Research progress and application prospects of keratinocyte growth factor 1 (KGF-1)

Keratinocyte Growth Factor 1 (KGF-1), as an important member of the Fibroblast Growth Factor (FGF) family, has attracted much attention in the biomedical field in recent years.

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Research Progress and Application Prospects of Keratinocyte Growth Factor 1 (KGF-1)

I. Introduction

Keratinocyte Growth Factor 1 (KGF-1), as an important member of the Fibroblast Growth Factor (FGF) family, has attracted much attention in the biomedical field in recent years. With the deepening of research on cell growth, differentiation, and tissue repair mechanisms, the unique biological functions of KGF-1 have gradually become clear. It shows significant effects in promoting epithelial cell proliferation, migration, and survival, providing new strategies and hopes for the treatment of various diseases and tissue repair.

II. Basic Information of KGF-1

2.1 Gene and Protein Structure

KGF-1 is encoded by the FGF7 gene located in the 10q26 region of human chromosome. The KGF-1 protein produced by transcription and translation of this gene consists of 194 amino acids with a relative molecular weight of approximately 26 kDa. Its protein structure contains typical FGF family characteristics, with a core β-cloverleaf domain, which is crucial for KGF-1 to bind to receptors and exert biological activities. Compared with other members of the family, KGF-1 has unique amino acid sequences at the N-terminal and C-terminal, endowing it with specific effects on epithelial cells.

2.2 Receptors and Signal Transduction

The specific receptor of KGF-1 is fibroblast growth factor receptor 2IIIb (FGFR2IIIb), which is mainly expressed on the surface of epithelial cells. When KGF-1 binds to FGFR2IIIb, it triggers receptor dimerization, thereby activating the tyrosine kinase activity of the intracellular domain of the receptor. This process recruits and phosphorylates a series of downstream signaling molecules, such as phospholipase Cγ (PLCγ), phosphatidylinositol-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK). Through the cascade reaction of these signaling pathways, the extracellular KGF-1 signal is transmitted into the nucleus, regulating the expression of related genes, and ultimately promoting biological behaviors such as proliferation, migration, and anti-apoptosis of epithelial cells.

III. Biological Characteristics of KGF-1

3.1 Promoting Epithelial Cell Proliferation

Under normal physiological conditions, KGF-1 plays an important role in maintaining the homeostasis of epithelial tissues. For example, in the epidermal layer of the skin, after KGF-1 is secreted by fibroblasts in the dermis, it acts on the FGFR2IIIb receptor on the surface of epidermal keratinocytes, stimulating keratinocytes to enter the cell cycle, accelerating DNA synthesis and cell division, thereby promoting the renewal and repair of epidermal cells. Studies have shown that in skin wound healing models, exogenous administration of KGF-1 can significantly increase the proliferation index of keratinocytes at the wound edge, significantly shortening the wound healing time.

KGF-1 is also crucial in gastrointestinal epithelium. Gastrointestinal epithelial cells renew rapidly, and KGF-1 continuously stimulates the proliferation and differentiation of epithelial stem cells, replenishing damaged or apoptotic epithelial cells and maintaining the integrity of the gastrointestinal mucosa. Experiments have shown that when animals receive radiotherapy or chemotherapy, the gastrointestinal epithelium is damaged. At this time, supplementing KGF-1 can effectively promote the proliferation of small intestinal crypt cells, reduce epithelial cell apoptosis, and alleviate gastrointestinal mucosal damage caused by radiotherapy and chemotherapy.

3.2 Inducing Epithelial Cell Migration

The migration of epithelial cells is indispensable in processes such as tissue repair and embryonic development. KGF-1 can induce epithelial cell migration by regulating cytoskeleton rearrangement, expression of cell adhesion molecules, and other mechanisms. In corneal epithelial wound repair, KGF-1 stimulates corneal epithelial cells to extend pseudopodia, regulates the adhesion between cells and extracellular matrix, promotes epithelial cells to migrate to the damaged area, accelerates the healing of corneal epithelium, and reduces scar formation. In the tracheal epithelial injury model, KGF-1 upregulates the expression of adhesion molecules such as integrins on the surface of epithelial cells, enhances cell migration ability, and promotes the repair of tracheal epithelium.

3.3 Maintaining Epithelial Cell Survival

KGF-1 has a strong anti-apoptotic effect and can protect epithelial cells from various damaging factors. In the skin cell damage model induced by ultraviolet irradiation, KGF-1 activates the PI3K/Akt signaling pathway, upregulates the expression of anti-apoptotic protein Bcl-2, and simultaneously inhibits the activity of pro-apoptotic protein Bax, reducing cell apoptosis and maintaining the survival of skin cells. In lung diseases such as acute respiratory distress syndrome (ARDS), KGF-1 inhibits inflammation-induced apoptosis of alveolar epithelial cells by activating the MAPK signaling pathway, protects the alveolar epithelial barrier function, and reduces lung inflammatory response.

IV. Research on Clinical Application of KGF-1

4.1 Skin Wound Repair

Skin trauma is a common clinical problem, and KGF-1 shows great potential in promoting skin wound healing. Multiple clinical trials have shown that applying biological dressings containing KGF-1 to superficial second-degree burn wounds can significantly accelerate wound healing speed and reduce healing time by about 3-5 days compared with traditional dressings. This is because KGF-1 not only promotes the proliferation and migration of keratinocytes but also stimulates fibroblasts to synthesize extracellular matrix such as collagen, improves the wound microenvironment, and is conducive to the formation of new tissues. For chronic refractory wounds such as diabetic foot ulcers, KGF-1 can improve local ischemia and hypoxia, promote the proliferation and migration of epithelial cells at the ulcer edge, and improve the ulcer healing rate. Studies have reported that using KGF-1 to treat diabetic foot ulcers, the ulcer healing rate can reach more than 60% after 6 months, which is significantly higher than that of the conventional treatment group.

4.2 Oral Mucosal Injury Repair

Radiotherapy and chemotherapy often cause oral mucosal damage, bringing great pain to patients and affecting the quality of life and treatment process. KGF-1 has a significant effect in repairing oral mucosal damage. Clinical studies have found that pretreatment with KGF-1 before radiotherapy in patients with head and neck tumors can effectively reduce the degree of oral mucosal inflammation, ulcers, and other damage caused by radiotherapy. The mechanism is that KGF-1 promotes the proliferation of oral mucosal epithelial cells, enhances the mucosal barrier function, and reduces the infiltration of inflammatory factors. In addition, KGF-1 can also accelerate the repair of oral mucosa after chemotherapy, shorten the duration of mucosal damage, and enable patients to better tolerate chemotherapy drugs.

4.3 Treatment of Lung Diseases

In the field of lung diseases, KGF-1 has potential therapeutic value for various lung diseases. For idiopathic pulmonary fibrosis (IPF), KGF-1 can inhibit alveolar epithelial cell apoptosis, reduce fibroblast activation and excessive collagen deposition, and delay the progression of pulmonary fibrosis. Animal experiments have shown that after treating IPF model mice with KGF-1, the content of hydroxyproline in lung tissue decreases, the expression of fibrosis-related genes is down-regulated, and lung function is improved to a certain extent. In terms of acute lung injury (ALI) and ARDS, KGF-1 can improve the oxygenation index of patients and shorten the mechanical ventilation time by protecting alveolar epithelial cells, reducing pulmonary edema, and regulating lung inflammatory response.

V. Challenges and Prospects in KGF-1 Application

5.1 Facing Challenges

Although KGF-1 has performed well in basic research and preclinical trials, it still faces many challenges in practical clinical application. Firstly, as a protein drug, KGF-1 has poor stability and is easily degraded by proteases in the body, resulting in a short half-life, generally only 2-4 hours. This means that frequent administration is required to maintain effective blood drug concentration, increasing the treatment burden and inconvenience for patients. Secondly, the large-scale production and purification process of KGF-1 is complex and costly, limiting its wide application. At present, although KGF-1 can be expressed in Escherichia coli or mammalian cells through genetic engineering technology, there are still problems such as low yield and difficult purification. In addition, long-term use of KGF-1 may have potential safety risks. For example, excessive stimulation of cell proliferation may increase the risk of tumor occurrence. Although relevant studies have not clearly confirmed its carcinogenicity, it is still an important issue to be concerned about in clinical application.

5.2 Future Prospects

In response to the problems of KGF-1 stability and short half-life, researchers are exploring various solutions. On the one hand, protein engineering technology is used to modify the structure of KGF-1, such as introducing site-directed mutations and fusion proteins, to improve its stability and anti-protease hydrolysis ability. For example, chemical coupling of KGF-1 with polyethylene glycol (PEG) to construct PEGylated KGF-1 can significantly prolong its half-life in vivo and reduce the number of administrations. On the other hand, developing new drug delivery systems, such as nanoparticles and microspheres, to encapsulate KGF-1, achieve its slow release, and maintain stable drug concentration in vivo. In terms of production process improvement, continuously optimize the genetic engineering expression system, increase the expression of KGF-1, and develop efficient purification technologies to reduce production costs. At the same time, conduct in-depth research on the safety of KGF-1, clarify its safety thresholds under different doses, administration times, and administration routes, and provide a basis for clinical safe medication. With the deepening of research and continuous innovation of technology, KGF-1 is expected to play an important role in more disease treatment fields, bringing new treatment options for patients.

VI. Conclusion

In summary, as a cytokine with unique biological functions, KGF-1 plays a key role in promoting epithelial cell proliferation, migration, and survival. It shows good application prospects in multiple clinical fields such as skin wound repair, oral mucosal injury repair, and lung disease treatment. Although the clinical application of KGF-1 still faces challenges such as stability, production cost, and safety, with the continuous progress of science and technology, it is expected to overcome these obstacles through protein engineering transformation, development of new drug delivery systems, and in-depth safety research, making KGF-1 an effective means for clinical treatment of various diseases. In the future, research related to KGF-1 will continue to deepen, bringing more breakthroughs and developments to the biomedical field.

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