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The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10) and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b), in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22) except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10's main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis.
5-aminolevulinic acid-photodynamic therapy (ALA-PDT) is known to be effective in several skin diseases such as acne, actinic keratoses, condyloma acuminata. However, some detailed mechanisms of ALA-PDT to treat these skin diseases still remain elusive. In this study, we aimed to investigate mechanism of ALA-PDT in in-vitro and in-vivo models. For in vitro, we use human keratinocyte cell line (HaCaT) cells. CCK-8 was used to detect cell proliferation activity, immunofluorescence and western blotting method to detect the content of keratin (K)1, K6, K16, protein kinase C (PKC), fibroblast growth factor receptor-2b (FGFR2b) protein, ELISA and RT-PCR to detect expression of interleukin (IL) 1α in the cell supernatant, and detect reactive oxygen species (ROS). For in vivo, we use 20 rabbits to induce hyperkeratosis acne model in their ear. Dermatoscope was used to see follicle hyperkeratosis and skin biopsy to analyze histology and immunohistochemical of PKC, FGFR2b, K1, K6 and K16. Results from this study suggest that ROS stimulated by ALA-PDT lead to inhibition of FGFR2b pathway in PKC downstream to cause reduction of IL1α expression, and eventually, keratinocytes differentiation and proliferation. Our data thus reveal a treatment mechanism of ALA-PDT underlying hyperkeratosis related dermatoses.
As an inducer of epithelial-mesenchymal transition (EMT), fibroblast growth factor-10 (FGF-10) has a role in cell proliferation and differentiation in the embryo in addition to invasion and metastasis during carcinogenesis. In this study, we aimed to investigate the FGF-10 gene expression in tumor tissues based on the pathological feature of tumor related to EMT and metastasis. 62 tumors were obtained from 62 colorectal cancer patients during surgery. The pathological characteristics of the patients were carefully collected and classified by Iran National Tumor Bank. To quantify FGF-10 gene expression, RNA extraction, reverse transcription-PCR and real-time PCR were respectively performed. In addition, three colorectal cancer cell lines including LS174T, SW-948 and SW-480 were collected and cultured for further molecular analysis. Consequently, FGF-10 gene expression showed increased expression level in LS174T and SW-948 while it displayed decreased level in SW-480. Considering the tumor samples, we found an upregulation of FGF-10 gene expression in 52.1 % of all tumors in stage III and only in 9.09 % of all tumors in stage I. Also, there were an upregulation of FGF-10 gene expression in 50 % of all positive lymph invasion patients. Besides, FGF-10 gene upregulation was observed in 50 % of all tumors with a size larger than 5 cm (P value < 0.05) and 69 % of all tumors located in the colon (P value < 0.05). To our knowledge, this is the first time that FGF-10 expression is reported based on pathological features of colorectal cancer.
FGF-10 plays an important role in development and disease, acting as the key ligand for FGFR2B to regulate cell proliferation, migration and differentiation. Aberrant FGF signalling is implicated in tumourigenesis, with several cancer studies reporting FGF-10 or FGFR2B upregulation or identifying activating mutations in Fgfr2. We used 5' RACE to identify a novel transcription start site for murine Fgf-10. Conventional in silico analysis predicted multiple binding sites for the transcription factor PEA3 upstream of this site. Binding was confirmed by chromatin immunopreciptation, and functional significance was studied by both RNAi knockdown and transient over-expression of PEA3. Knockdown of PEA3 message led to increased Fgf-10 expression, whereas overexpression of PEA3 resulted in decreased Fgf-10 expression. Thus, we have identified PEA3 as a negative regulator of Fgf-10 expression in a murine cell line and confirmed that activity also is seen in human breast cancer cell lines (MCF-7 and MDA-MB-231). Furthermore, over-expression of PEA3 in these cells resulted in impaired cell migration, which was rescued by treatment with FGF-10. Thus, PEA3 can regulate the transcription of Fgf-10 and such modulation can control breast cancer cell behaviour.
FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.
The fibroblast growth factor (FGF) family is essential to normal heart development. Yet, its contribution to cardiomyocyte differentiation from stem cells has not been systemically studied. In this study, we examined the mechanisms and characters of cardiomyocyte differentiation from FGF family protein treated embryonic stem (ES) cells and induced pluripotent stem (iPS) cells.
Hepatic ischemia-reperfusion injury (IRI) is a major complication of liver surgery and transplantation. IRI leads to hepatic parenchymal cell death, resulting in liver failure, and lacks effective therapeutic approaches. Fibroblast growth factor 10 (FGF10) is a paracrine factor which is well-characterized with respect to its pro-proliferative effects during embryonic liver development and liver regeneration, but its role in hepatic IRI remains unknown. In this study, we investigated the role of FGF10 in liver IRI and identified signaling pathways regulated by FGF10. In a mouse model of warm liver IRI, FGF10 was highly expressed during the reperfusion phase. In vitro experiments demonstrated that FGF10 was primarily secreted by hepatic stellate cells and acted on hepatocytes. The role of FGF10 in liver IRI was further examined using adeno-associated virus-mediated gene silencing and overexpression. Overexpression of FGF10 alleviated liver dysfunction, reduced necrosis and inflammation, and protected hepatocytes from apoptosis in the early acute injury phase of IRI. Furthermore, in the late phase of IRI, FGF10 overexpression also promoted hepatocyte proliferation. Meanwhile, gene silencing of FGF10 had the opposite effect. Further studies revealed that overexpression of FGF10 activated nuclear factor-erythroid 2-related factor 2 (NRF2) and decreased oxidative stress, mainly through activation of the phosphatidylinositol-3-kinase/AKT pathway, and the protective effects of FGF10 overexpression were largely abrogated in NRF2 knockout mice. These results demonstrate the protective effects of FGF10 in liver IRI, and reveal the important role of NRF2 in FGF10-mediated hepatic protection during IRI.
New neurons are generated in the postnatal rodent hypothalamus, with a subset of tanycytes in the third ventricular (3V) wall serving as neural stem/progenitor cells. However, the precise stem cell niche organization, the intermediate steps and the endogenous regulators of postnatal hypothalamic neurogenesis remain elusive. Quantitative lineage-tracing in vivo revealed that conditional deletion of fibroblast growth factor 10 (Fgf10) from Fgf10-expressing β-tanycytes at postnatal days (P)4-5 results in the generation of significantly more parenchymal cells by P28, composed mostly of ventromedial and dorsomedial neurons and some glial cells, which persist into adulthood. A closer scrutiny in vivo and ex vivo revealed that the 3V wall is not static and is amenable to cell movements. Furthermore, normally β-tanycytes give rise to parenchymal cells via an intermediate population of α-tanycytes with transient amplifying cell characteristics. Loss of Fgf10 temporarily attenuates the amplification of β-tanycytes but also appears to delay the exit of their α-tanycyte descendants from the germinal 3V wall. Our findings suggest that transience of cells through the α-tanycyte domain is a key feature, and Fgf10 is a negative regulator of postnatal hypothalamic neurogenesis.
Keratinocyte growth factor (KGF/FGF7) and fibroblast growth factor 10 (FGF10/KGF2) regulate keratinocyte proliferation and differentiation by binding to the tyrosine kinase KGF receptor (KGFR). KGF induces keratinocyte motility and cytoskeletal rearrangement, whereas a direct role of FGF10 on keratinocyte migration is not clearly established. Here we analyzed the motogenic activity of FGF10 and KGF on human keratinocytes. Migration assays and immunofluorescence of actin cytoskeleton revealed that FGF10 is less efficient than KGF in promoting migration and exerts a delayed effect in inducing lamellipodia and ruffles formation. Both growth factors promoted phosphorylation and subsequent membrane translocation of cortactin, an F-actin binding protein involved in cell migration; however, FGF10-induced cortactin phosphorylation was reduced, more transient and delayed with respect to that promoted by KGF. Cortactin phosphorylation induced by both growth factors was Src-dependent, while its membrane translocation and cell migration were blocked by either Src and PI3K inhibitors, suggesting that both pathways are involved in KGF- and FGF10-dependent motility. Furthermore, siRNA-mediated downregulation of cortactin inhibited KGF- and FGF10-induced migration. These results indicate that cortactin is involved in keratinocyte migration promoted by both KGF and FGF10.
Exposure to particulate matter (PM) is associated with increased incidence of respiratory diseases. The present study aimed to investigate the roles of fibroblast growth factor 10 (FGF10) in PM-induced lung injury. Mice were intratracheally instilled with FGF10 or phosphate-buffered saline at one hour before instillation of PM for two consecutive days. In addition, the anti-inflammatory impact of FGF10 in vitro and its effect on the high-mobility group box 1 (HMGB1)-toll-like receptor 4 (TLR4) pathway was investigated. It was found that PM exposure is associated with increased inflammatory cell infiltration into the lung and increased vascular protein leakage, while FGF10 pretreatment attenuated both of these effects. FGF10 also decreased the PM-induced expression of interleukin (IL)-6, IL-8, tumor necrosis factor-α and HMGB1 in murine bronchoalveolar lavage fluid and in the supernatants of human bronchial epithelial cells exposed to PM. FGF10 exerted anti-inflammatory and cytoprotective effects by inhibiting the HMGB1-TLR4 pathway. These results indicate that FGF10 may have therapeutic values for PM-induced lung injury.
Bronchopulmonary dysplasia (BPD) is a frequent complication of preterm birth. This chronic lung disease results from arrested saccular airway development and is most common in infants exposed to inflammatory stimuli. In experimental models, inflammation inhibits expression of fibroblast growth factor-10 (FGF-10) and impairs epithelial-mesenchymal interactions during lung development; however, the mechanisms connecting inflammatory signaling with reduced growth factor expression are not yet understood. In this study we found that soluble inflammatory mediators present in tracheal fluid from preterm infants can prevent saccular airway branching. In addition, LPS treatment led to local production of mediators that inhibited airway branching and FGF-10 expression in LPS-resistant C.C3-Tlr4(Lpsd)/J fetal mouse lung explants. Both direct NF-κB activation and inflammatory cytokines (IL-1β and TNF-α) that activate NF-κB reduced FGF-10 expression, whereas chemokines that signal via other inflammatory pathways had no effect. Mutational analysis of the FGF-10 promoter failed to identify genetic elements required for direct NF-κB-mediated FGF-10 inhibition. Instead, NF-κB activation appeared to interfere with the normal stimulation of FGF-10 expression by Sp1. Chromatin immunoprecipitation and nuclear coimmunoprecipitation studies demonstrated that the RelA subunit of NF-κB and Sp1 physically interact at the FGF-10 promoter. These findings indicate that inflammatory signaling through NF-κB disrupts the normal expression of FGF-10 in fetal lung mesenchyme by interfering with the transcriptional machinery critical for lung morphogenesis.
Renal ischemia-reperfusion (I/R) injury is a predominant cause of acute kidney injury (AKI), the pathologic mechanism of which is highly complex involving reactive oxygen species (ROS) accumulation, inflammatory response, autophagy, apoptosis as well as endoplasmic reticulum (ER) stress. Fibroblast growth factor 10 (FGF10), as a multifunctional growth factor, plays crucial roles in embryonic development, adult homeostasis, and regenerative medicine. Herein, we investigated the molecular pathways underlying the protective effect of FGF10 on renal I/R injury using Sprague-Dawley rats. Results showed that administration of FGF10 not only effectively inhibited I/R-induced activation of Caspase-3 and expression of Bax, but also alleviated I/R evoked expression of ER stress-related proteins in the kidney including CHOP, GRP78, XBP-1, and ATF-4 and ATF-6. The protective effect of FGF10 against apoptosis and ER stress was recapitulated by in vitro experiments using oxidative damaged NRK-52E cells induced by tert-Butyl hydroperoxide (TBHP). Significantly, U0126, a selective noncompetitive inhibitor of MAP kinase kinases (MKK), largely abolished the protective role of FGF10. Taken together, both in vivo and in vitro experiments indicated that FGF10 attenuates I/R-induced renal epithelial apoptosis by suppressing excessive ER stress, which is, at least partially, mediated by the activation of the MEK-ERK1/2 signaling pathway. Therefore, our present study revealed the therapeutic potential of FGF10 on renal I/R injury.
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.
The defects and imbalance in lung repair and structural maintenance contribute to the pathogenesis of chronic obstructive pulmonary diseases (COPD), yet the molecular mechanisms that regulate lung repair process are so far incompletely understood. We hypothesized that cigarette smoking causes glycocalyx impairment and endothelial apoptosis in COPD, which could be repaired by the stimulation of fibroblast growth factor 10 (FGF10)/FGF receptor 1 (FGFR1) signaling.
Ultraviolet light B (UVB) irradiation can induce skin injury and result in keratinocytes proliferation inhibition. However, the molecular understanding of the repair during UVB-induced cell proliferation inhibition remains poorly understood. The purpose of this study was to explore the role and potential mechanism of FGF10 in promoting keratinocytes cell cycle and proliferation after UVB injury.
Proliferation and transdifferentiation of lung stem cells (LSCs) could promote lung injury repair. The distal airways of the lung are innervated by the vagus nerve. Vagal-alpha7 nicotinic acetylcholine receptor (α7nAChR) signaling plays a key role in regulating lung infection and inflammation; however, whether this pathway could regulate LSCs remains unknown.
In an attempt to improve in vitro embryo production, we investigated the effect of FGF10 and 0.1 mM of cilostamide, cAMP modulator, during in vitro prematuration (PIVM) and in vitro maturation (IVM) on the developmental capacity of bovine oocytes. Five treatments (T) were used as follows: T1) IVM (control): COCs were matured for 22 h; T2) PIVM/IVM: COCs were submitted to 22 h of PIVM and 22 h of IVM; T3) PIVM + FGF10/IVM: COCs were submitted to PIVM for 22 h in the presence of FGF10 and matured for 22 h; T4) PIVM/IVM + FGF10: COCs were submitted to PIVM for 22 h and matured for 22 h in the presence of FGF10; and T5) PIVM + FGF10/IVM + FGF10: COCs were submitted to 22 h of PIVM and 22 h of IVM, both in the presence of FGF10. COCs were evaluated for CC expansion and nucleus configuration at 0 h, 22 h of PIVM and 22 h after IVM. At those time points, CCs were used for expression analysis of PTGS2, TNFAIP6, PTX3, HAS2, CASP8, CASP3, SLC2A1, SLC2A3 and FGFR2 genes. Then, embryo production was evaluated on D2 for cleavage and at D6, D7 and D8 for embryo development. Embryo quality was measured by the speed of development and by expression of KRT8, PLAC8, CD9, PAG2, PAG2, HSPB1, MSH6 genes. The percentage of COC that remained at GV after 22 h PIVM was lower (P < 0.05) in the treated group than in the control group, regardless of the addition of FGF10. Nevertheless at 22 h of maturation, none of the treatments affected the final rate of MII oocytes. No expansion of CCs was observed during the PIVM period. After 22 h of maturation expansion was similar (P > 0.05) for all groups but they all had lower expansion (P < 0.05) than control group. Except for PTGS2 and SLC2A1 which were unchanged during PIVM, all other genes changed their expression during PIVM. When we evaluated the changes in gene expression during IVM on the different groups, we noted a change in the expression of four genes (PTGS2, CASP8, PTX3 and TNFAIP6). No differences (P > 0.05) in the cleavage and blastocyst rates at D6 were observed among treatment groups. However, the blastocyst rates at D7 were lower (P < 0.05) than the control groups in which FGF10 was present either during PIVM or during IVM. When the speed of embryo development was evaluated on D7, embryos from groups PIVM-IVM and PIVM - IVM + FGF10 developed faster than the other groups. However, at D8, the hatching rate was similar (P > 0.05) for all groups. Of all the analysed genes, only PLAC8 was shown to be overexpressed in PIVM/IVM + FGF10, and MSH6 was less expressed (P < 0.05) in PIVM + FGF10/IVM + FGF10 group when compared with the control. According to these findings, the PIVM of COCs in the presence of FGF10 affected the molecular profile and the expansion of CCs without affecting the nuclear maturation and embryo production rates. Although the presence of FGF10 changed the expression of genes related to embryo quality it did not show a great impact when added either or both during PIVM and IVM.
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