Fibroblast Growth Factor Signaling Research Articles

Common modes of ERK induction resolve into context-specific signalling via emergent networks and cell-type-specific transcriptional repression.

Fibroblast Growth Factor signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling we generated cell and mouse lines that allow for tissue- and time-specific ERK activation. Using these tools, we find that specificity in ERK response is mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but produce cell-specific programmes as these responses interface with emergent networks in the responding cells. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context does not shape signalling response. Altogether, our data suggest that cell-type-specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programmes.

Low-Energy extracorporeal shockwave therapy improves locomotor functions, tissue regeneration and modulating the inflammation induced FGF1 and FGF2 signaling to protect damaged tissue in spinal cord injury of rat model: An experimental animal study.

Spinal cord injury (SCI) is a debilitating condition that results in severe motor function impairments. Current therapeutic options remain limited, underscoring the need for novel treatments. Extracorporeal shockwave therapy (ESWT) has emerged as a promising noninvasive approach for treating musculoskeletal disorders and nerve regeneration. This study explored the effects of low-energy ESWT on locomotor function, tissue regeneration, inflammation, and mitochondrial function in a rat SCI model. Experiments were performed using locomotor function assays, CatWalk gait analysis, histopathological examination, immunohistochemical and immunofluorescence staining. The findings demonstrated that low-energy ESWT had a dose-dependent effect, with three treatment sessions (ESWT3) showing superior outcomes compared to a single session. ESWT3 significantly improved motor functions (run patterns, run average speed, and maximum variation, as well as the Basso, Beattie, and Bresnahan (BBB) score) and promoted tissue regeneration while reducing inflammation. ESWT3 significantly decreased levels of IL-1β, IL6 and macrophages (CD68) while increasing leucocyte (CD45) infiltration. Additionally, ESWT3 upregulated NueN and mitofusin 2 (MFN2), suggesting enhanced neuronal health and mitochondrial function. Moreover, ESWT3 modulated the expression of fibroblast growth factor 1 (FGF1), FGF2, their receptor FGFR1 and phosphorylation of ERK, aiding tissue repair and regeneration in SCI. This study highlights the potential of low-energy ESWT as an effective noninvasive treatment for SCI, demonstrating significant improvements in motor recovery, tissue regeneration, anti-inflammatory effects, and mitochondrial protection. These findings provide valuable insights into the mechanisms of ESWT and its therapeutic application for SCI recovery.

Enhanced Age-Dependent Motor Impairment in Males of Drosophila melanogaster Modeling Spinocerebellar Ataxia Type 1 Is Linked to Dysregulation of a Matrix Metalloproteinase

Over the past two decades, Drosophila melanogaster has proven to be successful in modeling the polyglutamine (polyQ) (caused by CAG repeats) family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as polyQ length-dependent formation of protein aggregates and progressive neuronal degeneration. In this study, pan-neuronal expression of human Ataxin-1 with long polyQ repeat of 82 amino acids was driven using an elav-GAL4 driver line. This would essentially model the polyQ disease spinocerebellar ataxia type 1 (SCA1). Longevity and behavioral analysis of male flies expressing human Ataxin-1 revealed compromised lifespan and accelerated locomotor activity deficits both in diurnal activity and negative geotaxis response compared to control flies. Interestingly, this decline in motor response was coupled to an enhancement of matrix metalloproteinase 1 (dMMP1) expression together with declining expression of extracellular matrix (ECM) fibroblast growth factor (FGF) signaling by hedgehog (Hh) and branchless (bnl) and a significant decrease in expression of survival motor neuron gene (dsmn) in old (30 d) flies. Taken together, our results indicate a role for dysregulation of matrix metalloproteinase in polyQ disease with consequent impact on ECM signaling factors, as well as SMN at the neuromuscular junction causing overt physiological and behavioral deficits.

Shc1 cooperates with Frs2 and Shp2 to recruit Grb2 in FGF-induced lens development.

Fibroblast growth factor (FGF) signaling elicits multiple downstream pathways, most notably the Ras/MAPK cascade facilitated by the adaptor protein Grb2. However, the mechanism by which Grb2 is recruited to the FGF signaling complex remains unresolved. Here we showed that genetic ablation of FGF signaling prevented lens induction by disrupting transcriptional regulation and actin cytoskeletal arrangements, which could be reproduced by deleting the juxtamembrane region of the FGF receptor and rescued by Kras activation. Conversely, mutations affecting the Frs2-binding site on the FGF receptor or the deletion of Frs2 and Shp2 primarily impact later stages of lens vesicle development involving lens fiber cell differentiation. Our study further revealed that the loss of Grb2 abolished MAPK signaling, resulting in a profound arrest of lens development. However, disrupting the Grb2 binding site on Shp2 or abrogating Shp2 phosphatase activity only modestly influenced FGF signaling, whereas mutating the presumed Shp2 dephosphorylation site on Grb2 did not impede MAPK signaling in lens development, indicating that Shp2 is only partially responsible for Grb2 recruitment. In contrast, we observed that FGF signaling is required for the phosphorylation of the Grb2-binding sites on Shc1 and the deletion of Shc1 exacerbates the lens vesicle defect caused by Frs2 and Shp2 deletion. These results reveal that Shc1 collaborates with Frs2 and Shp2 to target Grb2 in FGF signaling.

Deleting fibroblast growth factor 2 in macrophages aggravates septic acute lung injury by increasing M1 polarization and inflammatory cytokine secretion.

Septic lung injury is strongly associated with polarization of M1 macrophages and excessive cytokine release. Fibroblast growth factor (FGF) signaling plays a role in both processes. However, the impact of FGF2 deficiency on macrophage polarization and septic acute lung injury remains unclear. To investigate this, we obtained macrophages from FGF2 knockout mice and examined their polarization and inflammatory cytokine expression. We also eliminated endogenous macrophages using clodronate liposomes and administered FGF2 knockout or WT macrophages intravenously in conjunction with cecal ligation and puncture (CLP) surgery to induce sepsis. In vitro analysis by flow cytometry and real-time PCR analysis demonstrated that FGF2 deficiency resulted in increased expression of M1 markers (iNOS and CD86) and inflammatory cytokines (CXCL1, IL1β, and IL6), especially after LPS stimulation. Additionally, immunofluorescence demonstrated increased nuclear translocation of p65 NF-κB in FGF2 knockout macrophages and RNA-seq analysis showed enrichment of differentially expressed genes in the IL17 and TNFα inflammatory signaling pathways. Furthermore, in vivo experiments revealed that depletion of FGF2 in macrophages worsened sepsis-induced lung inflammation, lung vascular leak, and lung histological injury, accompanied by an increase in CD86-positive cells and apoptosis. Our study suggests that FGF2 deficiency in macrophages plays a critical role in the pathogenesis of septic ALI, possibly because of the enhanced M1 macrophage polarization and production of proinflammatory cytokines. These findings provide empirical evidence for potential therapeutic interventions targeting FGF2 signaling to modulate the polarization of M1 and M2 macrophages in the management of sepsis-induced acute lung injury.

TNFα has differential effects on the transcriptome profile of selected populations in murine cartilage

ObjectiveTo further our understanding of the role of tumor necrosis factor (TNF)α on the inflammatory response in chondrocytes. DesignWe explored the effects of TNFα on the transcriptome of epiphyseal chondrocytes from newborn C57BL/6 mice at the total and single cell (sc) resolution. ResultsGene set enrichment analysis of total RNA-Seq from TNFα-treated chondrocytes revealed enhanced response to biotic stimulus, defense and immune response and cytokine signaling and suppressed cartilage and skeletal morphogenesis and development. scRNA-Seq analyzed 14,239 ​cells and 24,320 genes and distinguished 16 ​cell clusters. The more prevalent ones were constituted by limb bud and chondrogenic cells and fibroblasts comprising ∼73 ​% of the cell population. Genes expressed by joint fibroblasts were detected in 5 clusters comprising ∼45 ​% of the cells isolated. Pseudotime trajectory finding revealed an association between fibroblast and chondrogenic clusters which was not modified by TNFα. TNFα decreased the total cells recovered by 18.5 ​% and the chondrogenic, limb bud and mesenchymal clusters by 32 ​%, 27 ​% and 7 ​%, respectively. TNFα had profound effects on the insulin-like growth factor (IGF) axis decreasing Igf1, Igf2 and Igfbp4 and inducing Igfbp3 and Igfbp5, explaining an inhibition of collagen biosynthesis, cartilage and skeletal morphogenesis. Ingenuity Pathway Analysis of scRNA-Seq data revealed that TNFα enhanced the osteoarthritis, rheumatoid arthritis, pathogen induced cytokine storm and interleukin 6 signaling pathways and suppressed fibroblast growth factor signaling. ConclusionsEpiphyseal chondrocytes are constituted by diverse cell populations distinctly regulated by TNFα to promote inflammation and suppression of matrix biosynthesis and growth.

7434 Modulation of FGFR-FGF2-FGF23 Signaling Partially Rescues Osteoarthritis in Hyp Mice Homolog of Human X- Linked Hypophosphatemia

Abstract Disclosure: M.M. Hurley: None. L. Xiao: None. Human with X-linked hypophosphatemia (XLH) and its Hyp mice homolog develop several phenotypic abnormalities due to phosphate wasting mediated by abnormal Fibroblast Growth Factor Receptor-1 (FGFR1) and Fibroblast Growth Factor 23 (FGF23) signaling. XLH and Hyp mice also develop severe osteoarthropathy (OA) whose etiology is not fully defined. We previously reported that Fibroblast growth factor 2 (FGF2) regulates FGF23, specifically, mice overexpressing the high molecular weight FGF2 isoforms (HMWFGF2) in osteoprogenitors phenocopy Hyp mice including development of OA that worsens with age. Since we also reported that Hyp mice overexpress HMWFGF2 isoforms in osteoblasts and osteocytes, we examined whether the knee OA phenotype in Hyp mice was associated with aberrant FGFR1, FGF2, FGF23 signaling in knee joint articular cartilage and subchondral bone and whether in vivo FGFR tyrosine kinase inhibitor BGJ398 would modulate the OA phenotype in knee joints of Hyp mice. Ten weeks-old Control and Hyp mice were treated with Vehicle or BGJ398 for 12 weeks. Safranin-O staining of knee articular cartilage for proteoglycan revealed decreased staining in Hyp vehicle-treated mice that was partially restored to the cartilage thickness of Control mice in the Hyp-BGJ398-treated group. Significantly increased degradative enzyme matrix metalloproteinase-13 (MMP-13) in Hyp vehicle-treated knee articular cartilage was significantly reduced by BGJ398. Immunostaining revealed significantly increased phosphorylated FGFR1, FGF2 and FGF23 in both articular cartilage and subchondral bone. While BGJ398 significantly reduced immunostaining for phosphoFGFR1 and FGF2 in both articular cartilage and subchondral bone, it significantly reduced FGF23 in subchondral bone but not in articular cartilage. Significantly increased phospho-ERK1/2 labeling in Hyp-vehicle treated articular cartilage was partially rescued by BGJ398. This study demonstrates that increased FGFR1/FGF2 signaling contributes to OA in Hyp mice that can be partially rescued by FGF receptor inhibitor via reduction in MAPK signaling. Presentation: 6/1/2024

Cleft Palate Induced by Augmented Fibroblast Growth Factor-9 Signaling in Cranial Neural Crest Cells in Mice.

Although enhanced fibroblast growth factor (FGF) signaling has been demonstrated to be crucial in many cases of syndromic cleft palate caused by tongue malposition in humans, animal models that recapitulate this phenotype are limited, and the precise mechanisms remain elusive. Mutations in FGF9 with the effect of either loss- or gain-of-function effects have been identified to be associated with cleft palate in humans. Here, we generated a mouse model with a transgenic Fgf9 allele specifically activated in cranial neural crest cells, aiming to elucidate the gain-of-function effects of Fgf9 in palatogenesis. We observed cleft palate with 100% penetrance in mutant mice. Further analysis demonstrated that no inherent defects in the morphogenic competence of palatal shelves could be found, but a passively lifted tongue prevented the elevation of palatal shelves, leading to the cleft palate. This tongue malposition was induced by posterior spatial confinement that was exerted by temporomandibular joint (TMJ) dysplasia characterized by a reduction in Sox9+ progenitors within the condyle and a structural decrease in the posterior dimension of the lower jaw. Our findings highlight the critical role of excessive FGF signaling in disrupting spatial coordination during palate development and suggest a potential association between palatal shelf elevation and early TMJ development.

Regulation of Skeletal Development and Maintenance by Runx2 and Sp7.

Runx2 (runt related transcription factor 2) and Sp7 (Sp7 transcription factor 7) are crucial transcription factors for bone development. The cotranscription factor Cbfb (core binding factor beta), which enhances the DNA-binding capacity of Runx2 and stabilizes the Runx2 protein, is necessary for bone development. Runx2 is essential for chondrocyte maturation, and Sp7 is partly involved. Runx2 induces the commitment of multipotent mesenchymal cells to osteoblast lineage cells and enhances the proliferation of osteoprogenitors. Reciprocal regulation between Runx2 and the Hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathways and Dlx5 (distal-less homeobox 5) plays an important role in these processes. The induction of Fgfr2 (Fgf receptor 2) and Fgfr3 expression by Runx2 is important for the proliferation of osteoblast lineage cells. Runx2 induces Sp7 expression, and Runx2+ osteoprogenitors become Runx2+Sp7+ preosteoblasts. Sp7 induces the differentiation of preosteoblasts into osteoblasts without enhancing their proliferation. In osteoblasts, Runx2 is required for bone formation by inducing the expression of major bone matrix protein genes, including Col1a1 (collagen type I alpha 1), Col1a2, Spp1 (secreted phosphoprotein 1), Ibsp (integrin binding sialoprotein), and Bglap (bone gamma carboxyglutamate protein)/Bglap2. Bglap/Bglap2 (osteocalcin) regulates the alignment of apatite crystals parallel to collagen fibrils but does not function as a hormone that regulates glucose metabolism, testosterone synthesis, and muscle mass. Sp7 is also involved in Co1a1 expression and regulates osteoblast/osteocyte process formation, which is necessary for the survival of osteocytes and the prevention of cortical porosity. SP7 mutations cause osteogenesis imperfecta in rare cases. Runx2 is an important pathogenic factor, while Runx1, Runx3, and Cbfb are protective factors in osteoarthritis development.

A polarized FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids

Organoids generating major cortical cell types in distinct compartments are used to study cortical development, evolution and disorders. However, the lack of morphogen gradients imparting cortical positional information and topography in current systems hinders the investigation of complex phenotypes. Here, we engineer human cortical assembloids by fusing an organizer-like structure expressing fibroblast growth factor 8 (FGF8) with an elongated organoid to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. These polarized cortical assembloids mount a position-dependent transcriptional program that in part matches the in vivo rostrocaudal gene expression patterns and that is lost upon mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability. By producing spatially oriented cell populations with signatures related to frontal and temporal area identity within individual assembloids, this model recapitulates in part the early transcriptional divergence embedded in the protomap and enables the study of cortical area-relevant alterations underlying human disorders.

SIK2: A Novel Negative Feedback Regulator of FGF2 Signaling.

A wide range of cells respond to fibroblast growth factor 2 (FGF2) by proliferation via activation of the Ras/ERK1/2 pathway. In this study, the potential involvement of salt inducible kinase SIK2)in this cascade within retinal Müller glia is explored. It is found that SIK2 phosphorylation status and activity are modulated in an FGF2-dependent manner, possibly via ERK1/2. With SIK2 downregulation, enhanced ERK1/2 activation with delayed attenuation and increased cell proliferation is observed, while SIK2 overexpression hampers FGF2-dependent ERK1/2 activation. In vitro kinase and site-directed mutagenesis studies indicate that SIK2 targets the pathway element GRB2-associated-binding protein 1 (Gab1) on Ser266. This phosphorylation event weakens Gab1 interactions with its partners growth factor receptor-bound protein 2 (Grb2) and Src homology region 2 domain containing phosphatase 2 (Shp2). Collectively, these results suggest that during FGF2-dependent proliferation process ERK1/2-mediated activation of SIK2 targets Gab1, resulting in downregulation of the Ras/ERK1/2 cascade in a feedback loop.

Spatial Transcriptomics Analysis: Maternal Obesity Impairs Myogenic Cell Migration and Differentiation during Embryonic Limb Development.

Limb muscle is responsible for physical activities and myogenic cell migration during embryogenesis is indispensable for limb muscle formation. Maternal obesity (MO) impairs prenatal skeletal muscle development, but the effects of MO on myogenic cell migration remain to be examined. C57BL/6 mice embryos were collected at E13.5. The GeoMx DSP platform was used to customize five regions along myogenic cell migration routes (myotome, dorsal/ventral limb, limb stroma, limb tip), and data were analyzed by GeomxTools 3.6.0. A total of 2224 genes were down-regulated in the MO group. The GO enrichment analysis showed that MO inhibited migration-related biological processes. The signaling pathways guiding myogenic migration such as hepatocyte growth factor signaling, fibroblast growth factor signaling, Wnt signaling and GTPase signaling were down-regulated in the MO E13.5 limb tip. Correspondingly, the expression levels of genes involved in myogenic cell migration, such as Pax3, Gab1, Pxn, Tln2 and Arpc, were decreased in the MO group, especially in the dorsal and ventral sides of the limb. Additionally, myogenic differentiation-related genes were down-regulated in the MO limb. MO impedes myogenic cell migration and differentiation in the embryonic limb, providing an explanation for the impairment of fetal muscle development and offspring muscle function due to MO.

Fibroblast growth factor 8 promotes in vitro neurite outgrowth of placode-derived petrosal and nodose ganglia to varying degrees

Fibroblast growth factors (FGFs) are required for the specification and formation of the epibranchial placodes, which give rise to the distal part of the cranial sensory ganglia. However, it remains unclear whether FGFs play a role in regulating the neurite outgrowth of the epibranchial placode-derived ganglia during further development. Previous studies have shown that Fibroblast growth factor 8 (FGF8) promotes neurite outgrowth from the statoacoustic ganglion in vitro. However, these studies did not distinguish between the neural crest- and placode-derived components of the sensory ganglia. In this study, we focused on the petrosal and nodose ganglia as representatives of the epibranchial ganglia and investigated their axonal outgrowth under the influence of FGF8 signaling protein in vitro. To precisely isolate the placode-derived ganglion part, we labeled the placode and its derivatives with enhanced green fluorescent protein (EGFP) through electroporation. The isolated ganglia were then collected for qRT-PCR assay and cultured in a collagen gel with and without FGF8 protein. Our findings revealed that both placode-derived petrosal and nodose ganglia expressed FGFR1 and FGFR2. In culture, FGF8 exerted a neural trophic effect on the axon outgrowth of both ganglia. While the expression levels of FGFR1/2 were similar between the two ganglia, the petrosal ganglion exhibited greater sensitivity to FGF8 compared to the nodose ganglion. This indicates that the placode-derived ganglia have differential responsiveness to FGF8 signaling during axonal extension. Thus, FGF8 is not only required for the early development of the epibranchial placode, as shown in previous studies, but also promotes neurite outgrowth of placode-derived ganglia.

Neuritin Controls Axonal Branching in Serotonin Neurons: A Possible Mediator Involved in the Regulation of Depressive and Anxiety Behaviors via FGF Signaling.

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.

Research progress of fibroblast growth factors

Objective: To review the structure, distribution, and biological functions of Fibroblast Growth Factor (FGF) and its role in promoting the survival, growth, repair, and regeneration of neurons. Methods: We examines a wide range of studies on the FGF family, including its molecular characteristics, gene expression, and biological activities. Relative literature are collected and summarized to elucidate the structural differences among FGF members and their specific roles in various physiological processes. Results: The FGF family, comprising 23 members, regulates essential cellular processes such as growth, survival, differentiation, and migration. Key discoveries include the purification of FGF-2 and its recombinant expression, the identification of FGF receptors, and their signaling pathways. FGF-1 and FGF-2 are noted for their roles in promoting neurite growth and neuronal survival, while FGF-3 aids in neurogenesis and axonogenesis. FGF-10 and FGF-22 are pivotal in axonal regeneration and functional recovery post-injury. The significance of FGFRs in FGF signaling is emphasized, particularly the involvement of FGF-2 in the protein kinase pathway. These findings underscore the crucial role of FGFs in the nervous system, highlighting their therapeutic potential for neural injuries and neurodegenerative diseases. Conclusions: The FGF family plays a critical role in the nervous system, particularly in neuron survival, growth, and regeneration. The diverse functions of FGFs are mediated through their specific receptors and complex signaling pathways, offering potential therapeutic targets for neural injuries and neurodegenerative diseases. Further research into the molecular mechanisms of FGFs could lead to advanced treatments for a variety of neurological conditions.

Phospholipase Cγ regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism.

Although the regulation of branching morphogenesis by spatially distributed cues is well established, the role of intracellular signaling in determining the branching pattern remains poorly understood. In this study, we investigated the regulation and function of phospholipase C gamma (PLCγ) in Fibroblast Growth Factor (FGF) signaling in lacrimal gland development. We showed that deletion of PLCγ1 in the lacrimal gland epithelium leads to ectopic branching and acinar hyperplasia, which was phenocopied by either mutating the PLCγ1 binding site on Fgfr2 or disabling any of its SH2 domains. PLCγ1 inactivation did not change the level of Fgfr2 or affect MAPK signaling, but instead led to sustained AKT phosphorylation due to increased PIP3 production. Consistent with this, PLCγ1 mutant phenotype can be reproduced by elevation of PI3K signaling in Pten knockout and attenuated by blocking AKT signaling. This study demonstrated that PLCγ modulates PI3K signaling by shifting phosphoinositide metabolism, revealing an important role of signaling dynamics in conjunction with spatial cues in shaping branching morphogenesis.

Gene expression differences associated with intrinsic hindfoot muscle loss in the jerboa, Jaculus jaculus.

Vertebrate animals that run or jump across sparsely vegetated habitats, such as horses and jerboas, have reduced the number of distal limb bones, and many have lost most or all distal limb muscle. We previously showed that nascent muscles are present in the jerboa hindfoot at birth and that these myofibers are rapidly and completely lost soon after by a process that shares features with pathological skeletal muscle atrophy. Here, we apply an intra- and interspecies differential RNA-Seq approach, comparing jerboa and mouse muscles, to identify gene expression differences associated with the initiation and progression of jerboa hindfoot muscle loss. We show evidence for reduced hepatocyte growth factor and fibroblast growth factor signaling and an imbalance in nitric oxide signaling; all are pathways that are necessary for skeletal muscle development and regeneration. We also find evidence for phagosome formation, which hints at how myofibers may be removed by autophagy or by nonprofessional phagocytes without evidence for cell death or immune cell activation. Last, we show significant overlap between genes associated with jerboa hindfoot muscle loss and genes that are differentially expressed in a variety of human muscle pathologies and rodent models of muscle loss disorders. All together, these data provide molecular insight into the process of evolutionary and developmental muscle loss in jerboa hindfeet.

Role of Rhodomyrtus tomentosa (Aiton) Hassk. in regulating the expression of fibroblast growth factor family in the liver of rat in a breast cancer model

Context: Cellular abnormalities in the ducts and breast tissue cause breast cancer to invade nearby tissues like the liver. The fibroblast growth factor (FGF) signals are sent to its receptor and regulate various cellular processes to maintain liver homeostasis. However, this condition has few and inefficient treatments. Breast cancer is characterized by the development of cellular abnormalities within the ducts and breast tissue, leading to the invasion of adjacent tissues, such as the liver. Aims: To examine the impact of Rhodomyrtus tomentosa administration on the expression of the FGF family in cancer animal models, with a specific focus on the liver. Methods: Cancer model rats were administered at dosages of 100, 200, and 300 mg/kg BW for 30 days. Liver tissue and blood serum samples were extracted from the rat. Liver tissue was stained for immunohistochemistry using FGF1, FGF15, FGF19, and FGF21, and blood samples were collected for ELISA analysis. Results: The study found that DMBA in hepatocyte cells degrades parenchyma, making it hydrophilic and necrosating. Hepatocyte cell function improved with the greatest dose of R. tomentosa. The elevation was associated with an area around the portal vein where recently dividing hepatocytes form clusters. Conclusions: The promise of R. tomentosa as a candidate for the development of hepatoprotective medicines in cancer treatment arises from its ability to influence the expression of crucial liver health markers, including FGF1, FGF15, FGF19, and FGF21.

Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases.

Fibroblast growth factors (FGFs) are a versatile family of peptide growth factors that are involved in various biological functions, including cell growth and differentiation, embryonic development, angiogenesis, and metabolism. Abnormal FGF/FGF receptor (FGFR) signaling has been implicated in the pathogenesis of multiple diseases such as cancer, metabolic diseases, and inflammatory diseases. It is worth noting that macrophage polarization, which involves distinct functional phenotypes, plays a crucial role in tissue repair, homeostasis maintenance, and immune responses. Recent evidence suggests that FGF/FGFR signaling closely participates in the polarization of macrophages, indicating that they could be potential targets for therapeutic manipulation of diseases associated with dysfunctional macrophages. In this article, we provide an overview of the structure, function, and downstream regulatory pathways of FGFs, as well as crosstalk between FGF signaling and macrophage polarization. Additionally, we summarize the potential application of harnessing FGF signaling to modulate macrophage polarization.

Naive pluripotent stem cell-based models capture FGF-dependent human hypoblast lineage specification

The hypoblast is an essential extraembryonic tissue set aside within the inner cell mass in the blastocyst. Research with human embryos is challenging. Thus, stem cell models that reproduce hypoblast differentiation provide valuable alternatives. We show here that human naive pluripotent stem cell (PSC) to hypoblast differentiation proceeds via reversion to a transitional ICM-like state from which the hypoblast emerges in concordance with the trajectory in human blastocysts. We identified a window when fibroblast growth factor (FGF) signaling is critical for hypoblast specification. Revisiting FGF signaling in human embryos revealed that inhibition in the early blastocyst suppresses hypoblast formation. Invitro, the induction of hypoblast is synergistically enhanced by limiting trophectoderm and epiblast fates. This finding revises previous reports and establishes a conservation in lineage specification between mice and humans. Overall, this study demonstrates the utility of human naive PSC-based models in elucidating the mechanistic features of early human embryogenesis.