Platelet-derived growth factor (PDGF) is a class of disulfide-linked dimeric growth factors. It was originally named because it is present in platelet α-granules and is released after platelet activation. PDGF can promote the proliferation, migration, and chemotaxis of smooth muscle cells, fibroblasts, connective tissue cells, bone- and cartilage-related cells, and other cell types. It plays important roles in tissue repair, vascular maturation, embryonic development, neural development, and fibrosis.

Keywords: PDGF; platelet-derived growth factor; PDGFR; PDGF-AA; PDGF-BB; pericytes; fibroblasts; smooth muscle cells; tissue repair; fibrosis

1 Basic Characteristics of PDGF

1.1 Structural Composition of PDGF

PDGF belongs to the VEGF/PDGF-related growth factor family. Its typical structural feature is the presence of conserved cysteine residues and the formation of dimers through disulfide bonds. The PDGF family includes four polypeptide chains: PDGF-A, PDGF-B, PDGF-C, and PDGF-D. These chains can form dimeric forms such as PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD.

(1) Homodimers

PDGF-AA, PDGF-BB, PDGF-CC, and PDGF-DD are composed of identical polypeptide chains. Different homodimers vary in their binding capacity for PDGFR-α and PDGFR-β, which determines their target cell types and biological effects.

(2) Heterodimer

PDGF-AB is composed of an A chain and a B chain and has partial activities related to both PDGF-A and PDGF-B. It can participate in cell chemotaxis, proliferation, and tissue repair-related responses.

(3) Active forms

PDGF-C and PDGF-D usually require proteolytic processing to form mature active structures. Therefore, when studying these two members, the distinction among precursor protein, mature protein, and receptor activation status should be considered.

1.2 Sources of PDGF

PDGF is not only derived from platelets, but can also be produced by endothelial cells, macrophages, fibroblasts, vascular smooth muscle cells, tumor cells, and various stromal cells. After platelet activation, PDGF is released and can form a high-concentration growth factor environment at the injury site, promoting cell recruitment, migration, matrix remodeling, and repair responses.

1.3 Functional Differences Between PDGF and VEGF

PDGF and VEGF both belong to dimeric growth factor-related families, but their functional emphasis differs. VEGF mainly acts on vascular endothelial cells and promotes endothelial cell proliferation, migration, vascular permeability, and angiogenesis. PDGF preferentially acts on fibroblasts, vascular smooth muscle cells, and pericytes, and participates in vascular wall support, stromal cell expansion, tissue repair, and fibrosis. In vascular structure research, VEGF is more commonly used to explain “new blood vessel formation,” whereas PDGF-BB/PDGFR-β is more commonly used to explain “pericyte recruitment and vascular maturation.”

Table 1 PDGF Family Members and Receptor Selectivity

2 PDGF Receptors and Mechanisms of Action

2.1 PDGFR-α and PDGFR-β

PDGF mainly acts through two receptor tyrosine kinases, PDGFR-α and PDGFR-β. After ligand binding, the receptors undergo dimerization and activate intracellular tyrosine kinase domains, leading to receptor tyrosine autophosphorylation and recruitment of downstream signaling proteins.

(1) PDGFR-α

PDGFR-α can respond to PDGF-AA, PDGF-AB, PDGF-BB, and PDGF-CC. It is commonly associated with fibroblast activation, stromal cell proliferation, embryonic development, and oligodendrocyte precursor cell-related research.

(2) PDGFR-β

PDGFR-β mainly responds to PDGF-BB and PDGF-DD and can also participate in PDGF-AB-related responses. It is commonly found in pericytes, vascular smooth muscle cells, and some fibrosis models.

(3) Receptor combinations

Different PDGF ligands induce different receptor dimers. PDGF-AA mainly activates PDGFR-αα, PDGF-DD preferentially activates PDGFR-ββ, and PDGF-BB has a broader range of activity. Therefore, experimental design should first confirm whether the target cells express PDGFR-α or PDGFR-β before selecting the corresponding PDGF ligand.

2.2 Cellular Responses After PDGF Receptor Activation

After PDGF binds to PDGFR, multiple downstream branches can participate in cellular responses, including RAS/MAPK, PI3K/AKT, PLCγ/PKC, Src/FAK, and STAT-related mechanisms. These downstream mechanisms should not be interpreted separately from cellular phenotypes, but should be linked to functional outcomes such as proliferation, migration, chemotaxis, matrix production, or vascular maturation.

Figure 1 Schematic diagram of PDGF receptor signaling crosstalk

(1) RAS/MAPK branch

This branch mainly participates in cell proliferation, differentiation, and transcriptional regulation. Increased p-ERK after PDGF stimulation often suggests that cells have entered a proliferative or stress-responsive state, but EdU, Ki-67, or cell cycle assays are still needed for confirmation.

(2) PI3K/AKT branch

This branch mainly affects cell survival, migration, and anti-apoptotic responses. PDGF-BB-induced smooth muscle cell migration, pericyte survival, and fibroblast activation are often accompanied by enhanced AKT phosphorylation.

(3) PLCγ/PKC/Ca²⁺ branch

This branch mainly participates in Ca²⁺ changes, cytoskeletal remodeling, and migration responses. It is suitable for explaining PDGF-induced chemotaxis, morphological changes, and local cell movement.

(4) Src/FAK branch

This branch mainly participates in focal adhesion turnover, cytoskeletal remodeling, migration, and invasion. In PDGF-induced migration, p-FAK, p-Src, Paxillin, and cytoskeletal staining better reflect the motile phenotype than p-ERK alone.

Table 2 Major Downstream Mechanisms Mediated by PDGF Receptors

3 Major Biological Functions of PDGF

3.1 Mitogenic Activity and Cell Proliferation

PDGF is an important mitogen for smooth muscle cells, fibroblasts, connective tissue cells, and bone- and cartilage-related cells. After PDGF stimulation, cells can enter a proliferative state through MAPK, PI3K/AKT, and other mechanisms, showing enhanced DNA synthesis, cell cycle progression, and upregulation of proliferation markers.

(1) Recommended detection

EdU/BrdU incorporation, Ki-67, PCNA, Cyclin D1, cell cycle flow cytometry, p-ERK, and p-AKT.

(2) Interpretation focus

Increased cell number does not necessarily result entirely from enhanced proliferation; it may also result from reduced cell death. To prove that PDGF promotes proliferation, DNA synthesis, cell cycle progression, and apoptosis changes should be evaluated together.

3.2 Chemotaxis and Migration

PDGF can induce fibroblasts, smooth muscle cells, pericytes, and some stromal cells to migrate toward ligand gradients. It is an important chemotactic factor in tissue repair, vascular wall remodeling, and fibrosis.

(1) Recommended detection

Transwell chemotaxis assay, wound healing assay, real-time cell migration analysis, F-actin staining, p-FAK, p-Src, Rac/Rho-related indicators.

(2) Interpretation focus

Accelerated wound closure may result from cell migration or cell proliferation. If chemotaxis is the focus, Transwell assays or migration assays under proliferation-controlled conditions should be prioritized.

3.3 Vascular Maturation and Pericyte Recruitment

The PDGF-BB/PDGFR-β axis is a core topic in vascular maturation research. Endothelial cell-derived PDGF-BB can recruit PDGFR-β-positive pericytes or vascular smooth muscle-like cells, enabling newly formed vessels to acquire supporting structures and reduce abnormal permeability.

(1) Recommended detection

PDGF-BB, PDGFR-β, NG2, α-SMA, Desmin, CD31, pericyte coverage, and vascular permeability.

(2) Interpretation focus

Increased CD31-positive vessel number mainly reflects angiogenesis and does not equal vascular maturation. To demonstrate PDGF-BB involvement in vascular stabilization, pericyte coverage and vascular wall support structures should be detected.

3.4 Tissue Repair and Fibrosis

PDGF can promote fibroblast proliferation, migration, and extracellular matrix production, which is beneficial for wound healing. However, long-term or excessive activation can drive tissue fibrosis and pathological remodeling.

(1) Recommended detection

α-SMA, Collagen I/III, Fibronectin, PDGFR-α/β, p-PDGFR, p-ERK, p-AKT, and tissue collagen deposition.

(2) Interpretation focus

In acute repair, PDGF can promote cell migration and matrix remodeling. In chronic injury, it may promote fibroblast expansion and collagen deposition. Research should distinguish “repair-associated activation” from “pathological fibrosis.”

Table 3 Major Functions of PDGF and Detection Directions

4 PDGF-Related Diseases and Application Research

4.1 Tumors and the Tumor Microenvironment

PDGF can act on tumor cells and also on tumor-associated fibroblasts, pericytes, vascular smooth muscle-like cells, and other stromal cells. PDGF-related responses can promote tumor stroma formation, changes in vascular support structures, cell migration, and therapeutic tolerance.

(1) Research focus

PDGF-BB/PDGFR-β is commonly used to study pericyte recruitment and tumor vascular maturation. PDGFR-α abnormalities are often associated with stromal cell activation, proliferation of some tumors, and matrix responses.

(2) Recommended detection

PDGF-AA, PDGF-BB, PDGFR-α, PDGFR-β, p-PDGFR, p-ERK, p-AKT, α-SMA, Collagen I, CD31, NG2, and pericyte coverage.

(3) Interpretation focus

Increased PDGF does not necessarily indicate that tumor cells themselves are driven by PDGF. If PDGFR is mainly expressed in stromal cells or pericytes, it should be interpreted as tumor microenvironment regulation rather than a tumor cell-autonomous proliferation mechanism.

4.2 Vascular Remodeling and Atherosclerosis

PDGF can promote the phenotypic switching of vascular smooth muscle cells from a contractile phenotype to a synthetic phenotype, inducing their proliferation and migration. This process is closely associated with intimal hyperplasia after vascular injury, atherosclerosis, and vascular wall remodeling.

(1) Recommended detection

α-SMA, SM22α, OPN, PCNA, Ki-67, Transwell migration, p-PDGFR-β, p-ERK, and p-AKT.

(2) Interpretation focus

Enhanced smooth muscle cell migration should be interpreted together with phenotypic switching markers. Decreased α-SMA, increased OPN, enhanced migration, and increased proliferation together better support synthetic phenotype transition.

4.3 Fibrotic Diseases

PDGF can promote fibroblast expansion, myofibroblast formation, and extracellular matrix deposition. It is an important growth factor in research on pulmonary fibrosis, liver fibrosis, renal fibrosis, and skin fibrosis.

(1) Recommended detection

PDGFR-α/β, p-PDGFR, α-SMA, Collagen I/III, Fibronectin, p-ERK, p-AKT, and tissue collagen deposition.

(2) Interpretation focus

In fibrosis research, PDGF preferentially drives stromal cell expansion and migration, whereas TGF-β more strongly drives myofibroblast differentiation and matrix production. The two can act synergistically, but their mechanistic positioning differs.

4.4 Neural Development and the Neurovascular Unit

PDGF participates in embryonic neuronal development, oligodendrocyte lineage regulation, and neurovascular unit stability. PDGF-AA/PDGFR-α is associated with oligodendrocyte precursor cell proliferation and differentiation regulation, while PDGF-BB/PDGFR-β is commonly associated with blood-brain barrier pericyte function and neurovascular unit stability.

(1) Recommended detection

PDGFR-α, PDGFR-β, NG2, Olig2, MBP, pericyte markers, blood-brain barrier permeability, and neurological functional recovery indicators.

(2) Interpretation focus

In the nervous system, PDGF functions are cell type-specific. PDGFR-α is more suitable for oligodendrocyte lineage-related interpretation, whereas PDGFR-β is more suitable for pericyte and vascular support cell-related interpretation.

5 Experimental Design and Result Interpretation in PDGF Research

5.1 Ligand Selection

PDGF-AA, PDGF-BB, and PDGF-AB are commonly used for in vitro stimulation experiments. Ligand selection should match receptor expression.

(1) PDGF-AA

PDGF-AA is more suitable for PDGFR-α-positive cells, such as some fibroblasts, oligodendrocyte precursor cells, and stromal cells.

(2) PDGF-BB

PDGF-BB is more suitable for PDGFR-β-positive cells, such as vascular smooth muscle cells, pericytes, and fibroblasts in some fibrosis models.

(3) PDGF-AB

PDGF-AB is suitable for studying mixed PDGFR-α/β-related responses, but the actual response should be confirmed according to receptor expression in the cells.

5.2 Detection Levels

PDGF research should separate short-term receptor activation from long-term functional outputs.

(1) Short-term detection

This is commonly used to determine whether PDGF stimulation activates receptors and downstream mechanisms, including p-PDGFR, p-ERK, p-AKT, p-PLCγ, p-Src, and p-FAK.

(2) Long-term detection

This is used to determine functional outcomes of PDGF, including proliferation, migration, chemotaxis, extracellular matrix production, vascular support structure formation, and tissue repair outcomes.

(3) Dependency validation

To prove that a phenotype is mediated by PDGF-PDGFR, PDGFR inhibitors, neutralizing antibodies, receptor knockdown, or ligand blockade should be used, and synchronous decreases in signaling and functional phenotypes should be observed.

Table 4 PDGF Experimental Design and Interpretation Points

6 PDGF Research-Related Products

7 Common Questions in PDGF Research

7.1 Does Increased PDGF-BB Equal Enhanced Angiogenesis?

Not necessarily. PDGF-BB more commonly reflects pericyte recruitment, vascular wall support cell responses, and vascular maturation. To prove enhanced angiogenesis, endothelial cell indicators, tube formation, the number of CD31-positive vessels, and VEGF/VEGFR-related indicators should also be detected.

7.2 Is PDGF-Promoted Migration Necessarily ERK-Dependent?

Not necessarily. PDGF-induced migration can involve PI3K/AKT, PLCγ, Src/FAK, Rac/Rho, and cytoskeletal remodeling. Increased ERK only indicates activation of the MAPK branch and cannot independently explain the migration phenotype.

7.3 Does Increased PDGFR Expression Indicate Enhanced PDGF Response?

Not necessarily. Increased total PDGFR protein represents enhanced potential responsiveness, but true receptor activation should be assessed by detecting p-PDGFR and downstream indicators such as p-ERK, p-AKT, p-PLCγ, or p-FAK.

7.4 Does PDGF Play the Same Role in Repair and Fibrosis?

Not exactly. In acute injury, PDGF can promote cell migration, matrix remodeling, and vascular support. In chronic injury, persistent PDGF activation may drive fibroblast expansion, smooth muscle-like transition, and collagen deposition, thereby promoting fibrosis.

PDGF research should establish a mechanistic chain around ligand type, receptor subtype, target cell, and functional output. PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD differ in their selectivity for PDGFR-α/β, which determines their application differences in studies of proliferation, chemotaxis, vascular maturation, tissue repair, and fibrosis.

References

[1] Lechertier T, Reynolds LE, Kim H, et al. Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth. Nat Commun. 2020;11:2810.

[2] Bruveris FF, Ng ES, Stanley EG, et al. VEGF, FGF2, and BMP4 regulate transitions of mesoderm to endothelium and blood cells in a human model of yolk sac hematopoiesis. Exp Hematol. 2021;103:30-39.e2.