Acquisition of a Unique Mesenchymal Precursor-like Blastema State Underlies Successful Adult Mammalian Digit Tip Regeneration.

Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra-expressing mesenchymal cells in uninjured digits establish the regenerative blastema and are essential for regeneration. Single-cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb or digit Pdgfra-positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema-state genes and contribute to bone regeneration. Moreover, lineage tracing with single-cell profiling indicates that endogenous osteoblasts or osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a blastema state that enables cells from tissues such as bone to contribute to the regeneration of other mesenchymal tissues such as the dermis.

Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression.

BACKGROUND: Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-ß and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling. METHODS: The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts. Alterations in cell morphology were determined by immunofluorescence experiments. Flow-cytometry analysis and mRNA expression profiles were used to investigate cell differentiation. In vivo efficacy was investigated in human ovarian carcinoma implanted on the chicken chorioallantoic membrane (CAM). RESULTS: Crenolanib was found to inhibit endothelial cell viability, migration and sprout length, and induced apoptosis independently of PDGFR expression. Treated cells  showed altered actin arrangement and nuclear aberrations. Mitosis was affected at several levels including mitosis entry and centrosome clustering. Crenolanib suppressed human ovarian carcinoma tumour growth and angiogenesis in the CAM model. CONCLUSIONS: The PDGFR/FLT3 inhibitor crenolanib targets angiogenesis and inhibits tumour growth in vivo unrelated to PDGFR expression. Based on our findings, we suggest a broad mechanism of action of crenolanib.

Platelet-derived growth factor up-regulates Ca2+-sensing receptors in idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease associated with remodeling of the pulmonary artery. We previously reported that the Ca2+-sensing receptor (CaSR) is up-regulated in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic PAH (IPAH) and contributes to enhanced Ca2+ responses and excessive cell proliferation. However, the mechanisms underlying the up-regulation of CaSR have not yet been elucidated. We herein examined involvement of platelet-derived growth factor (PDGF) on CaSR expression, Ca2+ responses, and proliferation in PASMCs. The expression of PDGF receptors was higher in PASMCs from patients with IPAH than in PASMCs from normal subjects. In addition, PDGF-induced activation of PDGF receptors and their downstream molecules [ERK1/2, p38, protein kinase B, and signal transducer and activator of transcription (STAT) 1/3] were sustained longer in PASMCs from patients with IPAH. The PDGF-induced CaSR up-regulation was attenuated by small interfering RNA knockdown of PDGF receptors and STAT1/3, and by the treatment with imatinib. In monocrotaline-induced pulmonary hypertensive rats, the up-regulation of CaSR was reduced by imatinib. The combination of NPS2143 and imatinib additively inhibited the development of pulmonary hypertension. These results suggest that enhanced PDGF signaling is involved in CaSR up-regulation, leading to excessive PASMC proliferation and vascular remodeling in patients with IPAH. The linkage between CaSR and PDGF signals is a novel pathophysiological mechanism contributing to the development of PAH.-Yamamura, A., Nayeem, M. J., Al Mamun, A., Takahashi, R., Hayashi, H., Sato, M. Platelet-derived growth factor up-regulates Ca2+-sensing receptors in idiopathic pulmonary arterial hypertension.

PDGFR-induced autocrine SDF-1 signaling in cancer cells promotes metastasis in advanced skin carcinoma.

Advanced and undifferentiated skin squamous cell carcinomas (SCCs) exhibit aggressive growth and enhanced metastasis capability, which is associated in mice with an expansion of the cancer stem-like cell (CSC) population and with changes in the regulatory mechanisms that control the proliferation and invasion of these cells. Indeed, autocrine activation of PDGFRα induces CSC invasion and promotes distant metastasis in advanced SCCs. However, the mechanisms involved in this process were unclear. Here, we show that CSCs of mouse advanced SCCs (L-CSCs) express CXCR4 and CXCR7, both receptors of SDF-1. PDGFRα signaling induces SDF-1 expression and secretion, and the autocrine activation of this pathway in L-CSCs. Autocrine SDF-1/CXCR4 signaling induces L-CSC proliferation and survival, and mediates PDGFRα-induced invasion, promoting in vivo lung metastasis. Validation of these findings in patient samples of skin SCCs shows a strong correlation between the expression of SDF1, PDGFRA, and PDGFRB, which is upregulated, along CXCR4 in tumor cells of advanced SCCs. Furthermore, PDGFR regulates SDF-1 expression and inhibition of SDF-1/CXCR4 and PDGFR pathways blocks distant metastasis of human PD/S-SCCs. Our results indicate that functional crosstalk between PDGFR/SDF-1 signaling regulates tumor cell invasion and metastasis in human and mouse advanced SCCs, and suggest that CXCR4 and/or PDGFR inhibitors could be used to block metastasis of these aggressive tumors.

JAK/STAT3 and NF-κB Signaling Pathways Regulate Cancer Stem-Cell Properties in Anaplastic Thyroid Cancer Cells.

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and refractory cancers, and a therapy with a new concept needs to be developed. Recently, research on cancer stem cells (CSCs) has progressed, and CSCs have been suggested to be responsible for metastasis, recurrence, and therapy resistance. In ATC-CSCs, aldehyde dehydrogenase (ALDH) activity is the most reliable marker to enrich CSCs. However, it is just a marker and is not involved in CSC properties. The present study therefore aimed to identify key signaling pathways specific for ATC-CSCs. Methods: A small interfering RNA library targeting 719 kinases was used in a sphere formation assay and cell survival assay using ATC cell lines to select target molecules specific for CSC properties. The functions of the selected candidates were confirmed by sphere formation, cell survival, soft agar, and nude mice xenograft assays using small compound inhibitors. Results: The study focused on PDGFR, JAK, and PIM, whose small interfering RNAs had a higher inhibitory effect on sphere formation, as well as a lower or no effect on regular cell growth in both FRO and KTC3 cells. Next, inhibitors of PDGFR, JAK, STAT3, PIM and NF-κB were used, and all of them successfully suppressed sphere formation in a dose-dependent manner but not regular cell growth, confirming the screening results. Inhibition of the JAK/STAT3 and NF-κB pathways also reduced anchorage-independent growth in soft agar and tumor growth in nude mice. Conclusions: These results suggest that JAK/STAT3 and NF-κB signals play important roles in ATC-CSCs. Targeting these signaling pathways may be a promising approach to treat ATC.

Paracrine Mechanisms Involved in Mesenchymal Stem Cell Differentiation into Cardiomyocytes.

Cardiovascular Disease (CVD) is one of the world-wide healthcare problem that involves the heart or blood vessels. CVD includes myocardial infarction and coronary artery diseases (CAD). Dysfunctional myocardial cells are leading causes of low cardiac output or ventricular dysfunction after cardiac arrest and may contribute to the progression of CVD which could not generate new cardiomyocytes in human adult heart. The mesenchymal stem cells (MSCs) which are present in adult marrow can self-renew and have the capacity of differentiation into multiple types of cells including cardiomyocytes. Recent biochemical analyses greatly revealed that several regulators of MSCs, such as HGF, PDGF, Wnt, and Notch-1 signaling pathways have been shown to be involved in the proliferation and differentiation into cardiomyocytes. Preclinical studies are paving the way for further applications of MSCs in the repair of myocardial infarction. In this study, we discuss and summarize the paracrine mechanisms involved in MSCs differentiation into cardiomyocytes.

Huntingtin-interacting protein 1 (HIP1) regulates arthritis severity and synovial fibroblast invasiveness by altering PDGFR and Rac1 signalling.

OBJECTIVES: While new treatments for rheumatoid arthritis (RA) have markedly improved disease control by targeting immune/inflammatory pathways, current treatments rarely induce remission, underscoring the need for therapies that target other aspects of the disease. Little is known about the regulation of disease severity and joint damage, which are major predictors of disease outcome, and might be better or complementary targets for therapy. In this study, we aimed to discover and characterise a new arthritis severity gene. METHODS: An unbiased and phenotype-driven strategy including studies of unique congenic rat strains was used to identify new arthritis severity and joint damage genes. Fibroblast-like synoviocytes (FLS) from rats and patients with RA expressing or not Huntingtin-interacting protein 1 (HIP1) were studied for invasiveness, morphology and cell signalling. HIP1 knockout mice were used in in vivo confirmatory studies. Paired t-test was used. RESULTS: DNA sequencing and subcongenic strains studied in pristane-induced arthritis identified a new amino acid changing functional variant in HIP1. HIP1 was required for the increased invasiveness of FLS from arthritic rats and from patients with RA. Knocking down HIP1 expression reduced receptor tyrosine kinase-mediated responses in RA FLS, including RAC1 activation, affecting actin cytoskeleton and cell morphology and interfering with the formation of lamellipodia, consistent with reduced invasiveness. HIP1 knockout mice were protected in KRN serum-induced arthritis and developed milder disease. CONCLUSION: HIP1 is a new arthritis severity gene and a potential novel prognostic biomarker and target for therapy in RA.

The clinical significance of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in gastric cancer: A systematic review and meta-analysis.

BACKGROUND: The overexpression and mutation of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are widespread in cancers and have been recognized as attractive oncologic targets with diverse therapeutic targets. Reports of the overexpression of genes, proteins and mutations of PDGFs/PDGFRs in gastric cancer and their associations with clinicopathological features, Western and Asian patients, as well as prognostic role have shown variable outcomes. This study sought to employ meta-analysis to evaluate PDGFs/PDGFRs status prognostic significance and their association with clinicopathological features of gastric cancer. METHOD: A comprehensive search of PubMed database for studies that investigated the overexpression of mRNA/Protein and mutation of PDGFs/PDGFRs in gastric cancer of Western and Asian patients, their prognostic significance and association with clinicopathological characteristics in May, 2017 or earlier was carried out by two reviewers independently. Pooled odd ratios and hazard ratios at 95% confidence intervals were estimated and summarized using fixed-effect and random-effect Mantel-Haenszel models and Inverse Variance models in Review Manager software version 5.3. RESULTS: Fourteen studies with 16 datasets of 1178 patients were included in meta-analysis. Fourteen studies of 1178 patients with 1446 cases and 7 studies of 1076 patients with 1280 cases were included in meta-analysis of clinicopathological and prognostic significance of high or positive PDGF/PDGFR status respectively. Odd ratio at 95% confidence intervals for different groups of analysis are as follows: males versus females(OR = 1.38, 95% CI: 1.04-1.83, POR = 0.03); ≥T2 stage versus T1 stage(OR = 2.06, 95% CI: 1.22-3.49, POR = 0.007); nodal metastasis versus no nodal metastasis(OR = 2.78, 95% CI: 1.48-5.22, POR = 0.002); TNM stage ≥II versus TNM stage I(OR = 3.55, 95% CI: 1.89-6.69, POR<0.0001). Subgroup analysis of the association of PDGF/PDGFR among Western patients(OR = 0.24 95% CI: 0.10-0.58, POR = 0.002) and association of PDGFs/PDGFRs gene mutation among gastric cancer patients(OR = 0.15, 95% CI: 0.05-0.45, POR = 0.0008) were significant. The association of PDGFs/PDGFRs in young and middle age versus elderly aged, undifferentiated versus well differentiated tumors, large tumor size group(>6 cm) versus small tumor size group(≤6 cm) were insignificant. Subgroup analysis of the association of PDGFs/PDGFRs among Western Asian patients; PDGF/PDGFR mRNA expression and protein expression among gastric cancer patients were insignificant. In addition, PDGF/PDGFR status among gastric cancer patients was insignificant in overall effect analysis PDGF/PDGFR status has shown to predict reduced overall survival(HR = 1.25, 95% CI: 0.49-3.22, PHR = 0.64) and relapse free survival(HR = 0.93, 95% CI: 0.36-2.41, PHR = 0.88) insignificantly. Also, overall prognostic effect analysis(HR = 1.07, 95% CI: 0.58-1.96, PHR = 0.84) was insignificant. CONCLUSION: PDGFs/PDGFRs status amongst gastric cancer patients plays a key role in clinical variables and nodal metastasis. These insights might be helpful in providing guidelines for diagnosis, molecular target therapy, and prognosis of gastric cancer.

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-ß. Chromatin IP assay of the PDGFR-ß promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta.

Mural cells (vascular smooth muscle cells and pericytes) play an essential role in the development of the vasculature, promoting vascular quiescence and long-term vessel stabilization through their interactions with endothelial cells. However, the mechanistic details of how mural cells stabilize vessels are not fully understood. We have examined the emergence and functional role of mural cells investing the dorsal aorta during early development using the zebrafish. Consistent with previous literature, our data suggest that cells ensheathing the dorsal aorta emerge from a sub-population of cells in the adjacent sclerotome. Inhibition of mural cell recruitment to the dorsal aorta through disruption of pdgfr signaling leads to a reduced vascular basement membrane, which in turn results in enhanced dorsal aorta vessel elasticity and failure to restrict aortic diameter. Our results provide direct in vivo evidence for a functional role for mural cells in patterning and stabilization of the early vasculature through production and maintenance of the vascular basement membrane to prevent abnormal aortic expansion and elasticity.

Insights into the molecular roles of heparan sulfate proteoglycans (HSPGs-syndecans) in autocrine and paracrine growth factor signaling in the pathogenesis of Hodgkin's lymphoma.

Syndecans (SDC, SYND) comprise a group of four structurally related type 1 transmembrane heparan sulfate proteoglycans (HSPGs) that play important roles in tumorigenic processes. SDCs exert signaling via their protein cores and their conserved transmembrane and cytoplasmic domains or by forming complexes with growth factors (GFs). In classical Hodgkin's lymphoma (cHL), a lymphoid neoplasm of predominantly B cell origin, SDC1 and SDC4 are the active SDCs, and a number of GF (vascular endothelial growth factor, fibroblast growth factor, etc.) signaling pathways have been studied. However, despite extensive pre-clinical and clinical research on SDC-mediated GF signaling in many cancer types, there is very limited data for this interaction in cHL. Thus, this review highlights the relevant literature focusing on the potential interactions of SDCs and GFs in cHL pathogenesis. Also discussed are the pre-clinical and clinical studies targeting signaling through these pathways.

Platelet-derived growth factor receptor/platelet-derived growth factor (PDGFR/PDGF) system is a prognostic and treatment response biomarker with multifarious therapeutic targets in cancers.

Progress in cancer biology has led to an increasing discovery of oncogenic alterations of the platelet-derived growth factor receptors (PDGFRs) in cancers. In addition, their overexpression in numerous cancers invariably makes PDGFRs and platelet-derived growth factors (PDGFs) prognostic and treatment markers in some cancers. The oncologic alterations of the PDGFR/PDGF system affect the extracellular, transmembrane and tyrosine kinase domains as well as the juxtamembrane segment of the receptor. The receptor is also involved in fusions with intracellular proteins and receptor tyrosine kinase. These discoveries undoubtedly make the system an attractive oncologic therapeutic target. This review covers elementary biology of PDGFR/PDGF system and its role as a prognostic and treatment marker in cancers. In addition, the multifarious therapeutic targets of PDGFR/PDGF system are discussed. Great potential exists in the role of PDGFR/PDGF system as a prognostic and treatment marker and for further exploration of its multifarious therapeutic targets in safe and efficacious management of cancer treatments.

Genetic Deletion of the Stromal Cell Marker CD248 (Endosialin) Protects against the Development of Renal Fibrosis.

BACKGROUND: Tissue fibrosis and microvascular rarefaction are hallmarks of progressive renal disease. CD248 is a transmembrane glycoprotein expressed by key effector cells within the stroma of fibrotic kidneys including pericytes, myofibroblasts and stromal fibroblasts. In human disease, increased expression of CD248 by stromal cells predicts progression to end-stage renal failure. We therefore, hypothesized that the genetic deletion of the CD248 gene would protect against fibrosis following kidney injury. METHODS: Using the unilateral ureteral obstruction (UUO) model of renal fibrosis, we investigated the effect of genetic deletion of CD248 on post obstructive kidney fibrosis. RESULTS: CD248 null mice were protected from fibrosis and microvascular rarefaction following UUO. Although the precise mechanism is not known, this may to be due to a stabilizing effect of pericytes with less migration and differentiation of pericytes toward a myofibroblast phenotype in CD248-/- mice. CD248-/- fibroblasts also proliferated less and deposited less collagen in vitro. CONCLUSION: These studies suggest that CD248 stromal cells have a pathogenic role in renal fibrosis and that targeting CD248 is effective at inhibiting both microvascular rarefaction and renal fibrosis through modulation of pericyte and stromal cell function.

The pivotal role of PDGF and its receptor isoforms in adipose-derived stem cells.

Platelet-derived growth factor (PDGF) is one of the growth factors that reportedly regulates cell growth and division of mesenchymal cells. Although PDGF isoforms and their receptors reportedly play a pivotal role in mesenchymal stem cell regulation, there is a paucity of literature reviewing the role of PDGF in adipose-derived stem cells (ASCs). Therefore, we summarized previous reports on the expression and functional roles of PDGF and its receptor isoforms in this review. In addition, we examined findings pertaining to underlying molecular mechanisms and signaling pathways with special focus on PDGF-D/PDGFRß. ASCs only express PDGF-A, -C, -D, PDGFRα, and PDGFRß. PDGFRα expression decreases with adipocyte lineage, while PDGFRß inhibits white adipocyte differentiation. In addition, PDGFRß induces proliferation, migration, and angiogenesis and up-regulates the expression of paracrine factors in ASCs. Although PDGF-B and -D mediate their functions mainly by PDGFRß and ROS generation, there are many differences between them in terms of regulating ASCs. PDGF-D is endogenous, generates ROS via the mitochondrial electron transport system, and regulates the autocrine loop of ASCs in vivo. Furthermore, PDGF-D has stronger mitogenic effects than PDGF-B.

PDGF receptors in tumor biology: prognostic and predictive potential.

PDGF receptors (PDGFRs) exert cell type-specific effects in many different tumor types. They are emerging as key regulators of mesenchymal cells of the tumor microenvironment, and of many common malignancies, such as cancer of the breast, colon and prostate. In some tumor types PDGFRs are genetically activated and are thus directly involved in stimulation of malignant cell growth. Recent studies have uncovered clinically relevant variations in stromal PDGFR expression. High stromal PDGFRß expression or activation is associated with poor prognosis in breast and prostate cancer. Indications of prognostic significance of stromal PDGFRß expression in various GI tract tumor types also exist. The prognostic significance of PDGFRα and ß in malignant cells of common epithelial tumor types should be further studied. Collectively data suggest that continued characterization of PDGFR expression in human tumors should present opportunities for improved accuracy in prognosis and also allow novel biomarker-based clinical studies exploring the efficacy of PDGFR-directed tumor therapies.

A review of platelet derived growth factor playing pivotal role in bone regeneration.

This article is focused on the literature review and study of recent advances in the field of bone grafting, which involves platelet-derived growth factor (PDGF) as one of the facilitating factors in bone regeneration. This article includes a description of the mechanism of PDGF for use in surgeries where bone grafting is required, which promotes future application of PDGF for faster bone regeneration or inhibition of bone growth if required as in osteosarcoma. The important specific activities of PDGF include mitogenesis (increase in the cell populations of healing cells), angiogenesis (endothelial mitoses into functioning capillaries), and macrophage activation (debridement of the wound site and a second phase source of growth factors for continued repair and bone regeneration). Thus PDGF can be utilized in wound with bone defect to conceal the wound with repair of bony defect.

The roles of platelet-derived growth factors and their receptors in brain radiation necrosis.

BACKGROUND: Brain radiation necrosis (RN) occurring after radiotherapy is a serious complication. We and others have performed several treatments for RN, using anticoagulants, corticosteroids, surgical resection and bevacizumab. However, the mechanisms underlying RN have not yet been completely elucidated. For more than a decade, platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been extensively studied in many biological processes. These proteins influence a wide range of biological responses and participate in many normal and pathological conditions. In this study, we demonstrated that PDGF isoforms (PDGF-A, B, C, and D) and PDGFRs (PDGFR-α and ß) are involved in the pathogenesis of human brain RN. We speculated on their roles, with a focus on their potential involvement in angiogenesis and inflammation in RN. METHODS: Seven surgical specimens of RN, obtained from 2006 to 2013 at our department, were subjected to histopathological analyses and stained with hematoxylin and eosin. We qualitatively analyzed the protein expression of each isoform of PDGF by immunohistochemistry. We also examined their expression with double immunofluorescence. RESULTS: All PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB). PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN. PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-ß was specifically expressed in endothelial cells not only in PN but also in UB. CONCLUSIONS: PDGFs/PDGFRs play critical roles in angiogenesis and possibly in inflammation, and they contribute to the pathogenesis of RN, irrespective of the original tumor pathology and applied radiation modality. Treatments for the inhibition of PDGF-C, PDGF-D, and PDGFR-α may provide new approaches for the treatment of RN induced by common radiation therapies.

Targeting platelet-derived growth factor as a therapeutic approach in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the proliferation of fibroblasts and deposition of extracellular matrix. Since the prognosis of IPF is still poor, novel therapeutic modalities are strongly required. For this reason, to find molecular target for therapy of IPF is of much importance. The recent understanding of pathogenesis in IPF indicates the critical role of alveolar epithelial type II cells (AECII) and fibroblasts. Although the detailed mechanisms involved in IPF is still unclear, various profibrotic mediators which are produced by the injured AECII are thought to play a role in the progression of pulmonary fibrosis via stimulating fibroblasts. Among them, platelet-derived growth factor (PDGF) is one of critical growth factors by stimulating the proliferation and migration of fibroblasts. In this review, we discuss the role of PDGF in pulmonary fibrosis and the possibility as a therapeutic target for IPF.

Targeting of platelet-derived growth factor signaling in pulmonary arterial hypertension.

Despite recent advances in the management of patients with pulmonary arterial hypertension (PAH), this disease remains a devastating condition with limited survival. While the current therapies primarily target the vasoconstrictor/vasodilator imbalance in the pulmonary circulation, there is currently no cure for PAH, and pulmonary vascular remodeling-representing the underlying cause of the disease-is only modestly affected. Hence, novel therapeutic approaches directly targeting the vascular remodeling process are warranted. Recent studies provided compelling evidence that peptide growth factors, which elicit their signals via receptor tyrosine kinases, are important contributors to the development and progression of PAH. In particular, platelet-derived growth factor (PDGF) is a strong mitogen for pulmonary vascular smooth muscle cells and protects these cells from apoptosis, thus representing an important mediator of pulmonary vascular remodeling. PDGF ligand and receptors are upregulated in PAH, and experimental studies have shown that inhibition of PDGF receptor signaling by pharmacological or genetic approaches prevents the development of PAH in animal models and is even able to reverse pulmonary vascular remodeling once it has been established. Consistently, results from phase II and phase III clinical trials indicate that the tyrosine kinase inhibitor imatinib mesylate, which potently inhibits the PDGF receptor, is effective in improving exercise capacity and pulmonary hemodynamics as add-on therapy in patients with severe PAH (i.e., pulmonary vascular resistance >800 dynes s cm(-5)). Future studies will evaluate the long-term clinical efficacy and safety of imatinib, including patients with less impaired hemodynamics. Based on the current knowledge, targeting of PDGFR signaling is likely to become an anti-proliferative treatment option for patients with PAH and has the potential to at least partially correct the pathology of the disease.