From Growth Factors to Structure: PDGF and TGF-β in Granulation Tissue Formation. A Literature Review

Abstract

Platelet-Derived Growth Factors (PDGFs) and Transforming Growth Factor β (TGFβ) are pivotal in orchestrating the complex wound healing process, particularly in granulation tissue formation. This review aims to comprehensively examine the roles of PDGF alongisde TGFβ in granulation tissue formation and their implications for abnormal wound healing. PDGFs, as homodimeric or heterodimeric combinations, such that PDGF-AA, PDGF-AB and PDGF-BB stimulate fibroblast proliferation and extracellular matrix synthesis, which is crucial for tissue repair. TGFβ, with its three isoforms, influences granulation tissue through diverse functions, with TGFβ-1 pivotal in fibrosis formation. Understanding their signalling pathways, notably PDGF's engagement with PDGF receptors and subsequent activation of cellular pathways, illuminates their roles in wound healing cascades. Excessive granulation, a complication of abnormal wound healing, involves dysregulated PDGF and TGFβ activity, leading to hypertrophic scar formation. Clinical management, particularly in ophthalmology, addresses excessive granulation's impact on procedures like endo-dacryocystorhinostomy. Strategies employing steroid agents and Mitomycin-C aim to mitigate ostium granulation. The potential use of PDGF receptor blockers, such as olaratumab, warrants further investigation for managing excessive granulation. In conclusion, PDGF and TGFβ emerge as critical regulators in granulation tissue formation, underscoring their significance in wound healing processes and offering avenues for therapeutic intervention.

Keywords: PDGF; PDGF‐AA; PDGF‐AB; PDGF‐BB; TGFβ; granulation tissue formation; wound healing.

FIGURE 1

The wound healing process [5, 9, 10, 11, 12, 13]. The wound healing process consists of four overlapping phases: Haemostasis, inflammation, proliferative and remodelling. This figure focuses on the first three phases. The proliferative phase consists of fibroplasia and angiogenesis with granulation tissue as its outcome. Fibroplasia (activation of fibroblast) is affected by primarily PDGF and TGFβ as products of the haemostasis and inflammation phases. Angiogenesis is affected by PDGF, TGFβ and FGF‐2 as products of the previous phases. FGF‐2, fibroblast growth factor‐2; IGF‐1, insulin growth factor‐1; PDGF, platelet derived growth factor; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor.

FIGURE 2

Interaction between PDGF ligands and PDGFR homodimers/heterodimers [1, 15, 16]. PDGF subunits form heterodimeric or homodimeric combinations PDGF‐AA, PDGF‐AB, PDGF‐BB, PDGF‐CC and PDGF‐DD. Two types of PDGF receptor exist: PDGFR‐α and PDGFR‐β. These receptors come in dimeric form PDGFR‐ αα, PDGFR‐ αβ and PDGFR‐ ββ. PDGF subunits A, B and C exhibit binding affinity towards PDGFR‐α, while subunits B, C, and D display affinity for PDGFR‐β. Consequently, PDGF‐AA selectively engages PDGFR‐αα receptors, whereas PDGF‐BB binds to both PDGFR‐αα and PDGFR‐αβ. Additionally, PDGF‐CC interacts with PDGFR‐αα, PDGFR‐αβ, and PDGFR‐ββ, whereas PDGF‐DD exclusively binds to PDGFR‐ββ. PDGF, platelet derived growth factor; PDGFR: platelet derived growth factor receptor.

FIGURE 3

PDGF signalling cascade in fibroblasts [18, 19, 20, 21, 22]. Activation of PDGFR activates several pathways leading to cell proliferation, collagen production, myofibroblast differentiation and cell migration. IP3, inositol (1,4,5)‐triphosphate; MAP‐KK, MAP‐kinase kinase/MEK 1/2; MAP‐KKK, MAP‐kinase kinase kinase/RAF; PDGFR, platelet derived growth factor receptor; PIP‐2, phosphatydylinsoitol (4,5)‐biphosphate; PIP3, phosphatidylinositol (3,4,5)‐triphosphate; SRF, serum response factor; TGFβ, transforming growth factor β.

FIGURE 4

TGFβ R‐Smad signalling pathway [28, 29]. LTGFβ: latent transforming growth factor β, TGFβ: transforming growth factor β. LTGFβ is activated into TGFβ. TGFβ a dimer kinase binds to Type 1 and Type 2 receptors. Once activated these receptors activate Smad proteins 2 and 3. Smad 2 and 3 then activate Smad 4 and form a complex. This protein complex translocates to the nucleus to perform gene transcription and form active chromatin. This model summarises explanation from Lichtman et al. and Demidova‐Rice et al.

FIGURE 5

TGFβ signalling in fibroblast [17, 29]. After activation of receptors by TGFβ, R‐SMAD pathway, Rho‐associated coiled‐coil containing ROCKs, RAS–ERK pathway and PI3/AKT pathway are activated. This leads to the regulation of myofibroblast generation, fibroblast proliferation/ apoptosis, extracellular matrix (ECM) production and also upregulates DNA transcription factors, co‐activators and co‐repressors to regulate gene expression. LTGFβ, latent transforming growth factor β; MAP‐KK, MAP‐kinase kinase/MEK 1/2; MAP‐KKK, MAP‐kinase kinase kinase/RAF; PIP‐2, phosphatidylinositol (4,5)‐biphosphate; PIP3, phosphatidylinositol (3,4,5)‐triphosphate; ROCKs, Rho‐associated coiled‐coil containing protein kinases; TGFβ, transforming growth factor β.