogenesis. Here, we present a simple culture model to explore the effects of negative transpulmonary pressure on development of the embryonic airways. We found that negative transpulmonary pressure decreases branching, and that it does so in part by altering the expression of fibroblast growth factor 10 (Fgf10). The morphogenesis of lungs maintained under negative transpulmonary pressure can be rescued by supplementing the culture medium with exogenous FGF10. These data suggest that Fgf10 expression is regulated by mechanical stress in the developing airways. Understanding the mechanical signaling pathways that connect transpulmonary pressure to FGF10 can lead to the establishment of novel non-surgical approaches for ameliorating congenital lung defects.

Cross-Talk Between Inflammation and Fibroblast Growth Factor 10 During Organogenesis and Pathogenesis: Lessons Learnt From the Lung and Other Organs

The adult human lung is constantly exposed to irritants like particulate matter, toxic chemical compounds, and biological agents (bacteria and viruses) present in the external environment. During breathing, these irritants travel through the bronchi and bronchioles to reach the deeper lung containing the alveoli, which constitute the minimal functional respiratory units. The local biological responses in the alveoli that follow introduction of irritants need to be tightly controlled in order to prevent a massive inflammatory response leading to loss of respiratory function. Cells, cytokines, chemokines and growth factors intervene collectively to re-establish tissue homeostasis, fight the aggression and replace the apoptotic/necrotic cells with healthy cells through proliferation and/or differentiation. Among the important growth factors at play during inflammation, members of the fibroblast growth factor (Fgf) family regulate the repair process. Fgf10 is known to be a key factor for organ morphogenesis and disease. Inflammation is influenced by Fgf10 but can also impact Fgf10 expression per se. Unfortunately, the connection between Fgf10 and inflammation in organogenesis and disease remains unclear. The aim of this review is to highlight the reported players between Fgf10 and inflammation with a focus on the lung and to propose new avenues of research.

A Mixture of Tocopherol Acetate and L-Menthol Synergistically Promotes Hair Growth in C57BL/6 Mice

Oral finasteride and topical minoxidil are single components approved by the US FDA for treating hair loss. Some other compounds originating from natural products are also traditionally used for promoting hair growth. In this study, observations of treated keratinocyte cells were used to demonstrate that tocopherol acetate, L-menthol, and stevioside exert an effect on cell regeneration. Furthermore, these were topically applied to the shaved skin of C57BL/6 mice to observe their effects on hair growth. A mixture of tocopherol acetate, L-menthol, and stevioside showed the highest potential for promoting hair growth in vivo. In in vivo experiments, the mixture of tocopherol acetate, L-menthol, and stevioside was more effective than tocopherol acetate or L-menthol alone in promoting hair growth. The transcriptome analysis of skin from the dorsal side of a mouse treated with tocopherol acetate or L-menthol versus vehicle revealed key changes in keratin, keratin-associated protein, forkhead box, sonic hedgehog, fibroblast growth factor 10, desmoglein 4, deoxyribonuclease 1-like 2, and cadherin 3, known to play roles in promoting hair growth.

Topical Application of Fibroblast Growth Factor 10-PLGA Microsphere Accelerates Wound Healing via Inhibition of ER Stress

There is a high incidence of acute and chronic skin defects caused by various reasons in clinically practice. The repair and functional reconstruction of skin defects have become a major clinical problem, which needs to be solved urgently. Previous studies have shown that fibroblast growth factor 10 (FGF10) plays a functional role in promoting the proliferation, migration, and differentiation of epithelial cells. However, little is known about the effect of FGF10 on the recovery process after skin damage. In this study, we found that the expression of endogenous FGF10 was increased during wound healing. We prepared FGF10-loaded poly(lactic-co-glycolic acid) (FGF10-PLGA) microspheres, and it could sustain release of FGF10 both in vitro and in vivo, accelerating wound healing. Further analysis revealed that compared with FGF10 alone, FGF10-PLGA microspheres significantly improved granulation formation, collagen synthesis, cell proliferation, and blood vessel density. In the meantime, we found that FGF10-PLGA microspheres inhibited the expression of endoplasmic reticulum (ER) stress markers. Notably, activating ER stress with tunicamycin (TM) reduced therapeutic effects of FGF10-PLGA microspheres in wound healing, whereas inhibition of ER stress with 4-phenyl butyric acid (4-PBA) improved the function of FGF10-PLGA microspheres. Taken together, this study indicates that FGF10-PLGA microspheres accelerate wound healing presumably through modulating ER stress.

Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

The alveolar and vascular developmental arrest in the premature infants poses a major problem in the management of these infants. Although, with the current management, the survival rate has improved in these infants, but bronchopulmonary dysplasia (BPD) is a serious complication associated with a high mortality rate. During the neonatal developmental period, these infants are vulnerable to stress. Hypoxia, hyperoxia, and ventilation injury lead to oxidative and inflammatory stress, which induce further damage in the lung alveoli and vasculature. Development of pulmonary hypertension (PH) in infants with BPD worsens the prognosis. Despite considerable progress in the management of premature infants, therapy to prevent BPD is not yet available. Animal experiments have shown deregulation of multiple signaling factors such as transforming growth factorβ (TGFβ), connective tissue growth factor (CTGF), fibroblast growth factor 10 (FGF10), vascular endothelial growth factor (VEGF), caveolin-1, wingless & Int-1 (WNT)/β-catenin, and elastin in the pathogenesis of BPD. This article reviews the signaling pathways entailed in the pathogenesis of BPD associated with PH and the possible management.

FGF10 is differentially expressed in high-grade serous ovarian cancers.

Ovarian cancer is the most lethal gynecologic cancer (1). Soluble factors are an important part of the tumor microenvironment (2). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (3, 4). We found significant differential expression of the morphogen fibroblast growth factor 10 (FGF10) in high-grade serous ovarian tumors.