Publications by authors named "Andrius Kazlauskas"

93 Publications

Long-term follow-up after acute achilles tendon rupture - Does treatment strategy influence functional outcomes?

Foot (Edinb) 2021 Jun 13;47:101769. Epub 2021 Jan 13.

Orthopaedic Research Unit, Aalborg University Hospital, Aalborg, Denmark; Physiotherapy and Occupational Therapy, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. Electronic address:

Background: Patients struggle to fully recover after an Achilles tendon rupture. Although several studies has investigated surgical and non-surgical treatment, the best treatment is still uncertain. The aim of this study was to investigate long-term patient-reported outcomes and objective measures 4 years after acute Achilles tendon rupture and compare whether outcomes differed between patients treated on basis of the previous regimen preferring surgical treatment and the new regimen preferring functional rehabilitation.

Methods: Achilles tendon Total Rupture Score (ATRS), number of re-ruptures and the objective measures; Achilles tendon resting angle, calf circumference, heel-rise height, and muscle endurance were measured at a 4-year follow-up. Patients were recruited from Aalborg University Hospital.

Results: Seventy-six patients were included (29% female). The mean ATRS was 71.4 (95% CI: 65.8 to 77.1) at 4 years follow-up. No difference in ATRS was observed between Previous regimen and New regimen at any timepoint (time x group interaction, (p=0.851). The injured side was still significantly impaired compared with the non-injured side in terms of all objective measures. Impairments in objective measures were not dependent on the preferred treatment strategy.

Conclusions: Patient reported impairments and objective functional deficits persist 4 years after an acute Achilles tendon rupture. No differences in patient reported outcome or objective measures at the 4 years follow-up was observed between the old treatment regimen preferring surgery compared with the new treatment regimen preferring functional rehabilitation.
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http://dx.doi.org/10.1016/j.foot.2020.101769DOI Listing
June 2021

VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration.

Invest Ophthalmol Vis Sci 2021 Feb;62(2)

Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, United States.

Purpose: Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 are promising therapeutic targets for wet age-related macular degeneration (AMD). As a topically applicable option, we developed the peptide KAI to selectively interfere with VEGFR2 trafficking to the cell surface where it receives VEGF. This study sought to determine the efficacy of KAI in the mouse model of choroidal neovascularization (CNV).

Methods: The specificity of KAI was tested by surface plasmon resonance. The drug delivery was analyzed by cryosection and the ELISA after treatment of KAI eyedrop to the mouse eyes. For the laser-induced CNV model, mice with laser-induced ruptures in Bruch's membrane received daily treatment of KAI eyedrop or control peptide. The other groups of mice received intravitreal injection of anti-VEGF or IgG control. After two weeks, CNV was quantified and compared.

Results: First, we showed the specificity and high affinity of KAI to VEGFR2. Next, biodistribution revealed successful delivery of KAI eyedrop to the back of the mouse eyes. KAI significantly reduced the disease progression in laser-induced CNV. The comparison with current therapy suggests that KAI eyedrop is as effective as current therapy to prevent CNV in wet AMD. Moreover, the genetic deletion of a kinesin KIF13B, which mediates VEGFR2 trafficking to the cell surface, confirmed the pivotal role of KIF13B in disease progression of wet AMD and neovascularization from choroidal vessels.

Conclusions: Taken together, pharmacologic inhibition and genetic deletion complementarily suggest the therapeutic possibility of targeting VEGFR2 trafficking to inhibit pathological angiogenesis in wet AMD.
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http://dx.doi.org/10.1167/iovs.62.2.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862734PMC
February 2021

The Renin-Angiotensin-Aldosterone System (RAAS) Is One of the Effectors by Which Vascular Endothelial Growth Factor (VEGF)/Anti-VEGF Controls the Endothelial Cell Barrier.

Am J Pathol 2020 09 23;190(9):1971-1981. Epub 2020 Jun 23.

Departments of Ophthalmology & Visual Sciences, University of Illinois at Chicago, Chicago, Illinois; Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois. Electronic address:

Leakage of retinal blood vessels, which is an essential element of diabetic retinopathy, is driven by chronic elevation of vascular endothelial growth factor (VEGF). VEGF quickly relaxes the endothelial cell barrier by triggering signaling events that post-translationally modify pre-existing components of intercellular junctions. VEGF also changes expression of genes that are known to regulate barrier function. Our goal was to identify effectors by which VEGF and anti-VEGF control the endothelial cell barrier in cells that were chronically exposed to VEGF (hours instead of minutes). The duration of VEGF exposure influenced both barrier relaxation and anti-VEGF-mediated closure. Most VEGF-induced changes in gene expression were not reversed by anti-VEGF. Those that were constitute VEGF effectors that are targets of anti-VEGF. Pursuit of such candidates revealed that VEGF used multiple, nonredundant effectors to relax the barrier in cells that were chronically exposed to VEGF. One such effector was angiotensin-converting enzyme, which is a member of the renin-angiotensin-aldosterone system (RAAS). Pharmacologically antagonizing either the angiotensin-converting enzyme or the receptor for angiotensin II attenuated VEGF-mediated relaxation of the barrier. Finally, activating the RAAS reduced the efficacy of anti-VEGF. These discoveries provide a plausible mechanistic explanation for the long-standing appreciation that RAAS inhibitors are beneficial for patients with diabetic retinopathy and suggest that antagonizing the RAAS improves patients' responsiveness to anti-VEGF.
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http://dx.doi.org/10.1016/j.ajpath.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538812PMC
September 2020

PDGFRβ plays an essential role in patient vitreous-stimulated contraction of retinal pigment epithelial cells from epiretinal membranes.

Exp Eye Res 2020 08 16;197:108116. Epub 2020 Jun 16.

Shenzhen Eye Hospital, Shenzhen Eye Institute, Jinan University, Shenzhen, Guangdong Province, PR China. Electronic address:

Platelet-derived growth factor (PDGF) is associated with clinical proliferative vitreoretinopathy (PVR), which is characterized by formation of sub- or epi-retinal membranes that consist of cells including retinal pigment epithelial (RPE) cells and extracellular matrix. RPE cells play an important role in PVR pathogenesis. Previous findings indicated that PDGF receptor (PDGFR)α was essential in experimental PVR induced by fibroblasts. In RPE cells derived from epiretinal membranes from patients with PVR (RPEMs), Akt was activated by PDGF-B but not PDGF-A, which suggested that PDGFRβ was the predominant PDGFR isoform expressed in RPEMs. Indeed, CRISPR/Cas9-mediated depletion of PDGFRβ in RPEMs attenuated patient vitreous-induced Akt activation and cellular responses intrinsic to PVR including cell proliferation, migration, and contraction. We conclude that PDGFRβ appears to be the PVR relevant PDGFR isoform in RPEMs.
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http://dx.doi.org/10.1016/j.exer.2020.108116DOI Listing
August 2020

PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

Diabetes 2020 04 8;69(4):736-748. Epub 2020 Jan 8.

Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen, China

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.
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http://dx.doi.org/10.2337/db19-0713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085248PMC
April 2020

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review.

Med Res Rev 2018 09 12;38(6):1769-1798. Epub 2018 Mar 12.

Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL.

In recent years, lymphangiogenesis, the process of lymphatic vessel formation from existing lymph vessels, has been demonstrated to have a significant role in diverse pathologies, including cancer metastasis, organ graft rejection, and lymphedema. Our understanding of the mechanisms of lymphangiogenesis has advanced on the heels of studies demonstrating vascular endothelial growth factor C as a central pro-lymphangiogenic regulator and others identifying multiple lymphatic endothelial biomarkers. Despite these breakthroughs and a growing appreciation of the signaling events that govern the lymphangiogenic process, there are no FDA-approved drugs that target lymphangiogenesis. In this review, we reflect on the lessons available from the development of antiangiogenic therapies (26 FDA-approved drugs to date), review current lymphangiogenesis research including nanotechnology in therapeutic drug delivery and imaging, and discuss molecules in the lymphangiogenic pathway that are promising therapeutic targets.
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http://dx.doi.org/10.1002/med.21496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135718PMC
September 2018

Microenvironment dependent gene expression signatures in reprogrammed human colon normal and cancer cell lines.

BMC Cancer 2018 02 27;18(1):222. Epub 2018 Feb 27.

National Cancer Institute, Santariskiu 1, 08660, Vilnius, LT, Lithuania.

Background: Since the first evidence suggesting existence of stem-like cancer cells, the process of cells reprogramming to the stem cell state remains as an attractive tool for cancer stemness research. Current knowledge in the field of cancer stemness, indicates that the microenvironment is a fundamental regulator of cell behavior. With regard to this, we investigated the changes of genome wide gene expression in reprogrammed human colon normal epithelial CRL-1831 and colon carcinoma DLD1 cell lines grown under more physiologically relevant three-dimensional (3D) cell culture microenvironment compared to 2D monolayer.

Methods: Whole genome gene expression changes were evaluated in both cell lines cultured under 3D conditions over a 2D monolayer by gene expression microarray analysis. To evaluate the biological significance of gene expression changes, we performed pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Gene network analysis was used to study relationships between differentially expressed genes (DEGs) in functional categories by the GeneMANIA Cytoscape toolkit.

Results: In total, we identified 3228 and 2654 differentially expressed genes (DEGs) for colon normal and cancer reprogrammed cell lines, respectively. Furthermore, the expression of 1097 genes was commonly regulated in both cell lines. KEGG enrichment analysis revealed that in total 129 and 101 pathways for iPSC-CRL-1831 and for CSC-DLD1, respectively, were enriched. Next, we grouped these pathways into three functional categories: cancer transformation/metastasis, cell interaction, and stemness. β-catenin (CTNNB1) was confirmed as a hub gene of all three functional categories.

Conclusions: Our present findings suggest common pathways between reprogrammed human colon normal epithelium (iPSC-CRL-1831) and adenocarcinoma (CSC-DLD1) cells grown under 3D microenvironment. In addition, we demonstrated that pathways important for cancer transformation and tumor metastatic activity are altered both in normal and cancer stem-like cells during the transfer from 2D to 3D culture conditions. Thus, we indicate the potential of cell culture models enriched in normal and cancer stem-like cells for the identification of new therapeutic targets in cancer treatment.
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http://dx.doi.org/10.1186/s12885-018-4145-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827990PMC
February 2018

ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity.

J Mol Cell Biol 2017 12;9(6):533

Department of Ophthalmology, Harvard Medical School, The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

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http://dx.doi.org/10.1093/jmcb/mjx040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485902PMC
December 2017

ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity.

J Mol Cell Biol 2017 12;9(6):516-532

Department of Ophthalmology, Harvard Medical School, The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders. The precise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrA1 remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is implicated in unfolded protein response. In highly secretory cells of the retinal pigmented epithelia, endoplasmic reticulum (ER) stress upregulated HtrA1. HtrA1 co-localized with vimentin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions displayed reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mammalian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.
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http://dx.doi.org/10.1093/jmcb/mjx024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823240PMC
December 2017

Development of wound healing models to study TGFβ3's effect on SMA.

Exp Eye Res 2017 08 6;161:52-60. Epub 2017 Jun 6.

The Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

The goal of this study was to test the efficacy of transforming growth factor beta 3 (TGFβ3) in reducing α-smooth muscle actin (SMA) expression in two models-an ex vivo organ culture and an in vitro 3D cell construct-both of which closely mimic an in vivo environment. For the ex vivo organ culture system, a central 6.0 mm corneal keratectomy was performed on freshly excised rabbit globes The corneas were then excised, segregated into groups treated with 1.0 ng/ml TGFβ1 or β3 (T1 or T3, respectively), and cultured for 2 weeks. The corneas were assessed for levels of haze and analyzed for SMA mRNA levels. For the 3D in vitro model, rabbit corneal fibroblasts (RbCFs) were cultured for 4 weeks on poly-transwell membranes in Eagle's minimum essential media (EMEM) + 10% FBS + 0.5 mM vitamin C ± 0.1 ng/ml T1 or T3. At the end of 4 weeks, the constructs were processed for analysis by indirect-immunofluorescence (IF) and RT-qPCR. The RT-qPCR data showed that SMA mRNA expression in T3 samples for both models was significantly lower (p < 0.05) than T1 treatment (around 3-fold in ex vivo and 2-fold in constructs). T3 also reduced the amount of scarring in ex vivo corneas as compared with the T1 samples. IF data from RbCF constructs confirmed that T3-treated samples had up to 4-fold (p < 0.05) lower levels of SMA protein expression than samples treated with T1. These results show that T3 when compared to T1 decreases the expression of SMA in both ex vivo organ culture and in vitro 3D cell construct models. Understanding the mechanism of T3's action in these systems and how they differ from simple cell culture models, may potentially help in developing T3 as an anti-scarring therapy.
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http://dx.doi.org/10.1016/j.exer.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577797PMC
August 2017

PDGFs and their receptors.

Gene 2017 May 4;614:1-7. Epub 2017 Mar 4.

Schepens Eye Research Institute, Massachusetts Eye and Ear Institute, 20 Staniford St, Boston, MA 02114, United States. Electronic address:

The platelet-derived growth factor (PDGF)/PDGFR receptor (PDGFR) family is essential for a vast array of physiological processes such as migration and proliferation of percityes that contribute to the formation and proper function of blood vessels. While ligand-dependent de-repression of the PDGFR's kinase activity is the major mode by which the PDGFR is activated, there are additional mechanisms to activate PDGFRs. Deregulated PDGFR activity contributes to various pathological conditions, and hence the PDGF/PDGFR family members are viable therapeutic targets. An increased appreciation of which PDGFR contributes to pathology, biomarkers that indicate the amplitude and mode of activation, and receptor-specific antagonists are necessary for the development of next-generation therapies that target the PDGF/PDGFR family.
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http://dx.doi.org/10.1016/j.gene.2017.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728141PMC
May 2017

PDGFRα Is a Key Regulator of T1 and T3's Differential Effect on SMA Expression in Human Corneal Fibroblasts.

Invest Ophthalmol Vis Sci 2017 02;58(2):1179-1186

The Schepens Eye Research Institute/Massachusetts Eye and Ear and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.

Purpose: The goal of this study was to examine the mechanism behind the unique differential action of transforming growth factor β3 (TGF-β3) and TGF-β1 on SMA expression. It was our hypothesis that platelet-derived growth factor receptor α (PDGFRα) played a key role in determining TGF-β3's response to wounding.

Methods: A stable cell line, human corneal fibroblast (HCF)-P, was created from HCFs by knocking down PDGFRα expression using a lentivirus-delivered shRNA sequence. A three-dimensional (3D) in vitro model was constructed by culturing HCF or HCF-P on poly-transwell membranes for 4 weeks in the presence and absence of 0.1 ng/mL TGF-β1 or -β3. At the end of 4 weeks, the constructs were processed for immunofluorescence and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, HCF and HCF-P cell migration was evaluated.

Results: In HCF, TGF-β3 treatment resulted in significantly lower α-smooth muscle actin (SMA) mRNA expression and immunolocalization when compared to TGF-β1, while in HCF-P, both TGF-β1 and -β3 treatment increased the SMA mRNA expression and immunolocalization compared to both the untreated HCF-P control and TGF-β3-treated HCF. Human corneal fibroblast-P also had a lower migration rate and construct thickness when compared to HCF.

Conclusions: These results show that TGF-β3 decreases SMA in HCF, while remarkably increasing SMA in HCF-P, thus indicating that the presence or absence of PDGFRα elicits contrasting responses to the same TGF-β3 treatment. Understanding the role of PDGFRα in TGF-β3's ability to stimulate SMA may potentially help in understanding the differential functions of TGF-β1 and TGF-β3 in corneal wound healing.
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http://dx.doi.org/10.1167/iovs.16-20016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338631PMC
February 2017

Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

Invest Ophthalmol Vis Sci 2016 07;57(8):3935-43

Schepens Eye Research Institute, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.

Purpose: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -β) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -β and whether suppression of PI5P4Kα and -β would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR).

Methods: PI5P4Kα and -β encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4Kα and -β by re-expressing mouse PIP4K2A and -2B in the PI5P4Kα and -β knocked-down ARPE-19 cells. Expression of PI5P4Kα and -β was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection.

Results: We found that vitreous enhanced expression of PI5P4Kα and -β in RPE cells and that knocking down PI5P4Kα and -β abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kα and -β in the human PI5P4Kα and -β knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kα and -β abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kα and -β was abundant in epiretinal membranes from PVR grade C patients.

Conclusions: The findings from this study indicate that PI5P4Kα and -β could be novel therapeutic targets for the treatment of PVR.
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http://dx.doi.org/10.1167/iovs.16-19405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974024PMC
July 2016

Vascular Endothelial Cell Growth Factor A Acts via Platelet-Derived Growth Factor Receptor α To Promote Viability of Cells Enduring Hypoxia.

Mol Cell Biol 2016 09 26;36(18):2314-27. Epub 2016 Aug 26.

The Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

Vascular endothelial cell growth factor A (VEGF) is a biologically and therapeutically important growth factor because it promotes angiogenesis in response to hypoxia, which underlies a wide variety of both physiological and pathological settings. We report here that both VEGF receptor 2 (VEGFR2)-positive and -negative cells depended on VEGF to endure hypoxia. VEGF enhanced the viability of platelet-derived growth factor receptor α (PDGFRα)-positive and VEGFR2-negative cells by enabling indirect activation of PDGFRα, thereby reducing the level of p53. We conclude that the breadth of VEGF's influence extends beyond VEGFR-positive cells and propose a plausible mechanistic explanation of this phenomenon.
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http://dx.doi.org/10.1128/MCB.01019-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007796PMC
September 2016

Epitope Specificity Determines Pathogenicity and Detectability of Anti-Platelet-Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis.

Arthritis Rheumatol 2015 Jul;67(7):1891-903

Università Politecnica delle Marche and Ospedali Riuniti Ancona, Ancona, Italy.

Objective: To identify the epitopes recognized by autoantibodies targeting platelet-derived growth factor receptor α (PDGFRα) in systemic sclerosis (SSc) and develop novel assays for detection of serum anti-PDGFRα autoantibodies.

Methods: Epstein-Barr virus-immortalized B cells from 1 patient with SSc (designated PAM) were screened for expression of IgG binding to PDGFRα and induction of reactive oxygen species in fibroblasts. The variable regions of anti-PDGFRα IgG were cloned into an IgG expression vector to generate distinct recombinant human monoclonal autoantibodies (mAb), which were characterized by binding and functional assays. The epitopes of anti-PDGFRα recombinant human mAb were defined by molecular docking, surface plasmon resonance binding assays, screening of a conformational peptide library spanning the PDGFRα extracellular domains, and expression analyses of alanine-scanned PDGFRα mutants. Direct or competitive enzyme-linked immunosorbent assays were established to detect all serum anti-PDGFRα autoantibodies or, selectively, the agonistic ones.

Results: Three types of anti-PDGFRα recombinant human mAb, with the same VH but distinct VL chains, were generated. Nonagonistic VH PAM-Vκ 13B8 recognized 1 linear epitope, whereas agonistic VH PAM-Vλ 16F4 and VH PAM-Vκ 16F4 recognized 2 distinct conformational epitopes. Serum anti-PDGFRα antibodies were detected in 66 of 70 patients with SSc, 63 of 130 healthy controls, 11 of 26 patients with primary Raynaud's phenomenon (RP), and 13 of 29 patients with systemic lupus erythematosus (SLE). Serum VH PAM-Vκ 16F4-like antibodies were found in 24 of 34 patients with SSc, but not in healthy controls, patients with primary RP, or patients with SLE. Peptides composing the VH PAM-Vκ 16F4 epitope inhibited PDGFRα signaling triggered by serum IgG from SSc patients.

Conclusion: Agonistic anti-PDGFRα autoantibodies are enriched in SSc sera and recognize specific conformational epitopes that can be used to discriminate agonistic from nonagonistic antibodies and block PDGFRα signaling in patients with SSc.
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http://dx.doi.org/10.1002/art.39125DOI Listing
July 2015

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology.

Mol Cell Biol 2015 May 2;35(10):1673-85. Epub 2015 Mar 2.

Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) make profound contributions to both physiology and pathology. While it is widely believed that direct (PDGF-mediated) activation is the primary mode of activating PDGFRs, the discovery that they can also be activated indirectly begs the question of the relevance of the indirect mode of activating PDGFRs. In the context of a blinding eye disease, indirect activation of PDGFRα results in persistent signaling, which suppresses the level of p53 and thereby promotes viability of cells that drive pathogenesis. Under the same conditions, PDGFRβ fails to undergo indirect activation. In this paper, we report that RasGAP (GTPase-activating protein of Ras) prevented indirect activation of PDGFRβ. RasGAP, which associates with PDGFRβ but not PDGFRα, reduced the level of mitochondrion-derived reactive oxygen species, which are required for enduring activation of PDGFRs. Furthermore, preventing PDGFRβ from associating with RasGAP allowed it to signal enduringly and drive pathogenesis of a blinding eye disease. These results indicate a previously unappreciated role of RasGAP in antagonizing indirect activation of PDGFRβ, define the underlying mechanism, and raise the possibility that PDGFRβ-mediated diseases involve indirect activation of PDGFRβ.
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http://dx.doi.org/10.1128/MCB.01248-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405646PMC
May 2015

Insulin-like growth factor 1 (IGF-1) stabilizes nascent blood vessels.

J Biol Chem 2015 Mar 6;290(10):6349-60. Epub 2015 Jan 6.

From the Department of Ophthalmology, Harvard Medical School, The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02115

Here we report that VEGF-A and IGF-1 differ in their ability to stabilize newly formed blood vessels and endothelial cell tubes. Although VEGF-A failed to support an enduring vascular response, IGF-1 stabilized neovessels generated from primary endothelial cells derived from various vascular beds and mouse retinal explants. In these experimental systems, destabilization/regression was driven by lysophosphatidic acid (LPA). Because previous studies have established that Erk antagonizes LPA-mediated regression, we considered whether Erk was an essential component of IGF-dependent stabilization. Indeed, IGF-1 lost its ability to stabilize neovessels when the Erk pathway was inhibited pharmacologically. Furthermore, stabilization was associated with prolonged Erk activity. In the presence of IGF-1, Erk activity persisted longer than in the presence of VEGF or LPA alone. These studies reveal that VEGF and IGF-1 can have distinct inputs in the angiogenic process. In contrast to VEGF, IGF-1 stabilizes neovessels, which is dependent on Erk activity and associated with prolonged activation.
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http://dx.doi.org/10.1074/jbc.M114.634154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358271PMC
March 2015

Lysophosphatidic acid contributes to angiogenic homeostasis.

Exp Cell Res 2015 May 26;333(2):166-170. Epub 2014 Nov 26.

Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary/Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA. Electronic address:

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http://dx.doi.org/10.1016/j.yexcr.2014.11.012DOI Listing
May 2015

Vascular endothelial growth factor acts primarily via platelet-derived growth factor receptor α to promote proliferative vitreoretinopathy.

Am J Pathol 2014 Nov 26;184(11):3052-68. Epub 2014 Sep 26.

The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address:

Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration-approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti-VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated.
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http://dx.doi.org/10.1016/j.ajpath.2014.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215028PMC
November 2014

Plakophilin-2 promotes activation of epidermal growth factor receptor.

Mol Cell Biol 2014 Oct 11;34(20):3778-9. Epub 2014 Aug 11.

Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA

While growth factor-driven dimerization of receptor tyrosine kinases (RTKs) is a simple and intuitive mechanism of activating RTKs, K.-I. Arimoto et al. (Mol. Cell. Biol. 34:3843-3854, 2014, doi:10.1128/MCB.00758-14) describe a novel means of promoting the activity of RTKs. Namely, plakophilin-2 (PKP2) associates with the epidermal growth factor receptor (EGFR) and enhances its ligand-dependent and ligand-independent activity. This discovery suggests that antagonizing PKP2 may be a new therapeutic opportunity to combat tumors in which activation of EGFR contributes to pathogenesis.
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http://dx.doi.org/10.1128/MCB.00968-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187716PMC
October 2014

Pericytes prevent regression of endothelial cell tubes by accelerating metabolism of lysophosphatidic acid.

Microvasc Res 2014 May 27;93:62-71. Epub 2014 Mar 27.

Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA. Electronic address:

Efforts to eradicate pathological vessels in neovascular diseases and induce growth of mature, functional vasculature in ischemic diseases are limited by our incomplete understanding of molecular mechanisms of vessel stabilization. While it is well known that pericytes stabilize blood vessels, the underlying mechanisms have not been fully elucidated. The goal of this study was to further investigate the mechanisms by which pericytes stabilize vessels. In an in vitro model of blood vessels, in which regression is driven by lysophosphatidic acid (LPA), pericyte-mediated stabilization was associated with a decrease in the concentration of LPA. The decline in the concentration of LPA was not caused by a reduction in activity or expression of autotaxin, the main enzyme implicated in LPA production. Rather, pericytes accelerated LPA metabolism. Stabilization of tubes by pericytes correlated with accelerated LPA dephosphorylation and increased expression of lipid phosphate phosphatases (LPPs). Finally, pericytes failed to stabilize tubes exposed to an LPA analogue, which was resistant to degradation. Our results suggest that pericytes stabilize endothelial cell tubes by accelerating the metabolism of LPA.
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http://dx.doi.org/10.1016/j.mvr.2014.03.003DOI Listing
May 2014

Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy?

Prog Retin Eye Res 2014 May 9;40:16-34. Epub 2014 Jan 9.

The Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Proliferative vitreoretinopathy (PVR) is a blinding disorder that occurs in eyes with rhegmatogenous retinal detachment and in eyes that have recently undergone retinal detachment surgery. There are presently no treatment strategies to reduce the risk of developing PVR in eyes with retinal detachment, and surgical intervention is the only option for eyes with retinal detachment and established PVR. Given the poor visual outcome associated with the surgical treatment of PVR, considerable work has been done to identify pharmacologic agents that could antagonize the PVR process. Intensive efforts to identify molecular determinants of PVR implicate vitreal growth factors. A surprise that emerged in the course of testing the 'growth factor hypothesis' of PVR was the existence of a functional relationship amongst growth factors that engage platelet-derived growth factor (PDGF) receptor α (PDGFRα), a receptor tyrosine kinase that is key to pathogenesis of experimental PVR. Vascular endothelial cell growth factor A (VEGF), which is best known for its ability to activate VEGF receptors (VEGFRs) and induce permeability and/or angiogenesis, enables activation of PDGFRα by a wide spectrum of vitreal growth factors outside of the PDGF family (non-PDGFs) in a way that triggers signaling events that potently enhance the viability of cells displaced into vitreous. Targeting these growth factors or signaling events effectively neutralizes the bioactivity of PVR vitreous and prevents PVR in a number of preclinical models. In this review, we discuss recent conceptual advances in understanding the role of growth factors in PVR, and consider the tangible treatment strategies for clinical application.
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http://dx.doi.org/10.1016/j.preteyeres.2013.12.006DOI Listing
May 2014

A reactive oxygen species-mediated, self-perpetuating loop persistently activates platelet-derived growth factor receptor α.

Mol Cell Biol 2014 Jan 4;34(1):110-22. Epub 2013 Nov 4.

Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

The platelet-derived growth factor (PDGF) receptors (PDGFRs) are central to a spectrum of human diseases. When PDGFRs are activated by PDGF, reactive oxygen species (ROS) and Src family kinases (SFKs) act downstream of PDGFRs to enhance PDGF-mediated tyrosine phosphorylation of various signaling intermediates. In contrast to these firmly established principles of signal transduction, much less is known regarding the recently appreciated ability of ROS and SFKs to indirectly and chronically activate monomeric PDGF receptor α (PDGFRα) in the setting of a blinding condition called proliferative vitreoretinopathy (PVR). In this context, we made a series of discoveries that substantially expands our appreciation of epigenetic-based mechanisms to chronically activate PDGFRα. Vitreous, which contains growth factors outside the PDGF family but little or no PDGFs, promoted formation of a unique SFK-PDGFRα complex that was dependent on SFK-mediated phosphorylation of PDGFRα and activated the receptor's kinase activity. While vitreous engaged a total of five receptor tyrosine kinases, PDGFRα was the only one that was activated persistently (at least 16 h). Prolonged activation of PDGFRα involved mTOR-mediated inhibition of autophagy and accumulation of mitochondrial ROS. These findings reveal that growth factor-containing biological fluids, such as vitreous, are able to tirelessly activate PDGFRα by engaging a ROS-mediated, self-perpetuating loop.
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http://dx.doi.org/10.1128/MCB.00839-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911282PMC
January 2014

Detection of H2O2-mediated phosphorylation of kinase-inactive PDGFRα.

Methods Enzymol 2013 ;528:189-94

The Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

Platelet-derived growth factor (PDGF) receptor α (PDGFRα) belongs to the 58-member family of receptor tyrosine kinases and contributes to a variety of physiological and pathological settings. Activation of PDGFRα proceeds by at least two mechanisms. The traditional route involves PDGF-dependent dimerization and activation of the receptor's intrinsic kinase activity. The second mechanism proceeds intracellularly and involves reactive oxygen species and Src family kinases, which activate monomeric PDGFRα. Herein we describe an assay to investigate reactive oxygen species-mediated phosphorylation of PDGFRα that is independent of the receptor's intrinsic kinase activity.
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http://dx.doi.org/10.1016/B978-0-12-405881-1.00011-2DOI Listing
January 2014

Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis.

J Biol Chem 2013 Jul 10;288(29):21161-21172. Epub 2013 Jun 10.

From the Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114. Electronic address:

Although a high level of lactate is quintessential to both tumors and wound healing, the manner by which lactate impacts endothelial cells to promote angiogenesis and thereby create or restore vascular perfusion to growing tissues has not been fully elucidated. Here we report that lactate activated the PI3K/Akt pathway in primary human endothelial cells. Furthermore, activating this signaling pathway was required for lactate-stimulated organization of endothelial cells into tubes and for sprouting of vessels from mouse aortic explants. Lactate engaged the PI3K/Akt pathway via ligand-mediated activation of the three receptor tyrosine kinases Axl, Tie2, and VEGF receptor 2. Neutralizing the ligands for these receptor tyrosine kinases, pharmacologically inhibiting their kinase activity or suppressing their expression largely eliminated the ability of cells and explants to respond to lactate. Elucidating the mechanism by which lactate communicates with endothelial cells presents a previously unappreciated opportunity to improve our understanding of the angiogenic program and to govern it.
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http://dx.doi.org/10.1074/jbc.M113.474619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774382PMC
July 2013

Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease.

Am J Pathol 2013 May 9;182(5):1659-70. Epub 2013 Apr 9.

The Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, and the Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.

Proliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non-PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti-VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions.
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http://dx.doi.org/10.1016/j.ajpath.2013.01.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644731PMC
May 2013

Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1.

Mol Cell Biol 2013 May 11;33(10):1976-90. Epub 2013 Mar 11.

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD.
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http://dx.doi.org/10.1128/MCB.01283-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647976PMC
May 2013

SU9518 inhibits proliferative vitreoretinopathy in fibroblast and genetically modified Müller cell-induced rabbit models.

Invest Ophthalmol Vis Sci 2013 Feb 19;54(2):1392-7. Epub 2013 Feb 19.

Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, Biotech 5, 381 Plantation Street, Suite 250, Worcester, MA 01605, USA.

Purpose: Proliferative vitreoretinopathy (PVR) is a complication of retinal detachment that can lead to surgical failure and vision loss. Previous studies suggest that a variety of retinal cells, including RPE and Müller glia, may be responsible. Platelet-derived growth factor receptor alpha (PDGFRα) has been strongly implicated in the pathogenesis, and found to be intrinsic to the development of PVR in rabbit models. We examine whether SU9518, a tyrosine kinase inhibitor with PDGFRα specificity, can inhibit the development of PVR in fibroblast and Müller cell rabbit models of PVR.

Methods: SU9518 was injected in rabbit eyes along with fibroblasts, Müller cells (MIO-M1), or Müller cells transfected to increase their expression of PDGFRα (MIO-M1α). Indirect ophthalmoscopy and histopathology were used to assess efficacy and toxicity.

Results: SU9518 was an effective inhibitor of PVR in both fibroblast and Müller cell models of PVR. No toxic effects were identified by indirect ophthalmoscopy or histopathology.

Conclusions: SU9518 is an effective and safe inhibitor of PVR in rabbit models, and could potentially be used in humans for the treatment of this and other proliferative diseases of the retina involving fibrosis and gliosis. Further animal studies need to be performed to examine retinal toxicity and sustained delivery mechanisms.
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http://dx.doi.org/10.1167/iovs.12-10320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597189PMC
February 2013

PDGF receptor-α does not promote HCMV entry into epithelial and endothelial cells but increased quantities stimulate entry by an abnormal pathway.

PLoS Pathog 2012 Sep 13;8(9):e1002905. Epub 2012 Sep 13.

Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USA.

Epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFRα) were reported to mediate entry of HCMV, including HCMV lab strain AD169. AD169 cannot assemble gH/gL/UL128-131, a glycoprotein complex that is essential for HCMV entry into biologically important epithelial cells, endothelial cells, and monocyte-macrophages. Given this, it appeared incongruous that EGFR and PDGFRα play widespread roles in HCMV entry. Thus, we investigated whether PDGFRα and EGFR could promote entry of wild type HCMV strain TR. EGFR did not promote HCMV entry into any cell type. PDGFRα-transduction of epithelial and endothelial cells and several non-permissive cells markedly enhanced HCMV TR entry and surprisingly, promoted entry of HCMV mutants lacking gH/gL/UL128-131 into epithelial and endothelial cells. Entry of HCMV was not blocked by a panel of PDGFRα antibodies or the PDGFR ligand in fibroblasts, epithelial, or endothelial cells or by shRNA silencing of PDGFRα in epithelial cells. Moreover, HCMV glycoprotein induced cell-cell fusion was not increased when PDGFRα was expressed in cells. Together these results suggested that HCMV does not interact directly with PDGFRα. Instead, the enhanced entry produced by PDGFRα resulted from a novel entry pathway involving clathrin-independent, dynamin-dependent endocytosis of HCMV followed by low pH-independent fusion. When PDGFRα was expressed in cells, an HCMV lab strain escaped endosomes and tegument proteins reached the nucleus, but without PDGFRα virions were degraded. By contrast, wild type HCMV uses another pathway to enter epithelial cells involving macropinocytosis and low pH-dependent fusion, a pathway that lab strains (lacking gH/gL/UL128-131) cannot follow. Thus, PDGFRα does not act as a receptor for HCMV but increased PDGFRα alters cells, facilitating virus entry by an abnormal pathway. Given that PDGFRα increased infection of some cells to 90%, PDGFRα may be very useful in overcoming inefficient HCMV entry (even of lab strains) into the many difficult-to-infect cell types.
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http://dx.doi.org/10.1371/journal.ppat.1002905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441672PMC
September 2012

Retinal Pigment Epithelium and Müller Progenitor Cell Interaction Increase Müller Progenitor Cell Expression of PDGFRα and Ability to Induce Proliferative Vitreoretinopathy in a Rabbit Model.

Stem Cells Int 2012 23;2012:106486. Epub 2012 Aug 23.

Department of Ophthalmology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Purpose. Proliferative vitreoretinopathy (PVR) is a complication of retinal detachment characterized by redetachment of the retina as a result of membrane formation and contraction. A variety of retinal cells, including retinal pigment epithelial (RPE) and Müller glia, and growth factors may be responsible. Platelet-derived growth factor receptor alpha (PDGFRα) is found in large quantities in PVR membranes, and is intrinsic to the development of PVR in rabbit models. This study explores the expression of PDGFR in cocultures of RPE and Müller cells over time to examine how these two cell types may collaborate in the development of PVR. We also examine how changes in PDGFRα expression alter Müller cell pathogenicity. Methods. Human MIO-M1 Müller progenitor (MPC) and ARPE19 cells were studied in a transmembrane coculture system. Immunocytochemistry and Western blot were used to look at PDGFRα, PDGFRβ, and GFAP expression. A transfected MPC line cell line expressing the PDGFRα (MIO-M1α) was generated, and tested in a rabbit model for its ability to induce PVR. Results. The expression of PDGFRα and PDGFRβ was upregulated in MIO-M1 MPCs cocultured with ARPE19 cells; GFAP was slightly decreased. Increased expression of PDGFRα in the MIO-M1 cell line resulted in increased pathogenicity and enhanced ability to induce PVR in a rabbit model. Conclusions. Müller and RPE cell interaction can lead to upregulation of PDGFRα and increased Müller cell pathogenicity. Müller cells may play a more active role than previously thought in the development of PVR membranes, particularly when stimulated by an RPE-cell-rich environment. Additional studies of human samples and in animal models are warranted.
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http://dx.doi.org/10.1155/2012/106486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432558PMC
September 2012