Extensive studies have deepened our understanding of the intricate relationship between PDGFs expression and neurodegenerative diseases. Both PDGFRα and PDGFRβ receptors, expressed by various neuronal cell types, are crucial for brain development and function [30-32]. PDGFs are crucial for the development and specialization of oligodendrocyte progenitor cells, which are essential for myelination in the central nervous system [33-37]. PDGFs are vital for maintaining the integrity of the blood-brain barrier (BBB) and supporting neurovascular unit stability. Studies have shown that mice with disrupted meningeal PDGF-C signaling exhibit severe vascular abnormalities and impaired brain development [38,39].

Ischemic stroke prompts the formation of new blood vessels in damaged tissues to support repair and recovery. Brain pericytes, which interact closely with endothelial cells, regulate BBB formation, angiogenesis, and vascular functions [40-44]. During ischemic stroke, pericytes are rapidly lost in the infarct core and detach from the endothelial cells in the adjacent region, leading to vascular destabilization and secondary injury [45,46]. Following ischemic stroke, PDGFRβ expression in pericytes is upregulated, playing a vital role in regulating their survival, migration, and interactions with endothelial cells in the brain. PDGF-B, produced by endothelial cells involved in blood vessel formation, activates PDGFRβ signaling to recruit pericytes and ensure the stability of newly formed blood vessels [32,47-49]. Additionally, PDGF-D, another ligand of PDGFRβ, supports pericyte function and promotes angiogenesis, thereby enhancing neurovascular integrity, promoting neuronal survival, facilitating neovascularization, and improving neurological recovery post-stroke [50,51]. Pericyte activation has been found to be associated with neurorestorative effects and vascular stabilization observed in the striatum of Parkinson’s disease lesions [52,53]. PDGF-BB, which activates pericytes, has emerged as a potential therapeutic option for Parkinson’s disease, a debilitating neurodegenerative disorder characterized by deterioration of the nigrostriatal pathway and resulting motor dysfunction [54,55].

Glioblastoma multiforms (GBM) requires new treatments to enhance patient survival and quality of life. One promising strategy is CP-673451, an inhibitor of tyrosine kinase receptors that specifically targets PDGFRα/β [56-60]. This potent inhibitor induces the differentiation of GBM cells by downregulating phosphorylated p38 mitogen-activated protein kinase (MAPK), thereby reducing the proliferative and invasive properties of tumor cells [59,61]. The occurrence of PDGFRA abnormalities is more frequently observed in pediatric high-grade gliomas than in adults and is associated with enhanced pro-tumorigenic potential and less favorable prognosis [62-65]. However, when considering effective GBM treatments, monotherapies targeting a single receptor tyrosine kinase (RTK) may prove insufficient because of the presence of multiple RTK subpopulations in GBM. Considering the heterogeneity of tumors and enhanced treatment outcomes, it may be necessary to employ combinations or alternative therapies that target multiple pathways [66-69]. Studies suggest that PDGFRα and epidermal growth factor receptor (EGFR) amplications likely arise from common parental cells but can evolve independently, resulting in distinct subpopulations. In GBM, PDGFRα-amplified cells constitute a minor population interspersed within the EGFR-amplified regions [67-70]. An autophagy, a crucial cellular degradation process, plays a significant role in cancer, particularly glioblastoma, an aggressive and deadly brain tumor [71-73]. Despite the complexities arising from tumor heterogeneity and mutations, targeting autophagy may offer promising anti-cancer strategies. It regulates PDGF-A signaling, which is a key factor in uncontrolled tumor growth. Once activated, PDGF-A is degraded via autophagy, which involves SQSTM1/p62. Inhibiting autophagy has been observed to dramatically alter PDGFRα levels and activity, with reducing PDGFRα levels, thereby affecting tumor formation [72,74].

Neurodegenerative disorders are defined by the gradual loss of neurons and subsequent decline in nervous system function. Studies have identified the involvement of the PDGF/PDGFR signaling in several neurodegenerative conditions, notably Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis [55,75-77]. PDGF-BB plays a complex role in these diseases, particularly in Alzheimer’s disease. In this condition, PDGFRβ signaling deficiency leads to pericyte loss and BBB disruption. The observed correlation between reduced plasma PDGF-BB levels and mild cognitive impairments indicates that PDGF-BB could serve as both a diagnostic indicator and potential treatment strategy [55,76]. PDGF-BB exhibits neurorestorative effects by enhancing tyrosine hydroxylase fiber intensity, increasing tyrosine hydroxylase expression in dopaminergic neurons, and restoring dopamine transporter binding. These actions contribute to the alleviation of behavioral impairments associated with neurodegenerative diseases [55,78]. In contrast, PDGF-CC plays a different role in amyotrophic lateral sclerosis. It contributes to vascular abnormalities by disrupting the blood-spinal cord barrier. This finding suggests that inhibiting PDGF-CC may have therapeutic potential in experimental models of amyotrophic lateral sclerosis [77,79].

In our previous study, we analyzed large-scale gene expression data to identify genes that may be influenced by PDGFRα in gliomas. We compared the gene expression profiles across the entire genome between PDGFRα-positive and PDGFRα-negative cells originating from human oligodendrocyte progenitors [80]. Dysregulated genes in PDGFRα-positive cells, deemed PDGFRα-influenced, are strongly associated with cancer-related pathways. From this set of genes, we developed a prognostic gene signature capable of predicting clinical outcomes in two independent glioma cohorts, irrespective of conventional predictive indicators. Our results suggest that PDGFRα-regulated genes may function as valuable biomarkers and potential therapeutic targets in both clinical and therapeutic contexts. Understanding the diverse roles of PDGFs in nervous system development and cancer, particularly glioblastoma, offers significant insights into potential therapeutic strategies.

Rapid proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are crucial contributors to the onset of pulmonary arterial hypertension (PAH) and right ventricular failure [81,82]. This vascular remodeling is induced by growth factors such as VEGF, transforming growth factor-beta (TGF-β), and PDGF [83-86]. Studies have emphasized the importance of targeting PDGF signaling in the lungs, because PDGF and its receptors are crucial for regulating cellular growth, differentiation, migration, survival, and metabolic processes [87-94]. Gene knockout experiments have elucidated the essential role of PDGF-A and PDGFRα signaling in the development of lung alveoli [14,95]. PDGF-B signaling via PDGFRβ is primarily produced and secreted by endothelial and circulating inflammatory cells [85,96].

Increased activity of the PDGF pathway has been observed in pulmonary vascular lesions of patients with PAH [85,97]. Idiopathic pulmonary fibrosis (IPF), a fatal lung disorder characterized by advancing tissue scarring, is primarily mediated by the activation and transformation of fibroblasts into myofibroblasts via TGF-β1 and PDGF signaling [98-100]. Several novel targeted pathways are currently under investigation to improve the treatment of lung disorders, and preclinical and clinical studies have demonstrated increased expression and activation of PDGFRα and PDGFRβ in IPF PASMCs. Inhibition of PDGFR has been demonstrated to be effective in animal models of PAH [101,102], and blocking PDGFRα/β signaling has shown potential in attenuating the progression of IPF, fibrosis, and lung cancer, highlighting the importance of understanding this pathway for effective treatment [29,92,103,104]. For instance, olaratumab, a monoclonal antibody targeting PDGFRα, has been utilized in cancer therapy and has potential applications in lung diseases by neutralizing PDGFRα-mediated signaling pathways, thereby reducing lung cancer growth [92,105].

TGF-β interacts synergistically with other growth factors, such as fibroblast growth factor 2 and epidermal growth factor, providing additional opportunities for combination therapies targeting TGF-β. This indicates the inhibition of multiple kinases, including PDGFR, VEGRF, and FGFR, which can produce broader therapeutic effects [106-108]. Concurrently, targeting the TGF-β and PDGF-BB pathways has demonstrated synergistic effects in reducing the hyperproliferation and remodeling of PASMCs in PAH. Notably, dual inhibition of TGF-β and PDGF exhibited promising results in mitigating radiation-induced pulmonary fibrosis, suggesting the potential of this combination therapy [109,110]. Targeting the PDGFR, CSF1R, and KIT kinases may also offer a novel therapeutic approach, as these kinases are highly expressed and upregulated in cells characteristic of pulmonary arteriolar lesions in PAH [88]. These kinases induce inflammation and abnormal cell proliferation through autocrine and paracrine signaling pathways. Interests in the use of tyrosine kinase inhibitors (TKIs) for PAH has emerged from promising preclinical and clinical efficacy data, demonstrating that orally administered imatinib reduces pulmonary vascular resistance and improves exercise capacity [111]. However, its systemic side effects limit its use [112]. Seralutinib, a PDGFR/CSF1R/c-KIT inhibitor, has demonstrated higher potency and fewer systemic side effects than imatinib and, exhibits greater efficacy against PDGFRβ and CSF1R [88,113,114].

PDGF plays a crucial role in asthma pathogenesis by promoting several key processes involved in airway remodeling. It stimulates airway smooth muscle cell proliferation and migration, while also enhancing collagen production by lung fibroblasts. These effects contribute significantly to the structural changes observed in asthmatic airways [115-118]. Studies in mouse models have provided strong evidence for PDGF’s involvement in asthma. Overexpression of PDGF-BB in mouse airway epithelium resulted in increased airway smooth muscle and altered gene expression. Furthermore, chronic allergen exposure in mice led to elevated PDGF-BB levels in broncho-alveolar fluid, supporting its role in airway smooth muscle remodeling [115,117,118]. Given the importance of airway remodeling in asthma progression, researchers are exploring new therapeutic approaches targeting PDGF signaling. TKIs such as nilotinib, imatinib, and mastinib are being explored to evaluate their potential in modulating PDGF pathways and improving asthma management [118-121]. Beyond asthma, PDGF also plays a significant role in other lung pathologies, including non-small cell lung cancer. Studies have shown that PDGF-AA acts as a crucial autocrine regulator of VEGF expression in these tumors, influencing tumor size and patient prognosis [122]. Our knowledge of PDGF’s functions in multiple lung diseases emphasizes its significance as a potential treatment strategy, offering new possibilities for developing therapies for asthma and lung cancer.

Liver fibrosis is a pathological wound healing response triggered by chronic liver injury. This condition is characterized by excessive accumulation of ECM and abnormal connective tissue growth, leading to severe complications, such as liver failure, cirrhosis, or cancer [123-126]. Chronic liver diseases associated with fibrosis have increased global morbidity and mortality rates, which continue to rise. In the case of short-term liver injury, fibrosis is typically avoided because of the balance between pro-fibrosis and anti-fibrosis mechanisms. However, prolonged or chronic liver damage compromises the hepatocyte membranes, leading to hepatocyte necrosis and apoptosis [127-130]. Damaged hepatocytes release molecular signals that activate hepatic stellate cells (HSCs). These cells respond to chemotactic signals such as PDGFs, TGF-β1, epidermal growth factor, and type I collagen by migrating to inflamed regions, thus driving the progression of hepatic fibrosis [131-134]. Upon activation, the HSCs migrate to the site of liver injury, where they enhance contractility, upregulate alpha smooth muscle actin expression, and secrete a range of cytokines such as TGF-β1, PDGF, and connective tissue growth factor. Although this response initially aids wound healing, prolonged fibrosis ultimately alters the liver sinusoid structure, compromising liver function and potentially progressing to cirrhosis [132,135-138]. Emerging evidence has suggested that HSCs are the primary targets for liver fibrosis treatment, with dysregulated PDGF-B/PDGFRβ signaling playing a crucial role in the pathological trans-differentiation of HSC and the progression of liver fibrosis [139-141]. PDGF-BB is a potent mitogen for HSCs that, promotes the synthesis of various ECM components. Therefore, inhibiting the formation of the PDGF-BB/PDGFR-ββ complex is essential for anti-fibrosis therapies.

In addition to PDGFRβ, PDGFRα is also expressed in HSCs and myofibroblasts within the murine liver, indicating its involvement in cell proliferation and migration in human primary HSCs [142-144]. PDGF-C binds to and activates PDGFR; however, unlike PDGF-A and PDGF-B, it requires extracellular proteolytic cleavage to form the complete precursor [145,146]. PDGF-CC specifically interacts with PDGF-α/α homodimers and PDGFR-α/β heterodimers, but does not bind to PDGFR-β/β homodimers, ensures that its effects are dependent on the expression of PDGFRα [146-148]. It promotes DNA replication in various mesenchymal cells, including stellate cells, indicating its potential involvement in fibrogenesis [149-151]. Studies using transgenic mice expressing PDGF-C (PDGF-C Tg) have reported HSC activation, chronic inflammation, and liver injury [150,152,153].

Given the critical role of PDGF/PDGFR signaling in liver fibrosis, targeting this pathway offers a promising therapeutic strategy. Several TKIs that block PDGFR activity have been developed and evaluated in preclinical and clinical studies. These inhibitors are effective in reducing HSC proliferation and ECM production by inhibiting PDGFR signaling [154,155]. Olaratumab, a monoclonal antibody against PDGFRα, has shown to decrease cell proliferation and exhibit notable anti-tumor effects [28,144,156]. Kikuchi et al. [142] observed that HSCs and myofibroblasts exhibited elevated PDGFRα expression in chronic liver injury models. They found that olaratumab effectively inhibited HSCs proliferation and migration, while the fibrosis-promoting gene expression remained unaltered. These effects are mediated by various signaling pathways, such as Erk1/2, p38, Elk-1, AKT, mTOR, and CrkII/CrkL [144]. Although TKIs provide essential benefits, clinical cases have reported hepatotoxicity associated with various TKIs. For example, sorafenib demonstrates significant individual variability in pharmacokinetics and efficacy [157]. More concerning, severe hepatotoxicity and liver failure have been documented in patients receiving treatment with sorafenib and imatinib [158-160].

PDGFRα not only plays a profibrotic role in HSCs during chronic liver injury but also enhances the immune response by assisting macrophages in clearing dying hepatocytes, thereby improving liver health despite ongoing damage [142]. It has also been demonstrated that pharmacological intervention of PDGF-BB/PDGFRβ signaling migrates hepatocyte injury and cholestatic fibrosis caused by bile duct ligation [139]. Traditional Chinese medicine targets PDGFRβ, modulates the PDGF-BB/PDGFRβ signaling pathway, inhibits HSC activation and migration, promotes HSC apoptosis, and reduces CCl4-induced liver fibrosis [161,162]. The combination of PDGFR inhibitors with other anti-fibrotic agents has exhibited synergistic effects in reducing liver fibrosis. For instance, combining PDGFR inhibitors with TGF-β signaling inhibitors, another crucial pathway in fibrosis, has demonstrated enhanced anti-fibrotic outcomes [163,164].

GI tract development relies on complex signaling between epithelial and mesenchymal cells, resulting in the formation of organized villi and crypt structures, characterized by rapid cell renewal and differentiation [165,166]. This process is influenced by PDGF-A and its receptor, PDGFRα [167-171]. In the absence of these factors, the GI mucosal lining becomes abnormal, the villi are reduced in number, and the pericryptal mesenchyme is lost owing to disrupted villus morphogenesis and mesenchymal cell signaling. Mesenchymal cells expressing PDGFRα support intestinal stem cells, with distinct subpopulations found in the gastric corpus and antrum [169]. In the colon, mucosal subepithelial PDGFRα cells, located in the basement membrane beneath the epithelial layer, contribute to the formation of contractile cellular networks via gap junctions. These cells develop intricate subepithelial reticular networks around the crypts encompassing the lamina propria [172]. Within this region, PDGFRα cells are closely associated with neural and capillary networks, as well as myofibroblasts, epithelial cells, and immune cells. Furthermore, PDGF-A mesenchymal cells use myosin II forces to shape the intestinal lining into villi, aided by enzymes that increase tissue fluidity and create variations in surface tension [173]. These cellular dynamics highlight the critical role of PDGFRα signaling in maintaining the structural and physiological function of the GI tract.

In the normal GI tract, the interstitial cells of Cajal (ICCs), which are Kit-positive, function as pacemaker cells that regulate gut motility [174,175]. Gastrointestinal stromal tumors (GISTs) can arise in any part of the GI tract and are frequently occur because of mutations in KIT or PDGF-A in ICCs [176-180]. These advancements are crucial for the development of precision therapies that employ low-molecular-weight TKIs. Medications such as imatinib, sunitinib, regorafenib, and ripretinib have been approved for the treatment of advanced GIST, and imatinib has been approved as an adjuvant therapy for high-risk patients [181-185]. Mutations in either KIT or PDGF-A result in conformational changes in the ATP-binding domain, triggering the activation of downstream signaling pathways such as MAPK, AKT, STAT1, and STAT3, which drive unregulated cell proliferation and tumor growth [186-188]. TKIs such as imatinib typically function by competitively binding to the ATP site, thereby blocking these signaling pathways and improving patient survival [189]. Although mutations in KIT and PDGF-A drive the majority of GISTs, some GISTs (10%–15%) lack these mutations and are termed KIT/PDGF-A-wild-type GISTs, which are generally resistant to TKI treatment [190-193]. These subgroups often exhibit primary resistance to imatinib, which poses a significant challenge for treatment.

Based on RNA-sequencing data obtained from the small intestine of Pdgfratm11(EGFP)Sor/J mice [194], we investigated the expression profiles of K⁺ channels within PDGFRα cells. Our analysis demonstrated differential expression patterns in the smooth muscles of the jejunum and colon, as well as in the colonic mucosa. Among the various K⁺ channel subtypes, Kcnj8 exhibited predominant expression in PDGFRα cells located in both the smooth muscle of the jejunum and the smooth muscle and mucosa of the colon (Fig. 1). Notably, Kcnj8 showed the highest expression levels in the smooth muscle of the jejunum, whereas Kcng 4 was the most abundantly expressed in the smooth muscle of the colon, and Kcnj8 was significantly expressed in the colonic mucosa. Kcnj8 encodes the inwardly rectifying K⁺ channel subtype Kir6.1, a key component of ATP-sensitive K⁺ channels that plays a critical role in regulating smooth muscle contractility. Additionally, Kir6.1 is present in epithelial cells of the small intestine and directly influences intestinal permeability [195,196]. Kcng4 encodes a subunit of voltage-gated K⁺ channels that is involved in modulating the membrane potential of various cell types within the small intestine, including enteric neurons, smooth muscle cells, ICCs, and epithelial cells. Through this modulation, Kcng4 contributes to the regulation of motility and absorption [197-201].

Testes are essential for the development of the male reproductive system, primarily because of the function of interstitial Leydig cells, which produce testosterone necessary for spermatogenesis [202-204]. Several studies have reported that PDGF-A and PDGF-B are present in the testis, including the Leydig, peritubular myoid, and Sertoli cells, which form homodimers PDGF-AA and PDGF-BB, respectively [205-210]. In Leydig cells, the PDGF signaling, particularly through its receptors PDGFRα or PDGFRβ, is crucial for the proliferation, differentiation, and survival of cells [206,211-215]. PDGF signaling also affects stem cell differentiation, depending on the inducing factors. Peritubular stem cells in seminiferous tubules, also known as stem Leydig cells, can differentiate into both Leydig and myoid cells [214]. For instance, exposure to PDGF-AA and luteinizing hormone promotes the development of these stem cells into Leydig cells, while exposure to PDGF-BB and TGF-β promotes their differentiation into both Leydig and myoid cells. Additionally, PDGF-AA is involved in primary cilia function in the development of the male reproductive system, which is mediated by the AKT and ERK signaling pathways [207,216].

In our previous study using PDGFRα^EGFP mice, we investigated PDGFRα expression in testicular tissues. We observed that PDGFRα cells are primarily located in the interstitial spaces of the testis, specifically within Leydig cells and peritubular myoid cells, but not in germ cells, Sertoli cells, or vascular endothelial cells in adult mice [217]. Furthermore, we observed co-localization of PDGFRα cells with c-Kit, calcium-activated chloride channel, ANO-1, and TASK-1 in both Leydig and peritubular myoid cells in adult testicular tissues [218,219]. KIT functions through tyrosine kinase activity [220] and, along with its ligand, is crucial for postnatal testicular development. Sertoli cells secrete the Kit ligand, commonly referred to as the stem cell factor, along with its receptor, c-Kit, which is present in spermatogonia and Leydig cells [221]. Signaling pathways involving c-Kit and Kit ligands are crucial for primordial germ cell development and spermatogonial stem cell formation during embryogenesis [222-225]. Stem Leydig cells respond to the concentration of the Kit ligand, which stimulates differentiation at lower levels and also promotes proliferation at higher levels [223].

ANO1 plays a critical role in the regulation of spontaneous activity in various smooth muscle organs. It functions as a source of depolarization of smooth muscle cells, propagates slow waves, and modulates smooth muscle motility [226-229]. Activation of ANO1 channels influences cellular excitability by controlling the membrane potential. Chloride efflux through ANO1 can induce membrane depolarization, leading to the opening of voltage-gated Ca²⁺ channels, which facilitates increased Ca²⁺ entry into the cell and amplifies the initial Ca²⁺ signal [230-232]. This mechanism is essential for several physiological processes. Previous studies have demonstrated that increased intracellular Ca²⁺ levels are crucial for stimulating steroidogenesis in Leydig cells [233-235]. Therefore, ANO1 channels may regulate cell signaling pathways that are essential for steroidogenesis by increasing intracellular Ca²⁺ levels. This regulation affects testosterone production, which is essential for male reproductive health. Additionally, we identified the expression of the acid-sensitive potassium channel TASK-1 (encoded by the KCNK3 gene), a member of the K⁺ channel family, in PDGFRα-expressing cells located in Leydig cells. The TASK-1 channel is a member of the two-pore domain K⁺ channel family. This channel controls the resting membrane potential by facilitating the constant efflux of K⁺ ions, thereby maintaining the negative membrane potential essential for cellular stability and excitability [236-238]. A previous study showed that TASK-1 channels were expressed in both human and rodent α-cells in islets, and played a critical role in modulating the glucose-regulated suppression of glucagon release by pancreatic α-cells [239]. TASK-1 channels hyperpolarize the membrane potential, reducing excitability and Ca²⁺ influx during glucose stimulation, resulting in lowered glucagon secretion. In Leydig cells, TASK-1 may contribute to their proper functioning and the overall hormonal balance within the testis by influencing membrane potential and Ca²⁺ dynamics.

In our study, we found that PDGFRα exhibited differential expression across various organs, including the brain, lung, liver, intestine, and testis, as observed in PDGFRα^EGFP mice (Fig. 2). In the brain, PDGFRα expression was specifically localized to the hippocampus. In the lungs, it is associated with the blood vessels. In the liver, it was observed around the central vein. In the intestine, PDGFRα was present in the villi of the ileum, and in the testis, it was detected in the interstitial space around the peritubular myoid and Leydig cells. PDGFRs are integral to normal cellular function and development; however, their dysregulation can contribute to diseases pathogenesis in various organs, which requires further investigation. Advanced targeted therapies have markedly improved patient outcomes. Nonetheless, additional research is essential to overcome treatment resistance and tumor heterogeneity and to enhance management strategies targeting PDGF signaling. This includes the exploration of the molecular mechanisms and complexities of PDGFR-mediated pathways to facilitate the development of new clinical applications.