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Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

Background Temporal lobe epilepsy (TLE) is frequently associated with cognitive impairments, such as memory deficits, attention disorders, and executive dysfunction. Given that these cognitive deficits are closely linked to neuronal loss in TLE, fibroblast growth factor 10 (FGF10), a molecule recognized for its neuroprotective properties, has emerged as a promising therapeutic candidate. The kainic acid (KA)-induced epilepsy model can replicate key pathological features of TLE. The study aims to investigate the potential role of FGF10 in TLE, using the KA-induced model as an experimental framework. Methods We induced epilepsy in mice using KA and administered intranasal FGF10 over 14 days or delivered an AAV virus to overexpress FGF10. Seizure activity was monitored via video-electroencephalography (EEG), and behavioral tests were conducted to assess spatial cognition, anxiety-related behaviors, and depressive-like behaviors. Neuronal damage was evaluated using Nissl staining and TUNEL staining. To explore the molecular mechanisms underlying FGF10’s effects, we performed RNA sequencing, followed by validation with Western blotting and qRT-PCR. Additionally, we generated FGFR2 conditional knockout (cKO) mice to investigate the role of FGF10-FGFR2 signaling. Results FGF10 treatment significantly reduced seizure frequency and improved epilepsy-related cognitive deficits. It also exerted neuroprotective effects, as evidenced by reduced neuronal death in KA-induced epileptic mice. RNA sequencing revealed decreased CALB1 levels in the hippocampal dentate gyrus of epileptic mice, which were restored following FGF10 administration. Crucially, the therapeutic benefits of FGF10 were abolished in FGFR2-cKO mice, indicating that FGFR2 is essential for FGF10’s effects. Conclusions Our findings demonstrate that FGF10 alleviates seizures and cognitive dysfunction in epilepsy, likely through FGFR2-dependent mechanisms involving CALB1 modulation. These results highlight FGF10 as a potential therapeutic target for epilepsy, offering a novel strategy for improving treatment outcomes in patients with TLE.

Background Acute respiratory distress syndrome (ARDS) is a life‐threatening condition characterized by high mortality with no specific treatments. Fibroblast growth factor 10 (FGF10) is recognized for its tissue repair and anti‐inflammatory roles in injured lungs; however, its clinical relevance and mechanistic role in ARDS remain unclear. Methods Serum FGF10 levels were measured in patients with ARDS and analyzed for associations with clinical outcomes. An LPS‐induced mouse model of acute lung injury (ALI) was used to evaluate the effects of FGF10 treatment in vivo. Single‐cell RNA sequencing of lineage‐traced alveolar epithelial cells (AECs) was performed to identify transcriptional changes following FGF10 administration. In vitro co‐culture systems involving macrophages or neutrophils with AECs were established to investigate immune cell‐specific mechanisms. Results We found that serum FGF10 levels were significantly reduced in ARDS patients, and this reduction correlated with poor prognosis. Moreover, FGF10 treatment alleviated lung inflammation by decreasing inflammatory cell infiltration and pro‐inflammatory cytokine release in mice. Leveraging single‐cell RNA sequencing of lineage tracing alveolar epithelial cells (AECs), we identified that the mRNA expression of Ripk1, Casp8, and Casp3 were decreased after FGF10 treatment. In in vitro co‐culture experiments, we noticed that FGF10 did not inhibit macrophage pyroptosis. Instead, FGF10 effectively blocked the downstream RIPK1/caspase‐8/caspase‐3/gasdermin E (GSDME) signaling pathway in AECs. Additionally, FGF10 suppressed AMP‐activated protein kinase (AMPK) activation by modulating ATP production, thereby preventing RIPK1 cleavage. Conclusion FGF10 alleviates acute lung injury by inhibiting AMPK‐RIPK1/caspase‐8/caspase‐3/GSDME‐mediated pyroptosis in AECs primed by distinct immune cell populations, supporting its potential as a therapeutic strategy for ARDS. Key points Our study reveals a marked decrease of serum FGF10 levels in ARDS patients, correlating with P/F ratio, hospitalisation days and mortality rates. We clarify how FGF10 prevents AECs' pyroptosis triggered by different immune cell infiltrations in different ways. FGF10 restored ATP levels to attenuate RIPK1 phosphorylation via AMPK to disrupt pyroptosis in the AECs. Our study reveals a marked decrease of serum FGF10 levels in ARDS patients, correlating with P/F ratio, hospitalisation days and mortality rates. We clarify how FGF10 prevents AECs' pyroptosis triggered by different immune cell infiltrations in different ways. FGF10 restored ATP levels to attenuate RIPK1 phosphorylation via AMPK to disrupt pyroptosis in the AECs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced fibrotic stages are significant contributors to cirrhosis and liver-related mortality, yet no therapies directly target fibrosis in the later stages of the disease. Fibroblast growth factor 10 (FGF10) facilitates epithelial repair, yet its function and epithelial receptor requirements in chronic liver fibrogenesis are unclear. We quantified hepatic FGF10 and fibroblast growth factor receptor 2 (FGFR2) expression across fibrosis stages in biopsies from patients with MASLD and mouse models. We then augmented hepatic FGF10 using adeno-associated virus-mediated liver expression or subcutaneous recombinant human FGF10 in carbon tetrachloride (CCl ) and high-fat diet plus CCl -induced advanced fibrosis. Histology, immunohistochemistry, biochemistry, RNA sequencing and primary hepatocytes and hepatic stellate cells (HSCs) assays were used to assess the therapeutic effects and underlying mechanisms. Hepatic FGF10 and FGFR2 protein expression were significantly reduced at advanced disease stages. Restoring FGF10 led to regression-associated remodelling of established bridging fibrosis, a decrease in inflammatory cytokines and a reduction in hepatocyte apoptosis, even with continued CCl exposure, indicating histologic regression rather than slowed progression. These therapeutic effects required hepatocyte FGFR2, as hepatocyte-specific FGFR2 deletion abolished protection and the associated transcriptional reprogramming of matrix and cytokine networks. In primary hepatocytes, FGF10 activated FGFR2-FGFR substrate 2α (‌FRS2α) signalling, increased inhibitory phosphorylation of glycogen synthase kinase 3β at Ser9 and suppressed nuclear factor kappa B, thereby lowering transforming growth factor β1 and other cytokines and indirectly limiting HSC activation. The efficacy extended to a high-fat diet plus CCl model of steatohepatitis. These findings elucidate a hepatocyte-centric FGF10-FGFR2 axis functioning as an epithelial regulator of inflammation and fibrogenesis. Hepatocyte-targeted reinforcement of FGFR2 signalling, alone or combined with metabolic therapies, represents a translational strategy to reprogram the fibrotic niche and facilitate fibrosis regression-associated architectural remodelling in advanced liver fibrosis. Hepatic FGF10 and FGFR2 decline consistently with fibrosis stage in patient liver biopsies and complementary mouse models. Restoring FGF10 through AAV-Fgf10 or recombinant FGF10 reduces hepatocyte apoptosis, inflammation and extracellular matrix deposition. Hepatocyte FGFR2 is required for FGF10-mediated antifibrotic effects and drives transcriptional reprogramming that limits fibrogenesis.

Pancreatic cancer has one of the highest mortalities among all malignancies and there is an urgent need for new therapy. This might be achieved by resolving the detailed biological mechanism, and in this study we examined how pancreatic cancer cells develop aggressive properties by focusing on signalling through the fibroblast growth factor (FGF)10 and FGF receptor (FGFR)2, which play important roles in pancreatic organogenesis. Immunostaining of pancreatic cancer tissues showed that FGFR2 was expressed in cancer cells, whereas FGF10 was expressed in stromal cells surrounding the cancer cells. Patients with high FGFR2 expression in cancer cells had a shorter survival time compared to those with low FGFR2 expression. Fibroblast growth factor 10 induced cell migration and invasion of CFPAC-1 and AsPC-1 pancreatic cancer cells through interaction with FGFR2-IIIb, a specific isoform of FGFR2. Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)- β 1, and increased secretion of TGF- β 1 protein from these cell lines. These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis. This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1 / 2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10 , a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis. Double conditional knockout of Meis1/2 in the limb forming region of mouse embryos results in the complete absence of limb, while embryos developed with one functional Meis allele, so identifying the role of Meis in antero-posterior and proximo-distal patterning.

Abstract Fibroblast growth factor-10 (FGF10) is a mesenchymal growth factor, involved in epithelial and mesenchymal interactions during lung branching morphogenesis. In the present work, FGF10 overexpression was transiently induced in a temporally and spatially restricted manner, during the pseudoglandular or canalicular stages of rat lung development, by trans-uterine ultrasound-guided intraparenchymal microinjections of adenoviral vector encoding the rfgf10 transgene. The morphologic and histologic classification of the resulting malformations were dependent upon developmental stage and location. Overexpression of FGF10 restricted to the proximal tracheobronchial tree during the pseudoglandular phase resulted in large cysts lined by tall columnar epithelium composed primarily of Clara cells with a paucity of Type II pneumocytes, resembling bronchiolar type epithelium. In contrast, FGF10 overexpression in the distal lung parenchyma during the canalicular phase resulted in small cysts lined by cuboidal epithelial cells composed of primarily Type II pneumocytes resembling acinar epithelial differentiation. The cystic malformations induced by FGF10 overexpression appear to closely recapitulate the morphology and histology of the spectrum of human congenital cystic adenomatoid malformation (CCAM). These findings support a role for FGF10 in the induction of human CCAM and provide further mechanistic insight into the role of FGF10 in normal and abnormal lung development.

We have previously demonstrated that tooth size is determined by dental mesenchymal factors. Exogenous bone morphogenetic protein (BMP)4, Noggin, fibroblast growth factor (FGF)3 and FGF10 have no effect on tooth size, despite the expressions of Bmp2, Bmp4, Fgf3, Fgf10 and Lef1 in the dental mesenchyme. Among the wingless (Wnt) genes that are differentially expressed during tooth development, only Wnt5a is expressed in the dental mesenchyme. The aims of the present study were to clarify the expression pattern of Wnt5a in developing tooth germs and the role of Wnt5a in the regulation of tooth size by treatment with exogenous WNT5A with/without an apoptosis inhibitor on in vitro tooth germs combined with transplantation into kidney capsules. Wnt5a was intensely expressed in both the dental epithelium and mesenchyme during embryonic days 14–17, overlapping partly with the expressions of both Shh and Bmp4. Moreover, WNT5A retarded the development of tooth germs by markedly inducing cell death in the non-dental epithelium and mesenchyme but not widely in the dental region, where the epithelial–mesenchymal gene interactions among Wnt5a, Fgf10, Bmp4 and Shh might partly rescue the cells from death in the WNT5A-treated tooth germ. Together, these results indicate that WNT5A-induced cell death inhibited the overall development of the tooth germ, resulting in smaller teeth with blunter cusps after tooth-germ transplantation. Thus, it is suggested that Wnt5a is involved in regulating cell death in non-dental regions, while in the dental region it acts as a regulator of other genes that rescue tooth germs from cell death.

Folding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we show in mice that combining the Flrt1/3 double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 leads to a relative increase in Flrt-mutant neurons resulting in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 leads to a relative reduction in Flrt-mutant neurons resulting in enhanced formation of gyri. These results together with computational modeling identify key developmental mechanisms, such as adhesive properties, cell densities and migration of cortical neurons, that cooperate to promote cortical gyrification. The complex processes guiding mammalian cortical folding are incompletely understood. Here authors report that cortical folding was enhanced in mice by combining mutations affecting neuron adhesion and progenitor expansion, producing both sulci and gyri.

Sorcin, a key calcium-sensing protein, regulates calcium concentration within the endoplasmic reticulum (ER), promoting apoptosis resistance and ER stress. It also modulates downstream signaling pathways of the epidermal growth factor receptor (EGFR), influencing cellular migration and invasion in non-small-cell lung carcinoma (NSCLC) cell lines. For this purpose, this study investigates the relationship between Sorcin and EGFR expression during lung development at the physiological level. Our study was conducted on WT and Sorcin Knock-out ( Sri −/− ) mice, where we performed various analyses, including histological examination, gene and protein expression analysis, and confocal microscopy. Our findings reveal that Sri −/− mice, compared to wild-type controls, exhibit: (1) impaired alveolarization and abnormal development of bronchi and bronchioles, as observed in histological sections; (2) decreased expression of genes encoding branching morphogenesis markers (e.g., Fgf10 ) and surfactant proteins (e.g., Sp-b , Sp-c and Abca3 ), as shown by real-time PCR; (3) increased glycogen content decreased lipid droplets, indicative of type II pneumocyte immaturity and impaired surfactant lipid production; (4) reduced levels of EGFR, RAS and RAB5C proteins, consistent with defects in lung maturation and surfactant protein recycling, as demonstrated by Western blot analysis; and (5) increased expression of phalloidin, α-smooth muscle actin and vimentin, suggesting increased bronchial thickening associated with airway tissue remodeling. Collectively, these data reveal a novel role for Sorcin in lung alveolarization, pulmonary surfactant production, and airway remodeling associated with bronchial contractility, supporting its involvement in respiratory diseases such as respiratory distress syndrome (RDS), asthma and chronic obstructive pulmonary disease (COPD).