Platelet-derived growth factors are a family of cystine-knot-type growth factors composed of five functional subunits. Their structure is made up of highly homologous polypeptide chains (A, B, C, and D) that are formed by disulfide bonds (Kazlauskas, 2017; Huttunen and Saarma, 2019). These four types of polypeptide chains are encoded by four genes, among which PDGF-B was first identified via amino acid sequencing and presents a high homology with the simian sarcoma virus oncogene (Doolittle et al., 1983; Waterfield et al., 1983). The cDNA of PDGF-A was obtained by cloning, and its location was identified on Chromosome 7 (Betsholtz et al., 1986). The PDGF protein was discovered using biochemical methods; it is composed of PDGF-A and PDGF-B dimer proteins, as well as PDGF-AB heterodimers. In the early 2000s, genetic and biochemical methods were used to identify new ligands activated by PDGF-C and PDGF-D (Li et al., 2000; Bergsten et al., 2001; LaRochelle et al., 2001). As a receptor for PDGF, platelet-derived growth factor receptor (PDGFR) was also discovered in humans through cross-linking studies (Klinghoffer et al., 2002). Studies have also shown that PDGFR-α and PDGFR-β share common promoter proteins with c-Kit, c-Fms, and FLT (Kazlauskas and Cooper, 1989; Andrae et al., 2008). The five dimer isomers of PDGF have different affinities for the two PDGF tyrosine kinase receptors (TKRs) (Fredriksson et al., 2004; Janneth, 2015; Huttunen and Saarma, 2019); therefore, there are many possible interactions between PDGFs and PDGFRs (Figure 3). The phosphorylation of tyrosine residues in intracellular domains can be promoted by the polymerization of the associated subunit caused by the binding between the PDGF ligand and the receptor (Andrae et al., 2008; Janneth, 2015). Studies have shown that PDGFR-α and PDGFR-β share a common structure—five extracellular immunoglobulin (IG)-type domains and one intracellular tyrosine kinase domain (Figure 3). Various signaling pathways and mediators are activated by receptor phosphorylation, including MAPK, phosphoinositide 3-kinase (PI3K), the Wnt pathway, and phospholipase C (PLC). It has also been confirmed that the A-, B-, and C-polypeptide chains of PDGF can bind to PDGFR-α with high affinity, which means that PDGFR-α can be activated by homodimers PDGF-AA, PDGF-BB, and PDGF-CC, and the heterodimer PDGF-AB. The B- and D-polypeptide chains of PDGF can bind to PDGFR-β with high affinity, which means that PDGFR-β can only be activated by PDGF-BB and PDGF-DD (Carl-Henrik and Bengt, 1999). PDGFR-αβ heterodimers can be induced by PDGF-BB homodimers or PDGF-AB heterodimers. These interaction patterns suggest that PDGFR-α is more promiscuous than PDGFR-β, whereas PDGF-B is more promiscuous compared to other PDGFs. Smaller, less conformationally specific residues at the ligand–receptor interface account for the promiscuous nature of PDGFR-α, with fewer aromatic and hydrophobic residues than PDGFR-β, which has abundant aromatic residues on its ligand-binding surface. The presence of a large number of long-chain hydrophilic residues at the edge of the receptor-binding surface of PDGF-B explains its promiscuity (Lo Conte et al., 1999). PDGF-C is the only member of the PDGF family that has a propeptide-independent recombinant expression of growth factor domains (Shim et al., 2010), the receptor-binding surface, which may be more hydrophilic compared to that of other PDGFs. Thus, PDGF-C can adapt more easily to the ligand-binding surface of PDGFR-α. Finally, compared with other PDGFs, PDGF-CC is most similar to vascular endothelial growth factors (VEGFs), which implies that its underlying function is different from other PDGF members (Reigstad et al., 2005).

Platelet-derived growth factors can be synthesized in various cells, including brain cells, such as neuronal progenitor cells, neuronal cells, astrocytes, and oligodendrocytes, and mainly function by either autocrine or paracrine stimulation. In the processes of wound repair, angiogenesis, and atherosclerosis, cell cycle and gene expression patterns can be regulated by PDGFs. The normal blood vessel wall expresses low levels of PDGF under physiological conditions, whereas, when the intima is damaged, a local increase in PDGF levels predicts adverse remodeling after vascular injury (Andrae et al., 2008). PDGFs can bind to PDGF receptors (PDGFR-α and PDGFR-β) through receptor tyrosine kinase (RTK) activity, which can bind to ligands and phosphorylate tyrosine residues of target proteins, stimulate receptor dimerization, and initiate intracellular signal transduction during biological functions (Chen et al., 2013). PDGF-A transcripts are expressed in the brain during late embryonic development of most neurons, which precedes the differentiation of most glial cells. While proteins containing PDGF-B chains have been found to localize in neurons throughout the CNS of adult non-human primates, such as Macaca nemestrina (Hart et al., 1989), its positive immunohistochemical staining reaction is limited to neuronal perinuclear regions and dendrites. The strength of this response varies with the location of the neuron; blood vessels stain weakly, while glial cells are not stained (Sasahara et al., 1991). PDGF-C and PDGF-A are co-expressed in heart, brain, liver, kidney, and testes, and PDGF-C is widely synthesized in various tissue cells of mouse embryos, including somites, craniofacial mesenchymal cells, cardiomyocytes, arterial smooth muscle cells, cartilage, mast cartilage cells, and the CNS. The expression of PDGF-C is also related to the formation of glandular ducts during embryonic development (Aase et al., 2002), and, in the adult nervous system, it is expressed in cerebellar neurons, anterior olfactory nucleus, pontine nuclei, cochlear neuronal cells, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) (Tian et al., 2021). PDGF-D is widely synthetized in normal human tissues, and exhibits a high degree of expression in adrenal tissue; moderate expression in pancreas, adipose, heart, stomach, bladder, trachea, breast, ovary, and testis tissues; some degree of expression in brain, pituitary, liver, lung tissues; and low or no expression in small intestine, colon, skeletal muscle, thyroid, salivary gland, or thymus tissues (LaRochelle et al., 2001). PDGF-D can also be synthetized in VSMCs, endothelial cells, kidney epithelial cells, and fibroblasts (Borkham-Kamphorst et al., 2015).

Platelet-derived growth factor receptors, including PDGFR-α and PDGFR-β, are synthetized by various neuronal cell types during nervous system development, such as dopaminergic neurons in the SN, cortical neurons, striatal neurons, neurospheres, retinal ganglion cells, and neuronal cells in the inward and outer nuclear layers of the retina (Oumesmar et al., 1997).

PDGFR-α and PDGFR-β are class III RTKs (Lemmon and Schlessinger, 2010), although their expression patterns and physiological roles differ. For example, PDGFR-α signaling pathways regulate the development and formation of gastrula, neuroprotective tissues, and various organs, whereas PDGFR-β receptor expression is required for embryonic neural crest development, astrocyte development and differentiation, and dendritic spine morphogenesis and plasticity (Svitkina et al., 2010; Funa and Sasahara, 2014). In addition, the PDGFR-β signaling pathway plays an important role in the early stages of hematopoiesis and angiogenesis. Furthermore, a wide variety of mesenchymal cells are influenced in PDGFR-α-null embryos, while the deletion of embryonic PDGFR-β results in a lack of smooth muscle cells, particularly VSMCs and pericytes (Wu et al., 2008).

PDGF-BB is expressed in platelets, megakaryocytes, fibroblasts, smooth muscle cells, neurons, oligodendrocytes, and astrocytes (Krupinski et al., 1997; Yu et al., 2001, 2003; Board and Jayson, 2005; Kang, 2007; Trojanowska, 2008). As an important mitogenic factor, PDGF-BB is important for the induction of embryonic and vascular development, wound healing in vivo, chemotaxis regulation, and cell transformation in vitro (Yu et al., 2003; Andrae et al., 2008). PDGF-CC is widely expressed in different types of neuronal tissues, including the brain, eyes, and spinal cord (Hamada et al., 2000; Hao et al., 2000; Aase et al., 2002; Lei et al., 2007). Ding et al. (2004) also showed that a lack of PDGF-CC in mice leads to postnatal developmental defects and death, indicating that PDGF-CC is required for embryonic development (Ding et al., 2004).

Mitochondria balance cell death and survival, which is particularly important for maintaining aerobic balance in neurons in the brain, which consume 2% of the body’s total oxygen. The energy required to maintain the ionic gradient across nerve elementary membranes drives this oxygen demand, which also generates action potential. This demand for energy reflects the importance of mitochondrial function in neuronal cells, and, therefore, mitochondrial dysfunction, mitochondrial DNA mutations, mitochondria-related DNA gene mutations, and the presence of mitochondria-related mutant proteins may be associated with PD. Mitochondria involved in the generation of adenosine triphosphate (ATP) through oxidative phosphorylation participate in the regulation of intracellular calcium ion levels and control membrane excitation and neurotransmission, and, thereby, regulate cell energy metabolism. Thus, mitochondrial damage results in blocked ATP production and elevated reactive oxygen species (ROS), which are one-electron reduction products of a class of oxygen in vivo that can modulate intracellular calcium levels and damage dopaminergic neurons (Rose et al., 2017; Norat et al., 2020). Furthermore, PD is associated with mitochondrial deletion and apoptosis activation (Simpkins et al., 2010). Importantly, mitochondria have different physiological properties in different tissues. For example, mitochondria isolated from the liver are unable to produce free radicals, which, in turn, causes mitochondria in the brain to produce high amounts of oxygen- and carbon-centered free radicals (Dykens, 2007). Mitochondrial damage also impedes the transport of long-distance organelles, rendering neurons with long axons and/or dendrites more vulnerable (Chang and Reynolds, 2006). In addition to proximal mitochondrial damage, the selective susceptibility of different mitochondrial defects in different brain regions may also be related to other factors, such as dopamine- and iron-rich SN, which can jointly exacerbate the oxidative stress caused by catecholamine autoxidation, as well as mitochondrial dysfunction (Hermida-Ameijeiras et al., 2004).

Ceramide can inhibit mitochondrial respiratory chain activity and regulate the permeability of the mitochondrial inner membrane, although its production is not sufficient to induce apoptosis and necrosis in sphingomyelinase-deficient mutant cells or mitochondria (Martin et al., 2006). PDGFs promote mitochondrial glycosylation of ceramides to lactosylceramide (LacCer), which has been shown to potentially affect the function of mitochondria in nerve cells in various ways (Chatterjee et al., 2021). Novgorodov et al. (2016) also found that ceramide synthase activity is not proportional to ceramide levels, while LacCer levels are elevated. This confirmed the dominance of the glycosylation pathway in diabetic mice, showing that the synthesis of LacCer reduces ceramide levels. LacCer, one of the effectors of mitochondrial function, has also been shown to effectively inhibit State 3 respiration and reduce calcium retention capacity (CRC) in baseline mitochondria, resulting in mitochondrial dysfunction (Novgorodov et al., 2016).

The treatment of injured fibroblasts with PDGF-AB increases mitochondrial volume and the ridge surface area, reflecting its ability to induce ultrastructural changes associated with increased energy demand (Gosslau et al., 2001). Indeed, Gosslau et al. (2001) found that application of PDGF to NRK-49F fibroblasts led to a 57% increase in mitochondrial bulk density and a 65% increase in the cristae surface area compared to controls. At the same time, while the density of mitochondria in PDGF-treated cells decreased by 23%, their mean volume increased. These observations demonstrate the effect of PDGF on the mitochondria of nerve cells, which requires further research.

In conclusion, the existing research on the effects of the PDGF family on cell survival by affecting mitochondrial function remains limited and, in some cases, contradictory. As such, there are multiple promising avenues for future research on PDGFs.

Regulate oxidative stress (ROS) generated by cells under oxidative stress in patients with PD can target and attack mitochondria. The long unmyelinated axons of the SN dopaminergic neurons increase energy consumption; this energy state leads to the damage and death of dopaminergic neurons, which leads to compensation by the residual neurons by accelerating the synthesis, metabolism, and renewal rate of dopamine. This further leads to the generation of more oxidative free radicals and further increases oxidative stress, thereby promoting PD progression (Jenner, 2003; Dias et al., 2013; Pissadaki and Bolam, 2013). High levels of ROS, nitric oxide (NO), interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) are neurotoxic, and further activation of the apoptotic pathway via the action of cytochrome C and caspase 3 affects the mitochondrial energy production in dopaminergic neurons (Menza et al., 2010). The cumulative effect of these processes can cause degenerative changes in the associated neurons (Wachter et al., 2010).

Many studies have demonstrated that PDGFs exert neuroprotective effects by protecting neurons and brain cells from direct in vitro glutamate-derived excitotoxicity and hypoxic-ischemic (H-I) injury. Neuronal excitotoxic death can result from overstimulation via elevated levels of extracellular glutamate acting on N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The PDGF-B chain protects neurons by inhibiting NMDA-induced currents and transporting glutamate transporters to the cell membrane. It was found that the balance between N-methyl-D-aspartate receptor (NMDAR) and PDGF-B expression partly contributes to an individual’s susceptibility to brain injury. Furthermore, enhancement of PDGF-B/receptor signaling may protect neonatal brains from H-I injury. Tseng and Dichter (2005) found that PDGF-BB preincubation weakens neuronal death caused by transient exposure to glutamate or NMDA. This protection is concentration- and time-dependent, and excitatory neurons were selectively protected (Egawa-Tsuzuki et al., 2004; Tseng and Dichter, 2005; Ishii et al., 2010). Other signaling mechanisms mediated by signal transducers and activators of transcription (STATs)and activated by PDGF ligands are important for cell proliferation, differentiation, survival, and transformation (Kang, 2007). For example, in vascular muscle cells, the activation of STAT 1, 3, and 6 by PDGF ligands occurs during airway remodeling in asthma via the activation of transmembrane NOX enzymes (nicotinamide adenine dihydrogen phosphate (NADPH) oxidase/dioxidase), leading to the production of hydrogen peroxide (H₂O₂) independent from ROS produced by the mitochondria (Simon et al., 2002). H₂O₂ acts as a secondary messenger in the STAT-activated signaling pathway and is important for the regulation of downstream phosphatase proteins. Therefore, H₂O₂ produced by PDGF ligands may have beneficial effects (Thannickal and Fanburg, 2000). This possible cellular protective effect of PDGF has not yet been verified in any PD model. It was shown that the transient increase in ROS levels following PDGF administration is likely attributable to the induction of membrane NOX enzymatic complexes. PDGF-promoted LacCer synthesis also activates NADPH oxidase to produce ROS, leading to a high oxidative stress environment that stimulates a range of signaling molecules and pathways, resulting in inflammation and atherosclerosis (Pagano et al., 1997). Whether different PDGF isoforms are involved in ROS generation in the nervous system has not yet been determined nor validated in PD models.

Microarray analysis of human umbilical vein endothelial cells (HUVECs) showed that oxidized low-density lipoprotein (oxLDL) induces high expression of PDGF-A and PDGFR-α after 6 h of pretreatment (Virgili et al., 2003). Bovine aorta endothelial cells (BAECs) driving firefly luciferase activity with a 643-bp PDGF-A promoter and exposed to oxLDL and native LDL (40 μg/ml) also showed increased PDGF-A promoter activity compared to vector-transformed cells. Increased expression of PDGF-A, PDGFR-α, and PDGFR-β has also been observed in response to oxLDL in VSMCs (Stiko-Rahm et al., 1992). PDGF-BB preconditioning for 24 h was shown to have significant protective effects against H₂O₂, glucose deprivation, and excitotoxic injury in cultured neurons, as demonstrated in most neuronal models (Cheng and Mattson, 1995; Tseng and Dichter, 2005; Zheng et al., 2010). Cabezas et al. (2015; 2016; 2018) found that pretreatment with PDGF-BB (200 ng/ml) can maintain mitochondrial membrane potential (Δψm) by decreasing the generation of superoxide and peroxide radicals. This, in turn, protects human astrocyte T98G cells from rotenone (50 μM), maintains mitochondrial ultrastructure, and boosts the activation of the PI3K/AKT signaling pathway (Cabezas et al., 2015, 2016, 2018). Northern blot analysis of BAECs exposed to H₂O₂ (25 and 50 μM) for 30 min also demonstrated a significant increase in PDGF-B mRNA expression (Montisano et al., 1992). An early increase in PDGF-B mRNA levels was also observed by expression analysis of (total) RNA in rat lung cells extracted after oxidative injury (Fabisiak et al., 1989). Furthermore, oxLDL enhances PDGF-B expression in HUVECs in a dose-dependent fashion (Zhao and Xu, 2000). In contrast, in BAECs and human monocyte-originated macrophages, oxLDL reduces PDGF-B expression (Van Heek et al., 1998).

Based on this existing research, the protective effects of PDGF for cells under oxidative stress have been widely confirmed. However, the particular responses of different subtypes and in certain cells still require further research.

Previous works have confirmed that dopaminergic neuron activity is affected by an imbalance in Ca²⁺ homeostasis and the modulation of Ca²⁺ carriers (Cieri et al., 2017). Changes in mitochondrial dynamics are also associated with the formation of contact sites in the endoplasmic reticulum. Effective endoplasmic reticulum–mitochondrial communication is required for the maintenance of mitochondrial bioenergetics, Ca²⁺ homeostasis, and cell survival (Paillusson et al., 2016). Thus, disruption of Ca²⁺ signaling molecules and other components may trigger excess Ca²⁺ influx, leading to the degeneration of dopaminergic neurons. Neuroinflammation can also lead to the abnormal expression and aggregation of α-synuclein (Kilpatrick, 2016). Mutual aggravation of α-synuclein and mitochondrial dysfunction, as well as mutual promotion of mitochondrial dysfunction and oxidative stress, further leads to impaired Ca²⁺ homeostasis, creating positive feedback. Such damaging effects are, therefore, continuously enhanced until caspases are activated, thereby inducing cell death (Tran et al., 2020). It has been reported that PDGF can participate in the production of polycyclic aromatic hydrocarbons, and, upon binding to its specific RTK, PLC is activated through a G protein-dependent or independent process. This results in an increase in diacylglycerol (DAG) and inositol triphosphate (IP3) levels, which results in the activation of PLC and the mobilization of intracellular Ca²⁺ (Clark et al., 1995; Yamamura et al., 2021). Cell proliferation, differentiation, and migration are subsequently induced. Serum and glucocorticoid-inducible kinase 1 (SGK1) expression can be stimulated by PDGF in megakaryocytes and circulating platelets. In megakaryocytes, SGK1 activates NF-κB, which causes the expression of calcium release-activated calcium channel 1 (Orai1). Orai1 is a Ca²⁺ channel protein that promotes Ca²⁺ entry, termed store-operated calcium entry (SOCE). SOCE and several Ca²⁺-sensitive platelet functions can be enhanced by SGK1, including degranulation, activation of integrin αIIbβ3, phosphatidylserine exposure, aggregation, and thrombosis (Lang et al., 2015). The level of sphingosine 1-phosphate (SPP), a phosphorylated derivative of sphingosine that acts as an intracellular secondary messenger, can rapidly and transiently increase under the action of PDGF to release Ca²⁺ from internal sources. This occurs independently of inositol trisphosphate receptor (InsP3R), and SPP may link sphingolipid signaling to cellular Ras-mediated signaling by increasing phosphatidic acid levels (Spiegel et al., 1994).

Numerous studies have indicated that, under normal and pathological conditions, intracellular calcium concentration can modulate PDGF-BB signaling (Ridefelt et al., 1995; Pinzani, 2002; Peng et al., 2012; Paul et al., 2015). In this regard, PLC can be activated by PDGF-BB, leading to the formation of IP3 and DAG, which increase the mobilization of Ca²⁺ from the intracellular compartment and lead to the activation of protein kinase C (Powis et al., 1990; Ridefelt et al., 1995). PDGFR-β activates calcium channels, suggesting that PDGF-BB promotes calcium influx and mitosis (Hammerman et al., 1993; Johnson et al., 1993; Prncpadscussan, 1993; Ling et al., 1995). These findings suggest that PDGF-BB has important neuroprotective properties. Indeed, the signaling mechanism of PDGF-BB involved in neuronal protection also includes the activation of anti-apoptotic and survival pathways, such as MAPK, PI3K-AKT, c-JNK, and NF-κB pathways (Romashkova and Makarov, 1999; Wang et al., 2010; Zheng et al., 2010). Calcium influx into cells modulates the activation of these signaling pathways, further affecting the phosphorylation of glycogen synthase kinase 3β (GSK3β) and β-catenin (Zhu et al., 2009; Peng et al., 2012). During cell growth, differentiation, apoptosis, and stress response, PDGF-BB can activate NF-κB by regulating the PI3K/AKT pathway while reducing the production of matrix metalloproteinase 9 (MMP-9) and VEGF (Romashkova and Makarov, 1999; Wang et al., 2010). In other words, the inactivation of GSK3β can be caused by the activation of PI3K/AKT. Furthermore, the inactive form of GSK3β prevents the degradation of β-catenin, thereby promoting its accumulation in the cytoplasm and translocation to the nucleus. This contributes to the activation of genes involved in cell survival (Peng et al., 2012). Additionally, β-catenin is involved in mitochondrial homeostasis, regulation of ATP production, and lipid oxidation (Lehwald et al., 2012; Arrázola et al., 2015). PI3K/AKT also negatively regulates the transcription factor forkhead (FOXO), which contributes to cell survival, oxidative stress regulation, and mitochondrial membrane polarization (Burgering and Medema, 2003; Kato et al., 2006). The importance of the PI3K/AKT pathway in these cellular metabolic processes is self-evident, reflecting the potential value of PDGF-BB.

Insoluble α-synuclein fibers are made of proteins composed of oligomers formed from soluble α-synuclein monomers, and, as these proteins aggregate, they form Lewy bodies (Melki, 2015). In the substantia nigra pars compacta (SNpc), the generation of Lewy bodies is one of the main pathological characteristics of primary PD. Oligomers formed by α-synuclein monomers can induce neuroinflammation by activating microglia, thereby promoting PD. The main pathological features of PD have been replicated in an α-synuclein mouse model (Hasegawa et al., 2017), and oxidation, nitration, the ubiquitin-proteasome system, and the lysosomal autophagy system were all found to be closely related to the degradation of α-synuclein (Wong and Krainc, 2017). The ubiquitin-proteasome system can degrade short-lived soluble proteins by regulating the gene encoding of the protein parkin (PRKN). The lysosomal autophagy system mainly degrades long-lived macromolecular proteins and affects the occurrence and development of PD by regulating the genes encoding the proteins leucine-rich repeat kinase 2 (LRRK2), β-glucocerebrosidase (GBA), vacuolar protein sorting-associated protein 35 (VPS35), and DNAJC13 (Maraganore et al., 2004). The unfolded protein response (UPR) is also involved in PD (Hashida et al., 2012). Elevated levels of ROS and calcium homeostasis imbalance during episodes of PD lead to changes in proteins containing α-synuclein, which stimulate the activation of UPR-regulated proteins, such as PERK kinase, inositol 1α-dependent enzyme (Ire1α), transcription factor 6α (ATF6α), and GRP78/Bip (Wang et al., 2009; Gorbatyuk et al., 2012; Sen, 2015). UPR is a pro-survival response as it reduces protein biosynthesis and enhances the degradation function of the endoplasmic reticulum, thereby reducing the endoplasmic reticulum burden and maintaining intracellular homeostasis (Walter and Ron, 2011). For the first time, Ishimura et al. (2014) demonstrated that PDGF-BB can induce UPR activation in the proliferation of coronary artery smooth muscle cells (CASMC) (Ishimura et al., 2014). Dihazi et al. (2013) also demonstrated that PDGF-stimulated renal fibroblasts or tubular cell lines generate ER stress and activate the UPR. This means that rapidly growing fibroblasts stimulated by cytokines can induce ER stress, leading to the protective UPR and increased expression of folding partners as a protective response (Dihazi et al., 2013).

PDGF-AA and PDGF-BB levels are associated with plasma α-synuclein levels in patients with PD (p < 0.0003), indicating their potential as PD biomarkers. Lue et al. (2016) biochemically validated that levels of thymus, activation-regulated chemokine (TARC), and PDGF-AA are significantly different between the patients with PD with and without dementia (Lue et al., 2016). Furthermore, under the regulation of PDGF promoter, transgenic mice overexpressing human α-Synuclein were generated by Masliah et al. (2000); 12 months later, these mice were found to have motion defects and a loss of dopamine (Masliah et al., 2000). Subsequently, Rockenstein et al. (2002) verified that, in the neocortex and limbic system, the PDGF promoter promotes the expression of human α-synuclein (Rockenstein et al., 2002). Şengül et al. (2021) further verified that overexpression of α-synuclein upregulates the secretion levels of PDGF-AA and PDGF-BB; while the expression of PDGFR-B in cells was shown to increase, PDGFR-B was predicted to interact with α-synuclein based on the Fp-Class PPI prediction tool. Based on Reactome pathway analysis, these authors found that PDGF may trigger the ubiquitin-proteasome system (UPS) and autophagy via the intracellular PI3K/Akt or MAPK pathway (Şengül et al., 2021). These studies demonstrate that PDGF may regulate the degradation of α-synuclein through UPR and autophagy.

The occurrence of PD caused by neuroinflammation is closely related to a variety of genes, including LRRK2. Studies have found that neuroinflammation can activate innate and adaptive immunity in PD by promoting the misfolding and aggregation of α-synuclein (Gao et al., 2008). Inflammatory responses in the olfactory system and gut tissue can also trigger high levels of α-synuclein misfolding, allowing α-synuclein aggregates to escape normal degradation mechanisms (Tomé et al., 2013). Sampson et al. (2016) demonstrated that inflammatory responses in the gut microbiota can promote microglial activation as well as α-synuclein pathological states and motor deficit states (Sampson et al., 2016).

The pathological process of inflammation is related to leukocyte extravasation and migration and involves cell-derived mediators (e.g., cytokines and adhesion molecules) (McCurley et al., 2013). Accumulating evidence suggests that neuroinflammation may play an important role in the pathological changes in patients with PD. PDGF-D can selectively agonize PDGFR-β isoforms, while, on the other hand, PDGFR-β affects macrophage activation, cell infiltration, and cell migration in CNS inflammation (Yang et al., 2016). Transactivation of PDGFR can be induced through the action of the AT1 receptor in VSMCs and tissues, which may support cell growth and migration (Heeneman et al., 2000; Schellings et al., 2006; Suzuki and Eguchi, 2006). PDGFR transactivation also mediates angiotensin II (Ang II)-induced ERK activation in mesangial cells. Ang II, however, depends on the AT1 receptor and acts through RTKs (PDGFR and endothelial growth factor receptor, EGFR) and non-RTKs [proto-oncogene tyrosine-protein kinase (Src), non-receptor protein-tyrosine kinase (Pyk2), and JAK/STAT]. AT1R-mediated activation of NADPH oxidase leads to the production of ROS, thereby promoting neuroinflammation. Simultaneously, these signaling cascades lead to the development and progression of glutamate excitotoxicity, apoptosis, cerebral infarction, astrocyte proliferation, nociception, neuroinflammation, and other neurological disease processes (Mondorf et al., 2000). LacCer synthase/LacCer has also been shown to play a role in cell proliferation, inflammation, and cancer (Asada et al., 1997). Using primary rat astrocytes, Pannu et al. (2004) demonstrated the potential role of LacCer synthase/LacCer in TNF-α-induced inflammation (Pannu et al., 2004). Astrocyte proliferation and LacCer synthase activity increase after stimulation with TNF-α; this was alleviated using D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), along with a 20-mer antisense oligonucleotide in rats. This led to reduced PI3K, Ras, and ERK1/2 expression, and the inhibition of astrocyte proliferation. LacCer also activates inducible nitric oxide synthase (iNOS), thereby promoting NO generation. NO is a neuronal messenger that becomes toxic at high concentrations and exacerbates the progression of several neurodegenerative diseases (Won et al., 2007).

In recent years, research on stem cells in the treatment of neurodegenerative diseases, including PD, has made great progress. Preclinical studies have shown the potential of mesenchymal stem cells (MSCs) for neural transplantation, as this subtype of stem cells is able to migrate to sites of damaged neural tissue, following bone marrow-derived MSCs or amniotic fluid-derived stem cells by intravenous and intracranial transplantation (Li et al., 2001; Chopp and Li, 2002; Hellmann et al., 2006; Cipriani et al., 2007). As a type of MSCs, human endometrial-derived stem-like cells (HEDSCs) have been characterized, which can transdifferentiate into cartilage, bone, fat, and muscle in vitro (Schwab and Gargett, 2007; Gargett et al., 2009). It has also been confirmed that HEDSCs are able to differentiate into dopamine-producing neurons and have the ability to migrate. In vivo, HEDSCs can be transplanted, they migrate to the diseased site, and differentiate spontaneously. The therapeutic benefits of increasing dopamine concentrations in a mouse model of immunocompetent PD have been also demonstrated based on flow cytometry and HEDSC characterization, which were strongly positive for both PDGF-Rβ and CD146 (Wolff et al., 2011).

Ebrahimi-Barough et al. (2013) exposed endometrial stromal cells to growth factors and mitogen PDGF-AA and obtained oligodendrocyte progenitor cells. Their RT-qPCR results verified that these cells expressed OPC markers, including PDGFRα. Furthermore, mir-338 was successfully used to promote oligodendrocyte differentiation of human endometrial-derived stromal cell (hEnSC)-derived OPC, and the data suggest that these cells can be differentiated into the pre-oligodendrocyte phenotype in vitro (Ebrahimi-Barough et al., 2013).

Pelegri et al. (2019) found that 100-ng/ml VEGF/PDGF had the greatest effect on the proliferation of hippocampal neural stem cells (HNSC), and the differentiation pathway induction in this treatment group showed the most significant oligodendrocyte and neuronal markers and morphological characteristics (Pelegri et al., 2019). These promising findings should be verified in further studies on brain and spinal cord injuries, including PD. Additional studies showing that PDGF interacts with stem cells to affect cell function are summarized in Table 2.

The application of embryonic stem cells (ESCs) for PD therapy has been validated by multiple studies, yet the use of ESCs faces difficult ethical issues due to access and application methods. The discovery of the induced pluripotent stem cell (iPSC) technology has greatly helped address these problems. Specifically, numerous studies have demonstrated that iPSCs and ESCs are molecularly and functionally equivalent, avoiding the ethical issues and the constraints of traditional methods. This provides a meaningful solution for a sustainable source of pluripotent stem cells without the need for immunosuppressive agents to combat immune rejection after implantation therapy (Yefroyev and Jin, 2022). Similar to ESCs, iPSCs show self-renewal ability and multi-directional differentiation potential. In recent years, iPSCs and various neurons derived from them have been used in the treatment of neurodegenerative diseases, including PD. Rhee et al. (2011) demonstrated that the behavioral deficits in a rodent model of PD were significantly ameliorated by dopamine neurons derived from protein-based hiPSCs (human-induced pluripotent stem cells) (Rhee et al., 2011). Hartfield et al. (2014) also confirmed that hiPSC-induced dopaminergic neurons can synthesize, secrete, and reabsorb dopamine (Hartfield et al., 2014). Song et al. (2020) have recently developed a more efficient method for generating clinical-grade iPSCs by combining metabolic-regulating microRNAs with reprograming factors. The induced cells exhibit the electrophysiological characteristics of dopamine neurons, and these researchers reported that their transplantation into a PD rodent model potently restores motor function and reactivates the host brain, helping progress toward human personalized autologous cell therapy for PD (Song et al., 2020). The study by Kikuchi et al. (2017) demonstrated that human iPSC-derived dopaminergic progenitor cells survive and function as midbrain dopaminergic neurons in a PD primate model (a cynomolgus monkey) treated with the neurotoxin MPTP (Kikuchi et al., 2017). In addition, secondary changes in the GABAergic nervous system can also directly or indirectly affect the pathogenesis of PD (Mochizuki et al., 2008). Studies have also demonstrated that human-derived iPSCs can be directly induced into GABAergic neurons, thus providing candidate cells for PD therapy (Liu et al., 2013). However, while iPSCs can replace patient-specific diseased cells, this approach is not without limitations. For example, genomic instability and epigenetic aberrations must be considered, which may be caused by reprograming (Weissbein et al., 2014). Furthermore, due to the low degree of differentiation of iPSCs, once out of control, they may form difficult-to-treat tumors. At present, there is a lack of clinical research on the relationship between iPSCs and PDGFs, and their possible combined role in PD generation is unknown.

Several studies have shown that PDGFs can be combined with other cells, carriers, cytokines, and biological materials to deliver effects to the injury site (Johnson et al., 2010). In terms of genes, Liu et al. (2011) constructed the hS100B transgenic vector by inserting the human S100B gene downstream to the PDGF promoter, which was then microinjected to generate transgenic mice. They confirmed that S100B overexpression in the brain leads to a motor coordination disorder, which may be related to the downregulation of D2DR and GRK2 expression, increased dopamine anabolism, and reduced 5-HT levels (Liu et al., 2011).

As a rapidly developing technology, the efficient delivery of genetic material in neurons using viral vectors is a key approach of gene therapy, thus modulating the expression of one or more specific genes. Gene therapy for PD has undergone three significant changes in the past two decades (Bjorklund and Davidsson, 2021), from ex vivo gene transfer using retroviral vectors to in vivo gene expression using adenovirus, herpes simplex virus (HSV), or lentiviral vectors. Recently, a major breakthrough has been made in the application of adeno-associated virus (AAV) vectors in CNS gene therapy, involving the repair of dopamine synthesis, strengthening of trophic factor production and lysosomal function, or alteration of the interactions between different functional nodes of the basal ganglia, including clinical trials for PD (Merola et al., 2020).

In the case of PD gene therapy, AAV capsid engineering shows some promise. For example, an AAV-2 vector containing a hybrid CMV E/PDGF promoter was developed and found to be superior in driving gene expression in SN dopaminergic neurons (Wang et al., 2005). However, not every cell surface can be targeted for AAV-engineered therapy, making precise and specific regulation of each target difficult. Although gene therapy is generally irreversible, in some cases, it can be modulated by modulating the inflammatory state and the cascade of apoptosis. Earlier approaches to inserting cell-type-specific promoters into the AAV genome to drive its transgene expression led to disappointing results with unsatisfactory specificity (Mudannayake et al., 2016). Current sequencing technologies allow the addition of short enhancer sequences upstream of minimal promoters, which helps accurately identify short enhancer elements with specificity. This approach was successfully used to identify enhancer elements associated with PD (Graybuck et al., 2021). Relevant dopamine neuron subtypes and disease states can be identified by the AAV vector, enabling precise-targeted expression of therapeutic transgenes, avoiding immune responses, and reducing the dose required. Engineered AAV vectors can be combined with cell therapy from exogenous cell sources, such as ESC or IPS cells, to facilitate dopamine engraftment for enhanced therapeutic efficacy. Therefore, AAV engineering has the potential to radically improve target specificity (Xiong et al., 2021).

In a future where autologous cell transplantation (including reprograming) is commonplace, any disease-causing genetic changes in host cells may be treated by viral vector engineering (e.g., alpha-synuclein overexpression) (Stoddard-Bennett and Reijo Pera, 2019). Such therapies can target macroautophagy, slow neuronal aging, and rejuvenate dopamine neurons, even in presymptomatic PD or in people at high risk of developing PD (Benito-Cuesta et al., 2017; Lu et al., 2020; Minhas et al., 2021). Therefore, genetically targeted therapy could be used for neuroprotection and the prevention of neurodegenerative diseases in the wider population. In addition, delivery strategies based on nanoparticles (NPs) can improve the stability of NTFs and, thus, have potential for clinical applications. NPs have been confirmed to function as non-viral vehicles to deliver drugs to different cells and organs (Oberdörster et al., 2007). The advantage of this approach is that they can passively accumulate in specific cells by improving the stability and physicochemical properties of active drugs. However, most of the current approved nanomedicines are cancer drugs; the application of NPs in PDGF-replacement support therapy for PD may become an important clinical strategy to slow down or even reverse disease progression in the future (Bondarenko and Saarma, 2021).

Epigenetics refers to changes in gene expression or function that occur without changes to the DNA sequence. This plays an important role in regulating neural development, neural stem cells, and the physiological functioning of the nervous system. In recent years, epigenetic modification, as the link between heredity and the environment, has gradually attracted attention for its relationship with the pathogenesis of PD (Jasiulionis, 2018). Epigenetic modifications include DNA methylation, DNA hydroxymethylation, histone modifications, and non-coding RNA (ncRNA)-mediated changes in gene expression.

It has been confirmed that DNA methylation can regulate the PD pathogenic gene SNCA (Matsumoto et al., 2010). Based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-deactivated Cas9 (dCas9) fused with the catalytic domain of DNA-methyltransferase 3A (DNMT3A), Kantor et al. (2018) targeted methylation of SNCA intron 1 using a lentiviral vector, which resulted in the downregulation of SNCA mRNA and its protein in PD patient-derived neurons, thereby alleviating associated cellular phenotypic features, including mitochondrial ROS production and cellular activity (Kantor et al., 2018). In addition, the MAPT gene is associated with the pathogenesis of PD because it encodes the microtubule-associated protein tau. Different MAPT methylation levels have been observed in frontal cortex and peripheral blood leukocytes between patients with PD and the controls (Masliah et al., 2013). Marshall et al. (2020) found that more than 70% of 1,799 differentially methylated sites of enhancers in neurons of patients with PD had elevated methylation levels. Among the 2,885 genes involved, these researchers identified many risk genes related to the pathogenesis of PD, including DCTN1, PRKN, and DJ-1, and showed that the inactivation of the TET2 gene can have a therapeutic effect on PD by reducing neuroinflammation (Marshall et al., 2020). Han et al. (2014) demonstrated that VSMC proliferation can be caused by the epigenetic regulation of PDGFs; they found that homocysteine induces the hypomethylation of the PDGF gene promoter region and upregulates its mRNA and protein expression (Han et al., 2014). However, the specific roles of PDGF methylation in PD need to be explored in the future.

In recent years, the DNA hydroxymethylation epigenetic modification has gradually attracted attention, as its correlation with neurodegenerative diseases has been verified (Sherwani and Khan, 2015). Studies have shown that, in patients with PD, the median level of the hydroxylated form of 5-methylcytosine, 5-hydromethylcytosine (5hmC), almost doubles that in controls (Stöger et al., 2017). This suggests that DNA hydroxymethylation is associated with the pathogenesis of PD, although there is still a lack of research in this area. Thus far, no research has focused on the DNA hydroxymethylation of PDGF genes.

Histones are octamers composed of H2A, H2B, H3, and H4, with tail residues presenting various types of post-transcriptional modifications, including methylation, acetylation, phosphorylation, ubiquitination, ADP ribosylation, deamination, proline isomerization, and lysine threoninylation. Studies have shown that histone acetylation levels are significantly elevated in midbrain dopaminergic neurons of patients with PD (Park et al., 2016). Curcumin, a histone deacetylase (HDAC) inhibitor, was found to reduce apoptosis and improve motor deficits in a DJ-1 knockout rat model of PD (Chiu et al., 2013). HDAC inhibitors are also able to reduce neuroinflammation by reducing microglial activation, thereby protecting dopaminergic neurons. On the other hand, as the main cause of autosomal dominant familial PD, the pathogenic effects of LRRK2 mutations are closely related to histone modification. LRRK2 can bind to the ser424 site of HDAC3 and directly phosphorylate HDAC, thereby stimulating its activity and promoting histone H4 deacetylation, resulting in gene transcriptional repression. In addition, increased nuclear DNA damage and abnormal histone methylation were observed in striatal neurons of Lrrk2-/-aged mice (Chen et al., 2020). Histone modifications are also present in certain neural factors promoting dopaminergic neuron growth. These include modifications in the promoter regions of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). A variety of HDAC inhibitors can also cause upregulation of GDNF and BDNF gene expression (Yue et al., 2014). Owens (2007) showed that phenotypic switching of smooth muscle cells (SMCs) in response to PDGF-BB in vitro is ended, owing to the loss of a subset of activating histone modifications at gene loci encoding SMC marker genes (Owens, 2007). This may be enlightening for the research related to PDGF histone modifications.

m⁶A methylation is the most prevalent modification of eukaryotic mRNA. Foo et al. (2017) analyzed m⁶A-modified genes in 1,647 sporadic patients with PD and 1,372 controls. These authors found 214 rare mutations in all m⁶A-modified genes, and 16 common mutations were found in seven genes, implying that the pathogenesis of PD is related to m⁶A methylation (Foo et al., 2017). Studies have also shown that m⁶A reduction can induce the expression of NMDA receptor 1, increase oxidative stress and Ca²⁺ influx, and cause dopaminergic neuron apoptosis (Chen et al., 2019). At present, research on the role of m⁶A methylation in the pathogenesis of PD remains very limited. Zeng et al. (2021) showed that, compared with that in the controls, m⁶A methylation was increased in the lung tissues of a rat model with pulmonary arterial hypertension, and the up-methylated genes coding for the PDGF signaling pathway were primarily enriched (Zeng et al., 2021). Further research exploring the relationship between PDGFs and m⁶A methylation is needed.

Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been found to have varying expression levels in PD patients, and take part in regulating the pathogenetic mechanisms of PD (Roy et al., 2022). For example, miR-7 and miR-153 were proved to lower SNCA (synuclein α) expression levels (Junn et al., 2009; Doxakis, 2010), which is closely related to PD. Negatively controlled by LRRK2, miR-let-7 and miR-184 are involved in the reduction of dopamine levels in dopamine-producing cells (Gehrke et al., 2010). Both miRNAs and lncRNAs have been found to be diagnostic biomarkers for PD (Zhang et al., 2022). The interaction between PDGF and non-coding RNAs has been explored, especially in SMCs. MiR-24 can inhibit the proliferation and angiogenesis of VSMCs by suppressing the PDGF-BB signaling pathway (Yang et al., 2018). In PDGF-BB-stimulated airway smooth muscle cells (ASMCs), the expression of lncRNA PINT was reduced, while miR-26a-5p expression was increased (Gao et al., 2021). The current understanding of the interactions between non-coding RNAs (miRNA and lncRNA) and PDGF is summarized in Figures 5, 6 and more details are provided in Tables 3, 4. As the association between PDGFs and non-coding RNAs in PD treatment has not been explored, the information in these tables may help provide ideas for future research on PD-related treatments.

A variety of epigenetically related drugs is currently under investigation. For example, DNMT inhibitors can simultaneously upregulate the transcription of neuroprotective genes, including TH genes and PD causative genes, such as SNCA and UCHL1 (Wang et al., 2013). Although studies have confirmed that HDAC inhibitors can exert neuroprotective effects in vitro and in vivo, their mechanism of action in PD still needs further research (Hegarty et al., 2016). The study of epigenetic modifications in PD is of great significance for discovering potential biomarkers for early diagnosis of PD and its treatment; however, epigenetic modification itself is complex and affected by various factors, such as diet and environment. Therefore, the treatment of PD via epigenetic modification targets requires further basic and clinical research.

Exosomes are extracellular vesicles secreted by various kinds of cells. These can be loaded with different cargos, including proteins, lipids, non-coding RNAs, and drugs. Exosomes are ideal carriers as the cargos can be uptaken by target cells without provoking an immune response and avoiding the impediment of the BBB (Wang et al., 2020). Exosomes have been found to play important roles in neurodegenerative diseases, including PD. There is growing evidence that exosomal miRNAs play a key role in PD progression (Cardo et al., 2013; Hoss et al., 2016; Wang et al., 2020). Meanwhile, feasibility of a miRNA exosome-based delivery system has been confirmed in an animal model. Mao et al. found that exosomes carrying miR-34a, released from astrocytes, can enhance the sensitivity of dopaminergic neurons to neurotoxins in a PD model by targeting Bcl-2 (Mao et al., 2015). Moreover, delivery of the loaded drugs to target neuronal cells may increase therapeutic efficacy. For example, Haney et al. developed an exosome-based delivery system for a potent antioxidant, catalase, to treat PD; the catalase-loaded exosomes provided significant neuroprotective effects both in in vivo and in vitro models of PD (Haney et al., 2015). Yang et al., 2021 demonstrated that exosome-mediated antisense oligonucleotide delivery significantly improved locomotor functions in α-syn A53T mice after exosome–drug injection.

PDGF-loaded exosomes have also been explored. Exosomes, including PDGF-AA derived from differentiating human skeletal myoblasts (HSkM), can induce in vitro myogenesis of human adipose-derived stem cells (HASCs) and improve in vivo muscle regeneration (Choi et al., 2016). Adipose tissue, bone marrow, and umbilical cord MSCs secrete exosomes holding PDGF-BB, which can promote keratinocyte and dermal fibroblast proliferation and migration (Hoang et al., 2020). The interaction between exosomes and PDGFs is summarized in Table 5.

As an emerging technology, single-cell transcriptomics supports the direct analysis of gene expression at the single-cell level as well as the analysis of intracellular population heterogeneity and the definition of cell types, cell states, and dynamic transitions of cells. In addition to identifying novel cell subtypes and rare cell populations, single-cell sequencing techniques also contribute to understanding transcriptional dynamics and gene regulatory relationships. For example, Hook et al. (2018) characterized dopaminergic neuronal populations in the mouse brain at embryonic and early postnatal time points using single-cell RNA-seq. Their scRNA-Seq results confirmed 110 marker genes associated with PD in postnatal dopaminergic neurons, demonstrating how this approach opens up a new era in PD gene research (Hook et al., 2018). Lang et al. (2019) mimicked a disease model of PD in iPSC-dopamine neurons and further identified HDAC4 as a regulator of the PD cell phenotype. Their work demonstrates that single-cell transcriptomics can exploit cellular heterogeneity to clarify disease mechanisms and identify therapeutic targets (Lang et al., 2019). In an in vitro model of human PD, dopamine neuron-specific stress responses were revealed using single-cell transcriptomics, with implications for cell replacement therapy. The progression of PD involving multiple cell types, such as astrocytes, oligodendrocytes, and microglia, has also been validated with single-cell transcriptomics (Tiklová et al., 2020). Current research on single-cell omics in PD still needs to be developed to improve our understanding of the etiology of PD at the level of different cell types and has an irreplaceable role in targeted therapy.

Single-cell transcriptomics has been used to determine the roles of PDGFs in certain physiological and pathological mechanisms. Based on single-cell transcriptional profiling, Gan et al. found that the PDGF cascade is an important cue in the nucleus pulposus microenvironment of healthy human intervertebral disks (Gan et al., 2021). With the help of single-cell transcriptome profiling of fetal osterix-expressing cells, Bohm et al. identified PDGF-PDGFRβ signaling as a critical functional mediator of skeletal stem and progenitor cell expansion, migration, and angiotropism during bone repair (Böhm et al., 2019). No studies, however, have used single-cell transcriptomics to explore the roles of PDGFs in the pathophysiological mechanisms or treatment of PD.

The CRISPR-Cas system, a series of RNA-guided endonucleases, is an adaptive immune defense against viruses or foreign gene integration formed by bacteria during long-term evolution. The type II CRISPR system includes four genes (Cas9, Cas1, Cas2, and Csn1) and two non-coding RNAs (pre-crRNA and tracrRNA) that can target and degrade foreign DNA in a sequence-specific manner (Garneau et al., 2010). Soldner et al. (2016) used the CRISPR/Cas9 gene-editing method to introduce two mutations into isogenic human pluripotent stem cells, changing only the genes on one chromosome and leaving the other chromosome unchanged. Although one of these two mutations had no effect, the other mutation (from A to G) increased SNCA expression (Soldner et al., 2016). This approach could potentially be used to identify other causative genes in sporadic PD. Wang et al. (2016) also used the CRISPR/Cas9 system to inject Cas9 mRNA and a variety of sgRNAs into Bamaxiang pig prokaryotic embryos, targeting three different loci—DJ-1, Parkin, and Pink1. The piglets appeared healthy and behaved normally, with no manifestations of mutations being identified. This shows that the CRISPR/Cas9 system has great potential in the treatment of PD (Wang et al., 2016). Guhathakurta et al. (2021) further developed a CRISPR/dCas9-based site-specific H3K4me3 demethylation system that recruited the demethylase JARID1A catalytic domain to the SNCA promoter, significantly reducing the level of H3K4me3 modification at the SNCA promoter. At the same time, the level of α-synuclein was significantly reduced (Guhathakurta et al., 2021). The gene-editing technology mediated by the CRISPR system can not only accurately introduce disease-causing genes into specific cells to construct human disease model cells but also achieve repair through homologous recombination mediated by the CRISPR/Cas technology. This provides new opportunities for treatment at the gene level for genetic variant-related neurodegenerative diseases, including PD.

The CRISPR/Cas9 system, as well as PDGFR-B siRNA and pCMV3-PDGFR-B plasmid, was used to identify PDGFR-β as a potential therapeutic target for pterygium (Mai et al., 2019). Lin et al. established a thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions through CRISPR/Cas9, and demonstrated that xenograft distant lung metastasis was completely eliminated by PDGFRA gene editing; therefore, PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid carcinoma (Lin et al., 2021). CRISPR/Cas9-mediated depletion of PDGFRβ in cell lines derived from epiretinal membranes of patients with proliferative vitreoretinopathy attenuated vitreous-induced Akt activation and cell proliferation, migration, and contraction (Yang et al., 2020b). Therefore, the CRISPR/Cas9 system is a promising method to better understand the association between PD and PDGFs, and to treat PD with PDGF-derived drugs.