Role Of Platelet-derived Growth Factor Research Articles

The role of platelet-derived growth factor in spinal cord injury

Spinal cord injury (SCI) is a severe neurological injury that can cause long-term disability and dysfunction. Platelet-derived growth factor (PDGF), an important cell growth factor, has been known for its important role in nerve regeneration and repair. This review systematically summarizes the research progress on the role of PDGF in SCI. Firstly, we summarized the structure, mechanism of action, and biological effects of PDGF on the proliferation, differentiation, and migration of neural stem cells. Subsequently, we put more emphasis on the PDGF effects in neural repair, involving myelin sheath maturation, angiogenesis, and the promotion of neural tissue repair through the improvement of the blood supply to the damaged areas. Moreover, its clinical application and challenges were discussed in depth. However, future studies are needed to further validate the safety and efficacy of PDGF therapy and to explore its optimal application strategy in clinical practice. In conclusion, PDGF, as a potential therapeutic target for nerve repair, may offer new ideas and possibilities for the treatment of SCI.

Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.

Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant. We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (INa), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A down-regulation caused decreased peak INa, and that reduced PDGF receptor (PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa. Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (P<0.001). These results not only establish decreased SCN5A transcription by the TBX5 variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.

Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.

Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.

Insights Into the Role of Platelet-Derived Growth Factors: Implications for Parkinson's Disease Pathogenesis and Treatment.

Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, commonly occurs in the elderly population, causing a significant medical and economic burden to the aging society worldwide. At present, there are few effective methods that achieve satisfactory clinical results in the treatment of PD. Platelet-derived growth factors (PDGFs) and platelet-derived growth factor receptors (PDGFRs) are important neurotrophic factors that are expressed in various cell types. Their unique structures allow for specific binding that can effectively regulate vital functions in the nervous system. In this review, we summarized the possible mechanisms by which PDGFs/PDGFRs regulate the occurrence and development of PD by affecting oxidative stress, mitochondrial function, protein folding and aggregation, Ca2+ homeostasis, and cell neuroinflammation. These modes of action mainly depend on the type and distribution of PDGFs in different nerve cells. We also summarized the possible clinical applications and prospects for PDGF in the treatment of PD, especially in genetic treatment. Recent advances have shown that PDGFs have contradictory roles within the central nervous system (CNS). Although they exert neuroprotective effects through multiple pathways, they are also associated with the disruption of the blood–brain barrier (BBB). Our recommendations based on our findings include further investigation of the contradictory neurotrophic and neurotoxic effects of the PDGFs acting on the CNS.

Identifying the Potential Role and Prognostic Value of the Platelet-Derived Growth Factor Pathway in Kidney Renal Clear Cell Carcinoma.

The platelet-derived growth factor (PDGF) pathway is important in angiogenesis, which can accelerate the formation of vessels in tumor tissues and promote the progression of malignant tumors. To clarify the role of PDGF in the occurrence of renal cell carcinoma and targeted drug resistance, we explored the pathway in kidney renal clear cell carcinoma (KIRC) through bioinformatics analysis with the aim of supporting comprehensive and individualized therapy. First, we found 40 genes related to the PDGF pathway through gene set enrichment analysis and then obtained their expressions and clinical data in 32 different cancers from The Cancer Genome Atlas (TCGA). Mutations in these genes (including copy number and single-nucleotide variation) and mRNA expression were also detected. Next, we conducted a hazard ratio analysis to determine whether the PDGF pathway genes were risk or protective factors in tumors. Although PDGF-related genes acted as traditional oncogenes and were closely related to tumor angiogenesis in many cancers, our results indicated that most genes had a protective role in KIRC. We further analyzed the methylation modification of PDGF pathway genes and found that they were prevalent in 32 different cancers. Furthermore, 539 KIRC samples obtained from TCGA were divided into three clusters based on the mRNA expression of PDGF genes, including normal, inactive, and active PDGF gene expressions. The results from survival curve analysis indicated that the active PDGF cluster of patients had the best survival rate. Using the three clusters, we studied the correlation between the PDGF pathway and 12 common targeted drugs, as well as classical oncogenes and infiltrating immune cells. A prognostic risk model was constructed based on the PDGF score using LASSO-Cox regression analysis to analyze the value of the model in predicting the prognosis of patients with KIRC. Finally, 11 genes were selected for LASSO regression analysis, and the results demonstrated the high predictive value of this risk model and its close relationship with the pathological characteristics of KIRC (metastasis, size, grade, stage, etc.). In addition, we found that the risk score was an independent risk factor correlated with overall survival through univariate and multivariate analyses and a nomogram was built to assess patient prognosis. In conclusion, the occurrence and development of KIRC may be associated with an abnormally activated PDGF pathway, which may be a potential drug target in the treatment of KIRC.

Platelet-Derived Growth Factor B Is a Key Element in the Pathological Bone Formation of Ankylosing Spondylitis.

Enthesophyte formation plays a crucial role in the development of spinal ankylosis in ankylosing spondylitis (AS). We aimed to investigate the role of platelet-derived growth factor B (PDGFB) in enthesophyte formation of AS using in vitro and in vivo models and to determine the association between PDGFB and spinal progression in AS. Serum PDGFB levels were measured in AS patients and healthy controls (HC). Human entheseal tissues attached to facet joints or spinous processes were harvested at the time of surgery and investigated for bone-forming activity. The impact of a pharmacological agonist and antagonist of platelet-derived growth factor B receptor (PDGFRB) were investigated respectively in curdlan-treated SKG mice. PDGFB levels were elevated in AS sera and correlated with radiographic progression of AS in the spine. Mature osteoclasts secreting PDGFB proteins were increased in the AS group compared with HC and were observed in bony ankylosis tissues of AS. Expression of PDGFRB was significantly elevated in the spinous enthesis and facet joints of AS compared with controls. Moreover, recombinant PDGFB treatment accelerated bone mineralization of enthesis cells, which was pronounced in AS, whereas PDGFRB inhibition efficiently reduced the PDGFB-induced bone mineralization. Also, PDGFRB inhibition attenuated the severity of arthritis and enthesophyte formation at the joints of curdlan-treated SKG mice. This study suggests that regulating PDGFB/PDGFRB signaling could be a novel therapeutic strategy to block key pathophysiological processes of AS. © 2022 American Society for Bone and Mineral Research (ASBMR).

Role of platelet-derived growth factor in type II diabetes mellitus and its complications.

Type 2 diabetes mellitus is a type of metabolic disorder characterized by hyperglycaemia with multiple serious complications, such as diabetic neuropathies, diabetic nephropathy, diabetic retinopathy, and diabetic foot. Platelet-derived growth factors are growth factors that regulate cell growth and division, playing a critical role in diabetes and its harmful complications. This review focused on the cellular mechanism of platelet-derived growth factors and their receptors on diabetes development. Furthermore, we raise some proper therapeutic molecular targets for the treatment of diabetes and its complications.

Role of Platelet-Derived Growth Factor (PDGF) in Asthma as an Immunoregulatory Factor Mediating Airway Remodeling and Possible Pharmacological Target.

Asthma is a chronic and heterogenic disease of the respiratory system, one of the most common lung diseases worldwide. The underlying pathologies, which are chronic inflammatory process and airway remodeling (AR), are mediated by numerous cells and cytokines. Particularly interesting in this field is the platelet-derived growth factor (PDGF), one of the members of the human growth factor family. In this article, the authors analyze the available data on the role of PDGF in asthma in experimental models and in human research. PDGF is expressed in airway by various cells contributing to asthma pathogenesis—mast cells, eosinophils, and airway epithelial cells. Research confirms the thesis that this factor is also secreted by these cells in the course of asthma. The main effects of PDGF on bronchi are the proliferation of airway smooth muscle (ASM) cells, migration of ASM cells into the epithelium and enhanced collagen synthesis by lung fibroblasts. The importance of AR in asthma is well recognized and new therapies should also aim to manage it, possibly targeting PDGFRs. Further studies on new and already existing drugs, mediating the PDGF signaling and related to asthma are necessary. Several promising drugs from the tyrosine kinase inhibitors group, including nilotinib, imatinib masitinib, and sunitinib, are currently being clinically tested and other molecules are likely to emerge in this field.

Evaluation of VEGF, FGF and PDGF and Serum Levels of Inflammatory Cytokines in Patients with Glioma and Meningioma in Southern Iran.

Background:Meningioma and glioma are common central nervous system tumors. Hypoxic tumor cells secrete angiogenic cytokines, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) that stimulate neovascular formation and inflammatory cytokine, such as TNF-α and IL-1β. We measured these serum levels in patients with glial cell tumors and meningioma. Materials and Methods:This was a case-control study in 2014-2015 on patients diagnosed with meningioma/glioma. All demographic and clinical data were registered. The tumor volume and intraoperative bleeding were recorded. Serum levels of VEGF, PDGF, FGF, TNF-α and IL-1β were measured by ELISA methods. Results:Ninety-six patients were enrolled in this study, 32 in each group. Patients VEGF level with cranial tumor, glioma/meningioma had increased. VEGF level was highest among grade IV tumors, larger tumors, and in glioblastoma multiform. There was an upsurge in VEGF serum level as glioma grade increased. The highest VEGF levels were seen in parasagittal meningioma. In contrast to VEGF, PDGF was slightly elevated in glial cell tumors, which was significantly elevated in meningioma. Higher PDGF correlated with increased intraoperative bleeding, especially in meningioma cases. Oligodendroglial tumors expressed higher PDGF levels in contrast to other glial tumors. FGF level was not statistically significant. TNF-α and IL-1β expressions were significantly higher in the meningioma and glioma group in comparison to control group. Conclusion:We found increased VEGF and PDGF serum levels in CNS patient’s tumor. A different role for PDGF was found in the pathogenesis of neovascularization of meningioma, as well as oligodendroglioma. No significant result was found for FGF. TNF-α and IL-1β can serve as key prognostic biomarker in high-grade glioma and meningioma patients.

Current Insights into the Potential Misuse of Platelet-based Applications for Doping in Sports.

Platelet-based applications are currently used for the delivery of growth factors and other biomolecules as autologous biomaterials in regenerative medicine and cosmetic therapies. Many studies have revealed that platelet-based applications such as platelet-rich plasma and platelet releasate exhibit beneficial biological effects after a sports injury or trauma when administered locally by intramuscular injections. At present, treatment of the public, patients and athletes with platelet-based applications is permitted and regulated by the Food and Drug Administration and the World Anti-Doping Agency. Since 2011 the use of autologous platelet-rich plasma is permitted in competitive sports by the World Anti-Doping Agency, due to the lack of evidence in performance enhancement and anabolic effects. However, accumulating research has recently shed light on the role of platelet-derived growth factors in wound healing, skeletal myogenesis, muscle stem cell function and tissue regeneration. Although any ergogenic potential of platelet-rich plasma and platelet releasate on intact skeletal muscle and human sports performance remain to be established, novel evidence suggests that platelet-derived growth factors can modulate muscle, tendon, ligament, protein synthesis/degradation, vascularization, energy utilization and regenerative capacity in various experimental settings. Since platelet-based applications are currently not prohibited, they constitute a tool for potential abuse and doping in sports. The aim of this review is to critically discuss and assimilate current insights and biological evidence that set the ground for exploitation and misuse in competitive sports, and develop strategies to combat these activities.

Platelet-Rich Fibrin Scaffolds for Cartilage and Tendon Regenerative Medicine: From Bench to Bedside.

Nowadays, research in Tissue Engineering and Regenerative Medicine is focusing on the identification of instructive scaffolds to address the requirements of both clinicians and patients to achieve prompt and adequate healing in case of injury. Among biomaterials, hemocomponents, and in particular Platelet-rich Fibrin matrices, have aroused widespread interest, acting as delivery platforms for growth factors, cytokines and immune/stem-like cells for immunomodulation; their autologous origin and ready availability are also noteworthy aspects, as safety- and cost-related factors and practical aspects make it possible to shorten surgical interventions. In fact, several authors have focused on the use of Platelet-rich Fibrin in cartilage and tendon tissue engineering, reporting an increasing number of in vitro, pre-clinical and clinical studies. This narrative review attempts to compare the relevant advances in the field, with particular reference being made to the regenerative role of platelet-derived growth factors, as well as the main pre-clinical and clinical research on Platelet-rich Fibrin in chondrogenesis and tenogenesis, thereby providing a basis for critical revision of the topic.

Caracterização estrutural e papel do fator de crescimento derivado de plaquetas (PDGF) na foliculogênese ovariana

Background: : : : The platelet-derived growth factor (PDGF) is expressed in a wide variety of cell types, exerts a potent mitogenic role and acts on the growth, differentiation and cell chemotaxis. Studies have shown that during folliculogenesis, PDGF and their receptors are expressed in oocytes, granulosa cells and thecal cells of ovarian follicles at different developmental stages in several species. Although exist many information about its expression sites, as well as about its action in different cells types, the role of PDGF on ovarian folliculogenesis remains understudied. Thus, this article aims to review issues related to PDGF, suggesting the involvement of this mitogenic factor during follicular development. Review: Along this work, it was shown aspects related to structural characterization of PDGF and its receptors, as well as PDGF expression in different cells types, emphasizing its importance to follicular development. PDGF family is composed by four polypeptide chains (each encoded by a different gene), which are synthesized in the form of inactive pro-proteins. After a proteolytic processing, these chains undergo homo or heterodimerization, resulting in five isoforms (PDGF-AA, -BB, -AB, -CC e -DD). The cellular effects of these different PDGF isoforms are mediated by binding, with different specificities, to three transmembrane receptors isoforms of type tyrosine kinase generated by the association of subunits ? e ? (PDGFR- ??, - ??, - ??). PDGF was initially purified from platelets, being later verified its production by many varieties of cell types. It acts as an important mitogenic factor, especially to cells of mesenchymal origin as fibroblasts and smooth muscle cells, and also exerts a role on cellular migration and survival. Studies with PDGF and its receptors have demonstrated its importance as a paracrine growth factor for normal embryo development and angiogenesis. Although the action of this growth factor has been shown in several cellular responses, its role in ovarian folliculogenesis of mammals is understudied. Folliculogenesis, event initiated at pre-natal life in most species, can be defined as the process of follicular formation, growth and maturation, beggining with the primordial follicle formation and resulting in preovulatory stage. Until the present moment, the different PDGF types and their receptors were detected in ovarian follicles of murines, rodents, swines and humans according to developmental stage. Evidences suggest that this growth factor may acts as a potent regulator of ovarian function, increasing DNA synthesis in granulosa cells and stimulating theca cells growth in swines. In addition, PDGF has shown benefic effects in in vitro maturation of bovine oocytes when associated with follicle stimulating hormone (FSH). Conclusion: Nevertheless, the specific actions of PDGF on ovarian follicles development have not been described due to lack of data available in the literature about this subject. Therefore, this review was performed to clarify the involvement of this growth factor in the regulation of ovarian function in mammals. However, it is necessary to perform additional studies that may provide a greater understanding about the importance of PDGF during folicullogenesis.

Roles of platelet-derived growth factor in vascular calcification.

Vascular calcification (VC) is prevalent in aging, and patients with hypertension, chronic kidney disease (CKD), or diabetes. VC is regarded as an active and complex process that involves multiple mechanisms responsible for calcium deposition in vessel wall. In light of the complicated pathogenesis of VC, effective therapy for ameliorating VC is limited. Thus, it is urgent to explore the potential mechanisms and find new targets for the therapy of VC. Platelet-derived growth factor (PDGF), a potent mitogen, and chemoattractant have been found to disturb the vascular homeostasis by inducing inflammation, oxidative stress, and phenotype transition, all of which accelerate the process of VC. The aim of current review is to present a review about the roles of PDGF in affecting VC and to establish a potential target for treating VC.

Transcriptome Analysis of Human Reninomas as an Approach to Understanding Juxtaglomerular Cell Biology.

Renin, a key component in the regulation of blood pressure in mammals, is produced by the rare and highly specialized juxtaglomerular cells of the kidney. Chronic stimulation of renin release results in a recruitment of new juxtaglomerular cells by the apparent conversion of adjacent smooth muscle cells along the afferent arterioles. Because juxtaglomerular cells rapidly dedifferentiate when removed from the kidney, their developmental origin and the mechanism that explains their phenotypic plasticity remain unclear. To overcome this limitation, we have performed RNA expression analysis on 4 human renin-producing tumors. The most highly expressed genes that were common between the reninomas were subsequently used for in situ hybridization in kidneys of 5-day-old mice, adult mice, and adult mice treated with captopril. From the top 100 genes, 10 encoding for ligands were selected for further analysis. Medium of human embryonic kidney 293 cells transfected with the mouse cDNA encoding these ligands was applied to (pro)renin-synthesizing As4.1 cells. Among the ligands, only platelet-derived growth factor B reduced the medium and cellular (pro)renin levels, as well as As4.1 renin gene expression. In addition, platelet-derived growth factor B-exposed As4.1 cells displayed a more elongated and aligned shape with no alteration in viability. This was accompanied by a downregulated expression of α-smooth muscle actin and an upregulated expression of interleukin-6, suggesting a phenotypic shift from myoendocrine to inflammatory. Our results add 36 new genes to the list that characterize renin-producing cells and reveal a novel role for platelet-derived growth factor B as a regulator of renin-synthesizing cells.

The Role of PDGFs and PDGFRs in Colorectal Cancer

Introduction. Colorectal cancer (CRC) is an important cause of morbidity and mortality worldwide. Angiogenesis was reported as one important mechanism activated in colorectal carcinogenesis. Tumor microenvironment associated angiogenesis involves a large spectrum of signaling molecules and deciphering their role in colorectal carcinogenesis still represents a major challenge. The aim of our study is to point out the diagnosis and prediction role of PDGF family and their receptors in colorectal carcinogenesis. Material and Methods. A systematic search in Medline and PubMed for studies reporting the role of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in tumor biology related to CRC was made. Results. PDGFs are important growth factors for normal tissue growth and division, with an important role in blood vessel formation. PDGFs/PDGFRs signaling pathway has been demonstrated to be involved in angiogenesis mainly by targeting pericytes and vascular smooth muscle cells. High levels of PDGF-BB were reported in CRC patients compared to those with adenomas, while elevated levels of PDGFR α/β in the stroma of CRC patients were correlated with invasion and metastasis. Moreover, PDGF-AB and PDGF-C were correlated with early diagnosis, cancer grading, and metastatic disease. Conclusions. Both PDGFs and PDGFRs families play an important role in colorectal carcinogenesis and could be considered to be investigated as useful biomarkers both for diagnosis and treatment of CRC.

PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation.

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease for which there is currently no curative treatment available. Pathologic changes in this disease involve remodeling of the pulmonary vasculature, including marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Recently, the bioactive lipid sphingosine-1-phosphate (S1P) and its activating kinase, sphingosine kinase 1 (SphK1), have been shown to be upregulated in PAH and promote PASMC proliferation. The mechanisms regulating the transcriptional upregulation of SphK1 in PASMCs are unknown. In this study, we investigated the role of platelet-derived growth factor (PDGF), a PAH-relevant stimuli associated with enhanced PASMC proliferation, on SphK1 expression regulation. In human PASMCs (hPASMCs), PDGF significantly increased SphK1 mRNA and protein expression and induced cell proliferation. Selective inhibition of SphK1 attenuated PDGF-induced hPASMC proliferation. In silico promoter analysis for SphK1 identified several binding sites for early growth response protein 1 (Egr-1), a PDGF-associated transcription factor. Luciferase assays demonstrated that PDGF activates the SphK1 promoter in hPASMCs, and truncation of the 5'-promoter reduced PDGF-induced SphK1 expression. Stimulation of hPASMCs with PDGF induced Egr-1 protein expression, and direct binding of Egr-1 to the SphK1 promoter was confirmed by chromatin immunoprecipitation analysis. Inhibition of ERK signaling prevented induction of Egr-1 by PDGF. Silencing of Egr-1 attenuated PDGF-induced SphK1 expression and hPASMC proliferation. These studies demonstrate that SphK1 is regulated by PDGF in hPASMCs via the transcription factor Egr-1, promoting cell proliferation. This novel mechanism of SphK1 regulation may be a therapeutic target in pulmonary vascular remodeling in PAH.

Collective migration in tissues.

The Minisymposium on “Cell Migration in Tissues” focused on analysis of dynamic collective cell migration in several model systems and was cochaired by Alissa M. Weaver (Vanderbilt University Medical Center) and Celeste M. Nelson (Princeton University). The program highlighted both the physical forces exerted during migration and the signaling pathways involved in the process. Celeste Nelson (Princeton University) presented results suggesting that cells migrate collectively through fibrous extracellular matrix (ECM) by exerting tensile forces at the leading edge of the cohort. Three-dimensional traction force microscopy was used to quantify the physical forces exerted by normal and malignant mammary epithelial cells undergoing collective migration through collagen gels (Gjorevski et al., 2015 ). The forces and displacements were surprisingly dynamic, with the cohort periodically relaxing as it migrated forward. Jessica Konen (Marcus laboratory, Emory University) described a new technique called spatiotemporal genomic analysis, which was used to select rare populations of leader cells from three-dimensional (3D) lung cancer spheroids and compare their gene expression patterns to that of follower cells. Leader cells were found to express higher levels of genes related to cell adhesion and vascular sprouting. These gene expression changes persisted in purified cultures. Eliah Shamir (Ewald laboratory, Johns Hopkins University) showed that in 3D culture of mammary epithelial organoids, the myoepithelial layer was required to prevent invasion and dissemination of Twist1-expressing luminal epithelial cells. Surprisingly, Twist1-induced invasion required the expression of E-cadherin, and knocking down expression of this cell–cell adhesion protein prevented dissemination downstream of Twist1 (Shamir et al., 2014 ). Joshua Bloomekatz (Yelon laboratory, University of California, San Diego) showed a critical role for platelet-derived growth factor (PDGF) in the movement of cardiomyocytes during cardiac fusion. A forward genetic screen was used to identify a mutation called refuse-to-fuse, which causes inhibition of cardiac fusion and the subsequent formation of a bifurcated ventricle. This mutation was found to disrupt splicing of pdgfra, leading to expression of a truncated form of the PDGF receptor. Expression of PDGF ligands in relatively medial locations suggested a model in which PDGF signaling coordinates the movement of cardiomyocytes toward the midline during cardiac fusion. Bong Hwan Sung (Weaver laboratory, Vanderbilt University) showed that directionally persistent migration of cancer cells is promoted by autocrine secretion of exosomes, late endosome–derived extracellular vesicles (Sung et al., 2015 ). Exosomes were shown to contain ECM proteins as cargo and to be secreted at sites of nascent adhesions. Accordingly, exosome secretion promoted adhesion assembly, migrational polarity, and the stability of lamellipodia. David Matus (Stony Brook University) used an RNA interference screen to identify a transcriptional program that maintains invasive anchor cells in a cell cycle–arrested state during uterine-vulval attachment in Caenorhabditis elegans. Nuclear hormone receptor nhr-67 (TLX) expression leads to up-regulation of cyclin-dependent kinase inhibitor cki-1, causing cell cycle arrest in G1 (Matus et al., 2015 ). Cells that lack nhr-67 are proliferative and noninvasive, failing to express matrix or form invadopodia. The Minisymposium concluded with three lightning talks. Micah Webster (Fan laboratory, Carnegie Institution for Science) showed a role for “ghost fibers,” ECM remnants of damaged muscle fibers, in organizing skeletal muscle progenitor migration, division, and fusion during regeneration in mice (Webster et al., 2016 ). Rebecca Green (Oegema laboratory, University of California, San Diego) developed a four-dimensional high-content imaging approach to screen for developmentally important genes within C. elegans embryos. Yutaka Matsubayashi (Stramer laboratory, King’s College London) showed that formation of the basement membrane in the Drosophila embryo requires rapid anterior–posterior dispersal of macrophages (hemocytes), which first appear in the head of the embryo.

Роль тромбоцитарного фактора роста в патобиологии эпиретинальных мембран при пролиферативной витреоретинопатии (экспериментально-морфологическое исследование)

Роль тромбоцитарного фактора роста в патобиологии эпиретинальных мембран при пролиферативной витреоретинопатии (экспериментально-морфологическое исследование)

Abstract 3917: PDGF induces cell growth and glycolysis in colon cancer

Abstract The platelet derived growth factor (PDGF) plays an important role in several solid tumors. Involved in cell migration and proliferation primarily of stromal cells in cancers PDGF represents a key target in cancer therapy. The aim of this study was to analyze the specific role of PDGF on tumor cell proliferation and metabolism in colorectal cancer (CRC). The human colon cancer cell line HT-29 was cultured and stimulated time-dependently with PDGF. Additionally, inhibition of the PI3k/Akt/mTOR-pathway was performed simultaneously to PDGF stimulation. Whole cell and RNA extracts were analyzed by Western Blot and RT-q-PCR for the PI3k/Akt/mTOR-pathway and components of cellular metabolism. To investigate the effects of PDGF on proliferation MTS assays were performed. Additionally, mRNA levels of PDGF and metabolic factors in tumors from patients with CRC were analyzed by RT-qPCR. PDGF stimulation resulted in increased HT29 cell proliferation compared to untreated controls. Blocking of Akt resulted in inhibition of pS6, activation of Retinoblastoma (Rb) and reduced tumor cell growth. Additionally, under stimulation a higher glycolytic rate was observed while oxygen consumption remained unaltered. Investigated tumors from patients with CRC showed a stage-dependent increase in PDGF expression and a boosted glycolytic rate. The cytokine PDGF induced proliferation accompanied with an altered glycolysis in HT-29 colon cancer. An increased glycolysis and tumor cell proliferation support accelerated cell proliferation and tumor growth. The growth reducing effect of Akt inhibition indicates the PI3K/Akt/mTOR-pathway to play a crucial role in CRC progression and therefore could be an important target in cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Romana Moench, Vinicius Kannen, Tanja Grimmig, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser. PDGF induces cell growth and glycolysis in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3917. doi:10.1158/1538-7445.AM2015-3917

Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension.

Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine-kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. Patients with PAH exhibit enhanced expression and phosphorylation of β PDGF receptor (βPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of βPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated βPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (βPDGFR(F3/F3)). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in βPDGFR(F3/F3) pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in βPDGFR(F3/F3) mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. By means of a genetic approach, our data provide definite evidence that the activated βPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH.