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Growth factor

A growth factor is a secreted, biologically active protein that regulates cellular processes by binding to specific receptors on target cells, thereby influencing cell growth, proliferation, differentiation, migration, and survival.^[1]^[2] These molecules are naturally produced by various cells throughout the body and play essential roles in maintaining tissue homeostasis, embryonic development, and adult physiology.^[1]^[3] Growth factors exert their effects through autocrine, paracrine, or endocrine signaling mechanisms, where they bind to transmembrane receptors that activate intracellular pathways such as the MAPK/ERK and PI3K/AKT cascades, leading to gene expression changes that drive cellular responses.^[1] In normal physiology, they are critical for processes like wound healing, where they promote angiogenesis, fibroblast proliferation, and extracellular matrix synthesis to facilitate tissue repair.^[1]^[4] Dysregulation of growth factor signaling, however, contributes to pathological conditions, including cancer—where overexpression can stimulate uncontrolled cell proliferation—and fibrotic diseases, as well as diabetic complications like retinopathy.^[1]^[5] Prominent examples of growth factors include epidermal growth factor (EGF), which stimulates epithelial cell proliferation and is vital for skin and mucosal repair; platelet-derived growth factor (PDGF), involved in chemotaxis and proliferation of connective tissue cells during wound healing; and vascular endothelial growth factor (VEGF), which induces blood vessel formation and permeability.^[1] These belong to broader families, such as the EGF family, PDGF family, and VEGF family, each with distinct receptor interactions and tissue-specific functions.^[6] Additionally, neurotrophic growth factors like nerve growth factor (NGF) support neuronal survival and differentiation, underscoring their diverse applications in regenerative medicine and targeted therapies.^[7]

Definition and Fundamentals

Definition and Characteristics

Growth factors are naturally occurring proteins or polypeptides that bind to specific cell surface receptors on target cells, thereby regulating essential cellular processes such as growth, proliferation, differentiation, migration, and survival.^[1] These molecules function as signaling agents in intercellular communication, typically exerting their effects at low concentrations to modulate cellular behavior in a precise manner.^[8] Key characteristics of growth factors include their high specificity for particular cell types, mediated by the expression of corresponding receptors on responsive cells, which ensures targeted regulation of physiological responses.^[1] Their actions are often dose-dependent, where the magnitude and type of cellular response vary with concentration, allowing fine-tuned control over processes like proliferation.^[9] Growth factors predominantly operate through paracrine signaling, where they are secreted by one cell type to influence neighboring cells, or autocrine signaling, in which a cell responds to its own secreted factors; these modes facilitate short-range interactions critical for coordinated tissue responses.^[10] They play pivotal roles in embryonic development by guiding pattern formation and organogenesis, in wound healing by promoting tissue repair and angiogenesis, and in adult tissue homeostasis by maintaining cellular balance and preventing degeneration.^[11] Structurally, growth factors are generally small polypeptides ranging from 5 to 20 kDa in molecular weight, enabling efficient diffusion and stability in extracellular environments.^[10] Many possess specific motifs, such as heparin-binding domains in certain families, which facilitate interactions with extracellular matrix components like heparan sulfate proteoglycans, thereby modulating their bioavailability and localization.^[12] In terms of function, growth factors commonly stimulate mitosis and cell cycle progression by activating receptor tyrosine kinases upon binding, leading to downstream phosphorylation cascades that promote DNA synthesis and division through activation of transcription factors that induce gene expression and protein synthesis.^[9]

Historical Development

The concept of growth factors emerged from early 20th-century observations in tissue culture and wound healing research, where scientists noted that clotted blood serum stimulated cell proliferation more effectively than cell-free plasma, implying the release of bioactive substances during coagulation. These findings laid the groundwork for identifying specific mitogenic agents involved in tissue repair. In the 1930s, researchers proposed the existence of "wound hormones" to explain accelerated regeneration at injury sites, attributing it to diffusible factors from damaged tissues that promoted cellular growth and migration, though these remained uncharacterized at the time. A major milestone came in 1974 with the isolation of platelet-derived growth factor (PDGF) by Russell Ross and colleagues, who demonstrated that this serum component, absent in plasma, specifically stimulated the proliferation of arterial smooth muscle cells in vitro, highlighting its role as a key mitogen released from platelets during clotting. This discovery marked the first purification of a mammalian growth factor and shifted focus toward polypeptide mediators of cell growth. Building on this, the 1980s saw significant breakthroughs, including Stanley Cohen's identification of epidermal growth factor (EGF) in the 1960s, which earned him the 1986 Nobel Prize in Physiology or Medicine for revealing its mitogenic effects on epithelial cells; Cohen's work, detailed in his Nobel lecture, underscored EGF's isolation from mouse submaxillary glands and its stimulation of eyelid opening and incisor eruption in newborns. Concurrently, genes for fibroblast growth factors (FGFs), such as basic FGF (FGF2), were cloned in 1986 by Abraham et al., enabling molecular studies of their angiogenic and proliferative properties across bovine tissues.^[13] The 1990s and 2000s advanced understanding through the elucidation of vascular endothelial growth factor (VEGF) in angiogenesis, first cloned and characterized by Leung et al. in 1989 from bovine pituitary cells, with subsequent studies in the 1990s by Ferrara confirming its specific mitogenic activity on endothelial cells and central role in pathological vessel formation. Similarly, research on insulin-like growth factors (IGFs), particularly IGF-1 and IGF-2, intensified during this period, revealing their regulation of metabolism and growth; historical reviews trace their discovery to the 1950s but highlight 1990s-2000s advancements in linking IGFs to insulin signaling and metabolic disorders, as synthesized in Daughaday's foundational work and later genetic analyses. These developments expanded the growth factor paradigm to include diverse physiological contexts.^[14] From the 2000s onward, growth factor research integrated with stem cell biology and genome editing technologies, such as CRISPR-Cas9, to dissect gene functions and enhance regenerative applications.

Major Classes and Examples

Growth factors are classified into families primarily based on their structural features and the types of receptors they bind to, which are often receptor tyrosine kinases (RTKs) or serine/threonine kinase receptors.^[6] This classification helps in understanding their specificity and roles in cellular communication. Major families include the platelet-derived growth factor (PDGF) family, epidermal growth factor (EGF) family, fibroblast growth factor (FGF) family, insulin-like growth factor (IGF) family, vascular endothelial growth factor (VEGF) family, and transforming growth factor-β (TGF-β) superfamily, among others.^[6]^[15] The PDGF family consists of four ligand isoforms—PDGF-A, PDGF-B, PDGF-C, and PDGF-D—that dimerize to form various combinations such as PDGF-AA, PDGF-BB, and PDGF-AB, binding to PDGFRα and PDGFRβ receptors, which are class III RTKs characterized by five immunoglobulin-like domains and a kinase insert.^[6] These primarily target fibroblasts and smooth muscle cells.^[6] The EGF family includes ligands like EGF and transforming growth factor-α (TGF-α), which bind to ErbB receptors (EGFR/ErbB1, ErbB2–4), cysteine-rich RTKs, targeting epithelial cells.^[6] The FGF family encompasses 23 members (FGF1 through FGF23), with acidic FGF (FGF1) and basic FGF (FGF2) as prototypical examples, binding to FGFR1–4 receptors, which are RTKs with two to three immunoglobulin-like domains.^[6] They target a broad range of mesenchyme and epithelium.^[6] The IGF family comprises IGF-1 and IGF-2, which bind to the IGF-1 receptor (IGF-1R, a class II RTK) and IGF-2 receptor (IGF-2R/M6P receptor), influencing widespread cellular proliferation.^[16] The VEGF family includes VEGF-A through VEGF-D and placental growth factor (PlGF), binding to VEGFR1–3 receptors, which are RTKs with seven immunoglobulin-like domains, primarily targeting endothelial cells.^[6] The TGF-β superfamily consists of over 30 members, including TGF-β1–3, activins, and bone morphogenetic proteins (BMPs), which bind to heteromeric complexes of type I and type II serine/threonine kinase receptors (e.g., TGFBR1 and TGFBR2), regulating cell proliferation, differentiation, apoptosis, and extracellular matrix production across diverse tissues.^[15] Other notable growth factors include hepatocyte growth factor (HGF), which binds to the c-MET receptor (an RTK with a kinase domain), targeting epithelial and endothelial cells, and nerve growth factor (NGF), a member of the neurotrophin family that binds to TrkA and p75NTR receptors, targeting neurons.^[6]^[7] Emerging classifications recognize neurotrophins, such as brain-derived neurotrophic factor (BDNF), as a subset of growth factors acting on TrkB receptors to support neuronal survival, with 2020s research highlighting their roles in neuroplasticity and therapeutic applications.^[7]^[17] Bone morphogenetic proteins (BMPs), part of the TGF-β superfamily, function as growth factor subsets binding to BMP receptors (serine/threonine kinases), influencing bone and tissue development.^[18] Recent 2020s studies have explored cytokine-growth factor hybrids, such as BMPs exhibiting immunoregulatory cytokine-like properties alongside growth promotion.^[19]

Comparison to Cytokines

Growth factors and cytokines, while both serving as extracellular signaling proteins, exhibit notable structural differences. Growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), act as specific ligands for receptor tyrosine kinases (RTKs), enabling precise dimerization and activation upon binding.^[20] In contrast, cytokines like interleukins (e.g., IL-2) and interferons (e.g., IFN-α) bind to multi-subunit cytokine receptors lacking intrinsic kinase activity, often relying on associated Janus kinases (JAKs) for signaling initiation.^[20] This structural specificity in growth factors supports targeted cellular responses, whereas the modular architecture of cytokine receptors allows for broader, context-dependent interactions across immune cell types.^[20] Functionally, growth factors primarily drive cell proliferation, differentiation, and survival during embryonic development, tissue repair, and wound healing, with examples like vascular endothelial growth factor (VEGF) promoting angiogenesis in healing processes.^[20] Cytokines, however, predominantly orchestrate immune responses, inflammation, and hematopoiesis, often exerting both stimulatory and inhibitory effects; for instance, tumor necrosis factor (TNF) can induce apoptosis in infected cells while amplifying inflammatory cascades.^[20] These distinctions arise from divergent downstream pathways: growth factors typically activate RTK-mediated mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) routes for mitogenic effects, whereas cytokines engage JAK/STAT signaling to modulate immune cell activation and recruitment.^[20] Despite these differences, overlaps exist, particularly with molecules like transforming growth factor-β (TGF-β), which functions as both a growth factor—promoting extracellular matrix production and epithelial-mesenchymal transition (EMT) in development and fibrosis—and a cytokine, suppressing immune responses by inducing regulatory T cells (Tregs) and inhibiting pro-inflammatory T helper 1 (Th1) cells. In certain contexts, such as epithelial cell growth, TGF-β inhibits proliferation, blurring lines between growth promotion and immune modulation. Regulatory expression further differentiates them: growth factors are often constitutively produced by stromal cells to maintain developmental homeostasis, while cytokines are inducibly expressed by activated immune cells in response to pathogens or injury, ensuring rapid but transient signaling.^[21] Recent 2020s research highlights hybrid signaling in cancer immunology, where growth factors like EGF and VEGF contribute to elevated pro-inflammatory cytokine production (e.g., IL-6, TNF) in the tumor microenvironment, fostering immunosuppression and metastatic progression.^[22] For example, TGF-β's dual role exacerbates cytokine-driven inflammation in advanced tumors, promoting EMT and immune evasion, which has informed combination therapies targeting both pathways to mitigate tumor-promoting inflammation.^[21]^[22]

Biological Sources and Roles

Growth factors are produced by a variety of cells, including endothelial cells, fibroblasts, and macrophages, in addition to platelets, which serve as a key storage and rapid-release depot.

Production in Platelets

Platelets function as a major storage depot for growth factors, primarily within their alpha-granules, which serve as specialized reservoirs enabling rapid release during physiological responses. These granules contain high concentrations of key growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF). For instance, PDGF is stored at levels of approximately 80–100 ng per 10^9 platelets, while TGF-β reaches about 48 ng per 10^9 platelets, ensuring a potent local supply upon demand.^[23]^[24] The production of these growth factors begins in megakaryocytes during thrombopoiesis, where they are synthesized and packaged into nascent alpha-granules that are subsequently inherited by maturing platelets. Megakaryocytes actively produce PDGF and TGF-β through regulated biosynthetic pathways, contributing to the majority of the stored content. In addition, circulating platelets exhibit selective uptake of certain growth factors, such as IGF-I, from plasma via receptor-mediated endocytosis, further enriching alpha-granule contents and allowing adaptation to systemic levels.^[25]^[26]^[3] Release from alpha-granules is triggered by platelet activation during hemostasis, primarily by agonists such as thrombin, collagen, or adenosine diphosphate (ADP), which bind to surface receptors and initiate degranulation cascades. This process delivers growth factors in a localized manner at injury sites, with rapid kinetics: 70–80% of stored PDGF is released within the first 10 minutes of activation, facilitating immediate paracrine signaling. Such efficient discharge supports early wound repair and vascular homeostasis by promoting endothelial proliferation and matrix remodeling.^[27]^[28] Emerging research underscores the involvement of platelet-derived extracellular vesicles in augmenting growth factor delivery. A 2023 first-in-human clinical trial demonstrated that allogeneic platelet-derived extracellular vesicles are safe and well-tolerated, with potential for promoting wound healing in regenerative contexts.^[29]

Functions in Development and Homeostasis

Growth factors play essential roles in embryonic development by regulating spatial and temporal patterns of cell proliferation, differentiation, and morphogenesis. For instance, fibroblast growth factors (FGFs) are critical for limb bud formation, where FGF8 and FGF10 establish signaling centers that direct outgrowth and patterning of the limb axis through gradients that influence mesenchymal condensation and apoptosis.^[30] Similarly, bone morphogenetic proteins (BMPs), particularly BMP4 and BMP7, mediate dorsoventral patterning in the embryo by forming ventral-to-dorsal gradients that specify neural crest induction, somite formation, and tissue identity via differential activation of Smad-dependent transcription.^[31] In adult homeostasis, growth factors maintain organ size, vascular integrity, and epithelial integrity. Insulin-like growth factor 1 (IGF-1) sustains muscle and bone mass by promoting satellite cell proliferation in skeletal muscle and osteoblast activity in bone, thereby counterbalancing age-related atrophy and ensuring structural stability.^[32] Vascular endothelial growth factor (VEGF) regulates angiogenesis and vascular tone, supporting endothelial cell survival and permeability to preserve tissue perfusion under physiological conditions. Epidermal growth factor (EGF) drives epithelial renewal in the skin by stimulating keratinocyte migration and proliferation, facilitating continuous barrier maintenance against environmental stressors.^[33] During injury response, growth factors orchestrate wound healing phases from inflammation to resolution. Platelet-derived growth factor (PDGF), released from platelets at injury sites, promotes the proliferative phase by recruiting fibroblasts and stimulating extracellular matrix synthesis, accelerating granulation tissue formation.^[34] Transforming growth factor beta (TGF-β), particularly TGF-β1, guides the remodeling phase by inducing myofibroblast differentiation and collagen crosslinking, which contracts and strengthens the wound bed for scar maturation.^[35] Dysregulated TGF-β signaling can lead to excessive matrix deposition and fibrosis, transforming normal repair into pathological scarring with persistent inflammation and tissue stiffening.^[36] Growth factors integrate systemically through feedback loops with hormones, exemplified by IGF-1's interaction with insulin, where IGF-1 enhances insulin sensitivity in peripheral tissues while insulin reciprocally stimulates hepatic IGF-1 production to fine-tune glucose and anabolic homeostasis.^[37] These mechanisms exhibit evolutionary conservation across species, with core families like FGFs, BMPs, and IGFs retaining structural and functional homology from invertebrates to mammals, underscoring their ancient origins in metazoan development and tissue maintenance.^[38] Recent 2024 research highlights growth factors' involvement in microbiome-host interactions for gut homeostasis, where fibroblast growth factor 1 (FGF1) modulates microbial composition to reduce inflammation and improve epithelial barrier function in a high-fat diet model in rainbow trout, analogous to diabetic conditions.^[39]

Molecular Mechanisms

Receptor Binding and Activation

Growth factors exert their effects primarily through interaction with specific cell surface receptors, which transduce extracellular signals into intracellular responses. The majority of growth factors, such as those in the platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) families, bind to receptor tyrosine kinases (RTKs), a class of transmembrane proteins characterized by an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain. In contrast, transforming growth factor-β (TGF-β) family members engage serine/threonine kinase receptors, while fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs) also utilize RTKs but often require co-receptors for efficient signaling. While the majority signal through RTKs or serine/threonine kinase receptors, some growth factor receptors, including those for neurotrophins, can be transactivated by G-protein-coupled receptors (GPCRs), though RTKs predominate in canonical pathways.^[40]^[41]^[42]^[43] The binding process typically involves high-affinity interactions that induce receptor oligomerization, often dimerization, leading to activation. For instance, EGF binds to the epidermal growth factor receptor (EGFR) with a dissociation constant (Kd) of approximately 10^{-9} M, promoting homodimerization through conformational changes in the extracellular domain; this exposes a dimerization arm in subdomain II, stabilizing an asymmetric arrangement of the intracellular kinase domains. Similarly, PDGF induces dimerization of PDGF receptors (PDGFRα and PDGFRβ), either as homodimers or heterodimers, via ligand crosslinking that reorients extracellular domains and activates the kinase. In the case of TGF-β, the ligand sequentially binds the type II receptor (TβRII), which then recruits and phosphorylates the type I receptor (TβRI), forming a heterotetrameric complex of two type I and two type II subunits. These events trigger conformational shifts that expose kinase domains, initiating transphosphorylation.^[44]^[41]^[45] Receptor specificity is maintained through structural features of the extracellular domains, yet redundancy allows multiple receptors to respond to a single growth factor, enabling nuanced cellular responses. VEGFs, for example, exhibit this through three related RTKs: VEGFR1 binds VEGF-A with high affinity (Kd ~2–10 pM) but signals weakly, acting partly as a decoy; VEGFR2, the primary mediator of angiogenesis, binds VEGF-A with moderate affinity (Kd ~100–400 pM) and drives robust signaling; and VEGFR3 preferentially interacts with VEGF-C and VEGF-D to promote lymphangiogenesis. For FGFs, specificity is enhanced by co-receptors such as heparan sulfate proteoglycans (HSPGs), which stabilize the FGF-FGFR ternary complex by bridging the ligand and receptor, increasing binding affinity and facilitating dimerization essential for kinase activation. This redundancy and co-receptor dependence allow growth factors to elicit context-specific effects across tissues.^[46]^[47] Upon dimerization or oligomerization, receptor activation culminates in autophosphorylation of intracellular tyrosine (for RTKs) or serine/threonine (for TGF-β receptors) residues, primarily in the C-terminal tails or juxtamembrane regions. These phosphosites serve as docking platforms for adaptor proteins and effectors, such as Grb2, Shc, and PLCγ, via SH2 or PTB domains, thereby initiating downstream signaling without delving into those pathways here. For EGFR, key sites include tyrosines 1068, 1086, 1148, and 1173, which recruit multiple adapters to diversify responses like proliferation and migration.^[48]^[41] Recent structural studies using cryo-electron microscopy (cryo-EM) have provided high-resolution insights into these complexes, revealing dynamic interfaces and allosteric mechanisms. For example, the 2023 cryo-EM structure of the EGF-bound EGFR/HER2 heterodimer at 3.3 Å resolution elucidates how ligand-induced asymmetry propagates from the extracellular to kinase domains, refining models of activation and highlighting therapeutic targets. Similar advances for FGF-receptor-HS complexes confirm the coreceptor's role in ternary assembly, addressing prior gaps in understanding ligand specificity.^[49]^[47]

Intracellular Signaling Pathways

Upon binding to their receptors, growth factors initiate a cascade of intracellular signaling events that transduce extracellular cues into cellular responses such as proliferation, survival, and differentiation. These pathways are primarily activated through receptor tyrosine kinases (RTKs) or other receptor families, leading to phosphorylation events that recruit and activate downstream effectors.^[50] The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is a central mediator of growth factor-induced proliferation. In this cascade, ligand-bound RTKs phosphorylate adaptor proteins like Grb2 and Shc, which recruit the guanine nucleotide exchange factor Sos to activate Ras by promoting GTP binding. Active Ras then stimulates Raf kinase, which sequentially phosphorylates and activates MEK1/2, culminating in ERK1/2 activation; phosphorylated ERK translocates to the nucleus to phosphorylate transcription factors like Elk-1, driving expression of genes such as c-Fos and cyclin D1.^[51] This pathway is exemplified by epidermal growth factor (EGF) signaling through EGFR, where sustained ERK activation correlates with cell cycle progression.^[52] The phosphoinositide 3-kinase (PI3K)-Akt pathway promotes cell survival, growth, and metabolic adaptation in response to growth factors like insulin-like growth factor 1 (IGF-1). Upon RTK activation, PI3K is recruited via its regulatory subunit p85 and converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), which docks and activates Akt (also known as protein kinase B) at the plasma membrane through PDK1-mediated phosphorylation. Active Akt inhibits pro-apoptotic proteins like FoxO and Bad while activating mTOR to enhance protein synthesis and glycolysis.^[53] In certain contexts, particularly with growth factors overlapping cytokine functions such as interleukin-6 or granulocyte-macrophage colony-stimulating factor, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway directly influences transcription. Receptor-associated JAKs autophosphorylate upon ligand binding, creating docking sites for STAT proteins, which are then phosphorylated, dimerize, and translocate to the nucleus to regulate genes involved in proliferation and immune responses.^[54] Phospholipase Cγ (PLCγ)-mediated signaling mobilizes intracellular calcium to support processes like migration and secretion. Growth factors such as platelet-derived growth factor (PDGF) activate PLCγ via RTK phosphorylation, leading to hydrolysis of PIP2 into diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3); IP3 binds IP3 receptors on the endoplasmic reticulum, releasing Ca²⁺ stores that amplify downstream effectors like calmodulin-dependent kinases.^[55] These pathways exhibit extensive crosstalk and integration to fine-tune cellular decisions. For instance, ERK and PI3K-Akt converge on shared transcription factors: ERK activates AP-1 (c-Jun/c-Fos heterodimers) for proliferation genes, while both pathways can synergize to activate NF-κB, enhancing survival and inflammatory responses through IκB degradation.^[56] Negative feedback mechanisms, such as PTEN dephosphorylation of PIP3 to curb PI3K activity, prevent excessive signaling and maintain homeostasis.^[53] Regulation of these cascades involves temporal and spatial dynamics. ERK phosphorylation typically peaks 10-15 minutes after growth factor stimulation before declining due to phosphatase activity like that of DUSP6, ensuring transient signaling for proliferation rather than differentiation.^[57] Spatial control is achieved through scaffold proteins, such as KSR1 for the Ras-Raf-MEK-ERK module, which localize components to specific cellular compartments like endosomes or the plasma membrane.^[57] Dysregulation of growth factor signaling pathways contributes to oncogenesis, often through hyperactivation via mutant RTKs. For example, EGFR mutations in lung cancer lock the kinase in an active state, leading to constitutive MAPK/ERK and PI3K-Akt signaling that drives uncontrolled proliferation; similarly, KIT mutations in gastrointestinal stromal tumors sustain JAK-STAT activity.^[58] Recent advances using single-cell RNA sequencing (scRNA-seq) have revealed heterogeneity in growth factor signaling across tissues, highlighting cell-type-specific pathway activation. In muscle regeneration models, scRNA-seq demonstrated varied FGF7-mediated interactions between satellite cells and fibro-adipogenic progenitors, uncovering subpopulation-specific ERK and PI3K responses that influence repair outcomes.^[59] These findings, from 2024 studies, underscore the need for context-dependent models of signaling dynamics.

Medical and Therapeutic Applications

Clinical Uses and Therapies

Recombinant platelet-derived growth factor (PDGF-BB), marketed as becaplermin gel, was approved by the U.S. Food and Drug Administration (FDA) in 1997 for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond, with adequate blood supply and debridement.^[60] Clinical trials supporting this approval demonstrated that becaplermin accelerates wound healing by promoting granulation tissue formation and epithelialization, with patients achieving complete wound closure in approximately 14-20% more cases compared to placebo controls after 20 weeks of treatment.^[61] Granulocyte colony-stimulating factor (G-CSF), in the form of filgrastim (Neupogen), received FDA approval in 1991 to reduce the duration of severe neutropenia and the incidence of febrile neutropenia in patients with nonmyeloid malignancies undergoing myelosuppressive chemotherapy.^[62] Pivotal trials showed filgrastim shortening neutropenia duration by 2-3 days, thereby decreasing infection risk.^[63] Erythropoietin (EPO), a hematopoietic growth factor, was approved by the FDA in 1989 as epoetin alfa (Epogen) for treating anemia associated with chronic kidney disease, including in dialysis and non-dialysis patients.^[64] This approval was based on studies where EPO increased hemoglobin levels by 2-4 g/dL, reducing the need for transfusions.^[65] Vascular endothelial growth factor (VEGF) inhibitors, such as bevacizumab (Avastin), have been approved by the FDA since 2004 for various oncology indications, including metastatic colorectal cancer, non-small cell lung cancer, and glioblastoma, by blocking VEGF-mediated angiogenesis to starve tumors.^[66] In combination therapies, bevacizumab has extended progression-free survival by 4-6 months in advanced ovarian cancer patients.^[67] Fibroblast growth factor (FGF), particularly FGF-2, has been investigated for cardiac repair following myocardial infarction (MI); early phase I/II trials demonstrated safety and improved myocardial perfusion via intracoronary administration in refractory angina patients, though larger phase II trials did not confirm significant enhancements in left ventricular function or clinical outcomes.^[68]^[69] Combinations of growth factors with stem cell therapies are being explored in regenerative medicine for tissue repair, where factors like PDGF and VEGF enhance mesenchymal stem cell engraftment and differentiation, promoting vascularization and reducing scar formation in preclinical models of ischemic injury.^[70] Growth factors are delivered through various methods tailored to therapeutic needs, including topical gels for localized wound application, as in becaplermin for diabetic ulcers, which provides sustained release over 12-24 hours per application.^[71] Systemic or targeted injections, such as subcutaneous filgrastim for neutropenia or intravenous EPO for anemia, achieve rapid bioavailability with peak effects within hours to days.^[72] Investigational gene therapy vectors, including viral plasmids encoding FGF or VEGF, enable prolonged endogenous production at injury sites; early preclinical and phase I/II trials have shown accelerated wound closure rates when combined with scaffolds for chronic ulcers.^[73] Recent advancements include 2024 FDA approvals of biosimilars for established growth factor therapies, such as additional filgrastim variants, expanding access while maintaining efficacy equivalence to originators.^[74] Anti-NGF monoclonal antibodies like tanezumab have demonstrated approximately 30-40% pain reduction in phase III trials for diabetic peripheral neuropathy.^[75] These applications build on growth factors' roles in normal wound healing by amplifying cellular proliferation and migration at therapeutic sites.^[76]

Risks, Challenges, and Research Directions

Growth factor therapies pose significant risks, primarily due to their inherent pro-proliferative properties that can inadvertently promote pathological processes. For example, vascular endothelial growth factor (VEGF) enhances angiogenesis, which supports tumor growth, invasion, and metastasis in various cancers, raising concerns about exacerbating malignancies in patients with undetected tumors.^[77] Similarly, excessive administration of transforming growth factor-β (TGF-β) can induce fibrosis by stimulating extracellular matrix deposition and fibroblast activation, leading to tissue scarring in organs such as the liver or lungs.^[78] Additionally, recombinant growth factors often trigger immunogenicity, resulting in the development of neutralizing antibodies that reduce therapeutic efficacy and potentially cause hypersensitivity reactions.^[79] Key challenges in clinical application include the short half-life of growth factors, necessitating frequent dosing to maintain therapeutic levels, which complicates patient compliance and increases treatment burden.^[80] Off-target effects arise from receptor redundancy across tissues, where growth factors may activate unintended pathways, leading to systemic side effects like inflammation or aberrant cell proliferation.^[73] Furthermore, the high production costs of these biologics limit accessibility, particularly in resource-constrained settings, and contribute to economic barriers in widespread adoption.^[81] Emerging research directions aim to mitigate these issues through engineered variants, such as PEGylated growth factors, which enhance plasma stability and extend half-life while preserving bioactivity, as demonstrated in fibroblast growth factor 21 (FGF21) conjugates.^[82] Nanotechnology-based delivery systems, including nanoparticles and scaffolds, offer controlled release and targeted localization to minimize off-target actions and improve bioavailability.^[83] Artificial intelligence modeling is being applied to predict pathway dysregulation, enabling simulation of growth factor interactions in complex networks like the epidermal growth factor receptor pathway to identify safer intervention points.^[84] Preclinical studies, such as those evaluating nerve growth factor mimetics like BNN27 for neurodegenerative conditions, explore multi-factor cocktails combining growth factors with other agents to address multifactorial diseases like Alzheimer's.^[85] Ethical concerns surrounding gene-edited growth factors, particularly heritable modifications to enhance factor expression, include risks of unintended genetic changes passed to offspring and inequities in access to such technologies.^[86] Long-term safety data from over 20 years of recombinant human growth hormone therapy indicate no confirmed increased risk of leukemia or other neoplasias, though monitoring for rare events like adrenal insufficiency persists.^[87]

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Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis ...
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A Novel Mechanism Directing Them into α Granules of Platelets ...
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Signaling During Platelet Adhesion and Activation
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Specific epidermal growth factor receptor autophosphorylation sites ...
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Polyethylene Glycol Modified FGF21 Engineered to Maximize ...
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The Delivery and Activation of Growth Factors Using Nanomaterials ...
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Multimodal beneficial effects of BNN27, a nerve growth factor ...
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