Fibroblast Growth Factor 10 (FGF10): A Key Regulatory Factor from Developmental Biology to Regenerative Medicine

 I. What is Fibroblast Growth Factor 10 (FGF10)? How does it function in the human body?

Fibroblast Growth Factor 10 (FGF10) is an important member of the Fibroblast Growth Factor (FGF) family, belonging to the paracrine FGF subfamily (FGF7 subfamily). Unlike some other FGFs that can enter the bloodstream, FGF10 primarily functions locally in tissues through paracrine signaling. It binds specifically to its receptor, FGFR2b, thereby activating a series of complex intracellular signaling pathways, most notably the RAS/MAPK and PI3K/AKT pathways. The binding of FGF10 to FGFR2b is highly specific and high-affinity, akin to a "lock and key" mechanism, which is the first step in initiating all biological effects. Once the signaling pathway is activated, it regulates the expression of target genes, ultimately influencing various cellular behaviors, including proliferation, migration, differentiation, and survival. The expression of FGF10 during embryonic development is strictly spatiotemporally specific, and its expression pattern resembles a precise blueprint guiding the morphogenesis of various organs and structures. It is worth noting that the effective functioning of FGF10 also depends on the presence of heparin sulfate proteoglycans (HSPGs). These molecules are found on the cell surface and in the extracellular matrix, where they protect FGF10 from degradation and facilitate its binding to receptors, thereby finely regulating the strength and scope of signaling. In summary, FGF10 is a powerful morphogen and survival factor that plays an indispensable role as a conductor during the earliest stages of life and throughout the entire lifespan through precise local signaling.

II. What crucial role does FGF10 play in embryonic development?

FGF10 is a dominant morphogen during embryonic development. Its functional loss in animal models leads to severe developmental defects or even lethality in multiple organs, highlighting its irreplaceable role. In limb development, the expression of FGF10 is a key signal for initiating limb bud formation. It is produced by lateral plate mesoderm cells and induces the overlying ectoderm cells to form the apical ectodermal ridge (AER). The AER, in turn, secretes feedback signaling molecules such as FGF8, maintaining the expression of FGF10 in the mesoderm. This positive feedback loop drives the outward growth of the limb bud and its patterning along the proximodistal axis (from shoulder to fingertips). If FGF10 signaling fails, it can result in complete limb absence (amelia) or severe shortening. In lung development, FGF10 is equally critical. It is expressed by lung mesenchymal cells and acts as a chemoattractant, guiding the directional branching of epithelial cell buds derived from the foregut endoderm to form the bronchial tree-like structure. This process, known as "branching morphogenesis," is the foundation for the lung's vast gas exchange surface area. Mice with FGF10 knockout exhibit stalled lung development at the initial budding stage, unable to form normal tracheal branches. Additionally, FGF10 plays a central guiding role in multiple key processes, including craniofacial development (e.g., regulating palatal plate and salivary gland morphogenesis), tooth development (regulating enamel knot and root formation), eye development (participating in eyelid closure), ear development, and heart development (participating in epicardial and coronary artery development). It can be said that without the precise spatiotemporal expression and signaling of FGF10, the normal structure and function of multiple organ systems cannot be established.

III. What functions does FGF10 have in the adult body? How is it associated with diseases?

Although FGF10 is most active during the embryonic stage, it continues to play an important role in tissue homeostasis, injury repair, and regeneration in the adult body. In adult tissues, FGF10 expression is typically low but is rapidly upregulated after tissue injury to initiate repair programs. For example, during skin wound healing, FGF10 is produced by dermal fibroblasts and strongly promotes the migration and proliferation of keratinocytes, thereby accelerating epithelial regeneration and wound closure while reducing scar formation. As such, it is regarded as a potential pro-regenerative and anti-fibrotic therapeutic molecule. In the lungs, FGF10 plays a role in maintaining alveolar epithelial cell homeostasis and responding to injury. In models of acute lung injury or pneumonia, exogenous administration of FGF10 enhances lung repair by promoting the proliferation and differentiation of alveolar type II epithelial cells, reducing inflammation and fibrosis. However, dysregulation of FGF10 signaling is also closely associated with various diseases. Loss-of-function mutations in FGF10 have been confirmed as the cause of certain phenotypes in autosomal recessive disorders, such as APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) syndrome, as well as certain forms of congenital tooth agenesis and LADD syndrome (characterized by abnormal development of lacrimal and salivary glands). On the other hand, abnormal activation of FGF10 signaling may also promote disease development. Studies have shown that FGF10 is overexpressed in various cancers, such as breast cancer, pancreatic cancer, and prostate cancer. Through its pro-survival and pro-proliferative effects, it provides growth advantages to tumor cells and may participate in tumor angiogenesis, invasion, and metastasis. Therefore, the FGF10/FGFR2b signaling axis has become a potential target in cancer therapy.

IV. What is the application prospect of FGF10 in regenerative medicine and therapeutic strategies?

Given its powerful ability to promote cell proliferation, migration, differentiation, and tissue regeneration, FGF10 has become an highly attractive candidate therapeutic molecule in the field of regenerative medicine. Researchers are actively exploring its application for repairing and regenerating tissues damaged by disease, trauma, or aging. In the field of skin regeneration, recombinant human FGF10 has been developed as a topical drug (e.g., trafermin) for treating refractory wounds such as deep burns and diabetic foot ulcers. It accelerates healing by directly stimulating the epithelialization process and improves the quality of healing. In the treatment of lung diseases, preclinical studies show great potential. FGF10 protein or gene therapy has demonstrated protective effects in animal models of emphysema, pulmonary fibrosis, bronchopulmonary dysplasia, and acute respiratory distress syndrome (ARDS), promoting alveolar regeneration, inhibiting abnormal inflammation and collagen deposition, and improving lung function. This offers new hope for patients with lung diseases for which there are currently no effective treatments. In salivary gland regeneration, for patients who have permanently lost salivary gland function due to head and neck radiotherapy (often resulting in severe dry mouth), ductal perfusion of FGF10 protein to activate residual progenitor cells and promote the regeneration and functional recovery of salivary gland tissue is a highly promising therapeutic direction. Additionally, the therapeutic potential of FGF10 in corneal injury repair, neuroprotection (e.g., after spinal cord injury), and hair follicle regeneration is being widely studied. However, translating FGF10 into clinical applications also faces challenges, primarily related to the stability of its protein drug, delivery methods, dosing, and long-term safety (especially its potential tumor-promoting risk, which requires strict evaluation). Future research will focus on developing more optimized delivery systems (e.g., sustained-release hydrogels, nanoparticles) and exploring more precise regulatory strategies (e.g., small molecule agonists) to maximize its therapeutic benefits while minimizing side effects.

V. What challenges does current FGF10 research face, and what are the future directions?

Although significant progress has been made in understanding FGF10, its complex biological characteristics still present many research challenges and future opportunities. The primary challenge lies in the precise regulation of its signaling pathways. The output of FGF10 signaling is not static; its final effects are finely regulated by developmental stage, cell type, microenvironment, and interactions with other signaling pathways (e.g., Sonic Hedgehog, BMP, Wnt). How to precisely "fine-tune" rather than simply "turn on" or "turn off" this pathway in different pathological states is key to its safe clinical application. Second, obstacles in translational applications need to be addressed urgently. Recombinant FGF10 protein has a short half-life and poor stability, requiring the development of efficient targeted delivery systems to ensure its sustained delivery to specific tissue sites while avoiding systemic exposure. Exploring FGF10 gene therapy, engineered cell therapies, or developing small molecule agonists that mimic its function are potential ways to overcome these obstacles. Future research directions will place greater emphasis on the depth of mechanistic studies, such as using single-cell sequencing and spatial transcriptomics technologies to map the cellular targets and signaling networks of FGF10 in different tissues and disease states at higher resolution. Meanwhile, interdisciplinary collaboration will drive the birth of innovative therapies. Material scientists, bioengineers, and clinicians need to work together to design intelligent biomaterials (e.g., scaffolds, hydrogels) based on FGF10 for tissue engineering and organ regeneration. Additionally, large animal model studies and rigorous clinical trials are crucial for verifying its safety and efficacy. As these challenges are gradually overcome, FGF10 is expected to transform from an important basic biological molecule into a regenerative medicine tool that can truly repair human tissues and treat major diseases, opening a new chapter in the field of regenerative medicine.

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