DOCSLIB.ORG

Clonally Expanding Smooth Muscle Cells Promote Atherosclerosis by Escaping Efferocytosis and Activating the Complement Cascade

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clonally Expanding Smooth Muscle Cells Promote Atherosclerosis by Escaping Efferocytosis and Activating the Complement Cascade Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade Ying Wanga,b, Vivek Nandaa,b,c, Daniel Direnzoa, Jianqin Yea, Sophia Xiaoa, Yoko Kojimaa, Kathryn L. Howea, Kai-Uwe Jarra, Alyssa M. Floresa, Pavlos Tsantilasa, Noah Tsaoa, Abhiram Raob,d, Alexandra A. C. Newmane, Anne V. Eberharda, James R. Priestf, Arno Ruusaleppg, Gerard Pasterkamph,i, Lars Maegdefesselj,k, Clint L. Millerl,m,n, Lars Lindo, Simon Koplevp, Johan L. M. Björkegrenp, Gary K. Owense, Erik Ingelssonb,o,q, Irving L. Weissmanr,1, and Nicholas J. Leepera,b,1 aDivision of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; bStanford Cardiovascular Institute, Stanford University, Stanford, CA 94305; cDepartment of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; dDepartment of Bioengineering, Stanford University, Stanford, CA 94305; eRobert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22904; fDivision of Pediatric Cardiology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; gDepartment of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia 50406; hDepartment of Cardiology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands; iLaboratory of Clinical Chemistry, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands; jDepartment for Vascular and Endovascular Surgery, Klinikum Rechts der Isar, Technical University Munich, 80333 Munich, Germany; kGerman Center for Cardiovascular Research (DZHK partner site), 10785 Munich, Germany; lCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22904; mDepartment of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22904; nDepartment of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904; oDepartment of Medical Sciences, Uppsala University, SE-751 05 Uppsala, Sweden; pDepartment of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574; qDivision of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305; and rInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Irving L. Weissman, April 20, 2020 (sent for review April 8, 2020; reviewed by Joshua Beckman and Yogen Kanthi) Atherosclerosis is the process underlying heart attack and stroke. This is one of the reasons why all currently approved therapies Despite decades of research, its pathogenesis remains unclear. target risk factors for disease (e.g., hypertension, diabetes, and Dogma suggests that atherosclerotic plaques expand primarily via hyperlipidemia) rather than the cells that actually constitute the accumulation of cholesterol and inflammatory cells. However, the lesion. recent evidence suggests that a substantial portion of the plaque While there is little doubt that bone marrow-derived in- “ ” may arise from a subset of dedifferentiated vascular smooth flammatory cells home to the developing lesion (3, 5), emerging muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the ma- ture SMC can give rise to a hyperproliferative cell which appears to Significance promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with pro- Cardiovascular disease remains the world’s leading killer, de- phagocytic complement fragments, we find that this cell also es- spite the widespread use of cholesterol-lowering medicines. capes immune surveillance by neighboring macrophages, thereby Recent studies suggest a portion of this residual risk may result exacerbating its relative survival advantage. Mechanistic studies from the clonal expansion of cells within the atherosclerotic indicate this phenomenon results from a generalized opsonin- plaques of diseased blood vessels. How these cells promote sensing defect acquired by macrophages during polarization. This inflammation and whether they can be therapeutically tar- defect coincides with the noncanonical up-regulation of so-called geted remain unclear. The current study suggests that clonally don’t eat me molecules on inflamed phagocytes, which reduces expanding cells may cause disease by triggering the comple- their capacity for programmed cell removal (PrCR). Knockdown ment cascade while evading immune surveillance. However, or knockout of the key antiphagocytic molecule CD47 restores these cells also appear to be susceptible to therapies that the ability of macrophages to sense and clear opsonized targets reactivate phagocytic clearance pathways, suggesting a po- in vitro, allowing for potent and targeted suppression of clonal tential treatment approach for heart disease similar to current SMC expansion in the plaque in vivo. Because integrated clinical oncology efforts directed against the cancer stem cell. and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that Author contributions: Y.W., D.D., Y.K., J.R.P., L.M., G.K.O., E.I., and N.J.L. designed re- the clonally expanding SMC may represent a translational target search; I.L.W. guided experimental design; Y.W., V.N., D.D., J.Y., S.X., Y.K., K.L.H., K.-U.J., for treating atherosclerosis. A.M.F., P.T., N.T., A. Rao, A.A.C.N., A.V.E., J.R.P., G.P., L.M., J.L.M.B., E.I., and N.J.L. per- formed research; Y.W., A.A.C.N., J.R.P., A. Ruusalepp, G.P., L.M., C.L.M., L.L., S.K., J.L.M.B., G.K.O., E.I., I.L.W., and N.J.L. contributed new reagents/analytic tools; Y.W., V.N., D.D., atherosclerosis | clonality | smooth muscle cells | efferocytosis | CD47 J.Y., Y.K., K.L.H., K.-U.J., A.M.F., J.R.P., G.P., L.M., C.L.M., L.L., S.K., J.L.M.B., G.K.O., E.I., and N.J.L. analyzed data; I.L.W. provided feedback on data; and Y.W., K.-U.J., G.K.O., E.I., and N.J.L. wrote the paper. espite being the world’s leading killer (1), the root causes of Reviewers: J.B., Vanderbilt University Medical Center; and Y.K., University of Michigan. Datherosclerotic cardiovascular disease remain elusive (2, 3). Competing interest statement: I.L.W. and N.J.L. are cofounders of Forty Seven, Inc., an This is due in part to the fact that cells which contribute to immunooncology company. This company was recently acquired by Gilead Sciences; the growing atherosclerotic plaque frequently undergo extensive purchase did not include stock in Gilead. I.L.W. and N.J.L. do not currently have any phenotypic modulation, wherein they down-regulate the very consulting agreement with Gilead Sciences. “cell-specific” markers needed for their definitive identification Published under the PNAS license. 1 (4). This process is commonly referred to as “dedifferentiation” To whom correspondence may be addressed.Email:[email protected] or nleeper@ stanford.edu. in the field of vascular biology. As a result, there are major This article contains supporting information online at https://www.pnas.org/lookup/suppl/ ambiguities regarding the origins of the individual components doi:10.1073/pnas.2006348117/-/DCSupplemental. of the plaque and how they contribute to disease pathogenesis. First published June 15, 2020. 15818–15826 | PNAS | July 7, 2020 | vol. 117 | no. 27 www.pnas.org/cgi/doi/10.1073/pnas.2006348117 Downloaded by guest on September 25, 2021 data suggest that it is a phenotypically-modulated (“dediffer- whether systemic C3 expression is associated with risk for coronary entiated”) cell in the vascular smooth muscle cell (SMC) lineage artery disease (CAD); 2) if the dedifferentiated SMC is a source of which may actually give rise to the majority of cells within the C3 in human plaque; and 3) if CAD patients harbor a C3- atherosclerotic plaque (6, 7). Sophisticated lineage-tracing studies producing cell that resembles the Sca1+ SMC identified above. revealed that the progeny of these cells have remarkable plasticity First, we measured circulating complement levels in 1,003 el- and can assume a wide variety of phenotypes. These range from derly individuals enrolled in the Prospective Investigation of the cells which resemble cap-stabilizing myofibroblasts (which are Vasculature in Uppsala Seniors (PIVUS) study (SI Appendix, likely beneficial), to cells previously assumed to represent bone Fig. S3A) (17). Consistent with prior reports (18), we found that marrow-derived macrophages (which are likely detrimental), and age- and sex-adjusted C3 levels were associated with endothelial- even to cells which express stem cell markers (whose role is un- dependent vasodilation (a marker of vascular function), carotid known) (6, 8–13). This final point is important because Benditt and intimal–medial thickness (CIMT; a measure of atherosclerotic colleagues reported a clonal origin of human atherosclerosis nearly plaque burden), and major adverse cardiovascular event rate 50 y ago (14), and recent studies revealed that murine SMCs can (MACE; a composite end point which includes incident heart expand in a clonal fashion under periods of stress (7, 8, 10). attack and stroke) (Fig. 2A). These associations were attenuated These data indicate that there may be a cell which resembles after adjusting for inflammatory comorbidities, such as body an “atherosclerotic
Load more

Recommended publications
  • Calreticulin Controlling the Membrane Translocation of Immunogenicity Of
    ERP57 Membrane Translocation Dictates the Immunogenicity of Tumor Cell Death by Controlling the Membrane Translocation of Calreticulin This information is current as of September 25, 2021. Michel Obeid J Immunol 2008; 181:2533-2543; ; doi: 10.4049/jimmunol.181.4.2533 http://www.jimmunol.org/content/181/4/2533 Downloaded from References This article cites 26 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/181/4/2533.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology ERP57 Membrane Translocation Dictates the Immunogenicity of Tumor Cell Death by Controlling the Membrane Translocation of Calreticulin1 Michel Obeid2 Several pieces of experimental evidence indicate the following: 1) the most efficient antitumor treatments (this principle applies on both chemotherapy and radiotherapy) are those that induce immunogenic cell death and are able to trigger a specific antitumor immune response; and 2) the immunogenicity of cell death depends very closely on the plasma membrane quantity of calreticulin (CRT), an endoplasmic reticulum (ER) stress protein exposed to the cell membrane after immunogenic treatment.
    [Show full text]
  • Viewed Under 23 (B) Or 203 (C) fi M M Male Cko Mice, and Largely Unaffected Magni Cation; Scale Bars, 500 M (B) and 50 M (C)
    BRIEF COMMUNICATION www.jasn.org Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron Camille Ansermet,* Matthias B. Moor,* Gabriel Centeno,* Muriel Auberson,* † † ‡ Dorothy Zhang Hu, Roland Baron, Svetlana Nikolaeva,* Barbara Haenzi,* | Natalya Katanaeva,* Ivan Gautschi,* Vladimir Katanaev,*§ Samuel Rotman, Robert Koesters,¶ †† Laurent Schild,* Sylvain Pradervand,** Olivier Bonny,* and Dmitri Firsov* BRIEF COMMUNICATION *Department of Pharmacology and Toxicology and **Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland; †Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; ‡Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia; §School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; |Services of Pathology and ††Nephrology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland; and ¶Université Pierre et Marie Curie, Paris, France ABSTRACT Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is crit- leaves.4 Most recently, Legati et al. have ical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the shown an association between genetic kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical polymorphisms in Xpr1 and primary fa- sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the milial brain calcification disorder.5 How- molecular identity of the protein(s) participating in the basolateral Pi efflux remains ever, the role of XPR1 in the maintenance unknown. Evidence has suggested that xenotropic and polytropic retroviral recep- of Pi homeostasis remains unknown. Here, tor 1 (XPR1) might be involved in this process. Here, we show that conditional in- we addressed this issue in mice deficient for activation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi Xpr1 in the nephron.
    [Show full text]
  • A Single-Cell Transcriptional Atlas Identifies Extensive Heterogeneity in the Cellular Composition of Tendons
    bioRxiv preprint doi: https://doi.org/10.1101/801266; this version posted October 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A single-cell transcriptional atlas identifies extensive heterogeneity in the cellular composition of tendons Jacob B Swanson1, Andrea J De Micheli2, Nathaniel P Disser1, Leandro M Martinez1, Nicholas R Walker1,3, Benjamin D Cosgrove2, Christopher L Mendias1,3,* 1Hospital for Special Surgery, New York, NY, USA 2Meining School of Biomedical Engineering, Cornell University, Ithaca, NY, USA 3Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA *Corresponding Author Christopher Mendias, PhD Hospital for Special Surgery 535 E 70th St New York, NY 10021 USA +1 212-606-1785 [email protected] Keywords: tenocyte; tendon fibroblast; pericyte; single-cell RNA sequencing bioRxiv preprint doi: https://doi.org/10.1101/801266; this version posted October 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Tendon is a dense, hypocellular connective tissue that transmits forces between muscles and bones. Cellular heterogeneity is increasingly recognized as an important factor in the biological basis of tissue homeostasis and disease, but little is known about the diversity of cells that populate tendon. Our objective was to explore the heterogeneity of cells in mouse Achilles tendons using single-cell RNA sequencing. We identified 13 unique cell types in tendons, including 4 previously undescribed populations of fibroblasts.
    [Show full text]
  • KLF2 Induced
    UvA-DARE (Digital Academic Repository) The transcription factor KLF2 in vascular biology Boon, R.A. Publication date 2008 Link to publication Citation for published version (APA): Boon, R. A. (2008). The transcription factor KLF2 in vascular biology. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:23 Sep 2021 Supplementary data: Genes induced by KLF2 Dekker et al. LocusLink Accession Gene Sequence Description Fold p-value ID number symbol change (FDR) 6654 AK022099 SOS1 cDNA FLJ12037 fis, clone HEMBB1001921. 100.00 5.9E-09 56999 AF086069 ADAMTS9 full length insert cDNA clone YZ35C05. 100.00 1.2E-09 6672 AF085934 SP100 full length insert cDNA clone YR57D07. 100.00 6.7E-13 9031 AF132602 BAZ1B Williams Syndrome critical region WS25 mRNA, partial sequence.
    [Show full text]
  • The Atf6β-Calreticulin Axis Promotes Neuronal Survival Under Endoplasmic Reticulum Stress and Excitotoxicity
    bioRxiv preprint doi: https://doi.org/10.1101/2021.02.01.429116; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 1 The ATF6β-calreticulin axis promotes neuronal survival under 2 endoplasmic reticulum stress and excitotoxicity 3 4 Dinh Thi Nguyen1, Thuong Manh Le1, Tsuyoshi Hattori1, Mika Takarada-Iemata1, 5 Hiroshi Ishii1, Jureepon Roboon1, Takashi Tamatani1, Takayuki Kannon2, 6 Kazuyoshi Hosomichi2, Atsushi Tajima2, Shusuke Taniuchi3, Masato Miyake3, Seiichi 7 Oyadomari3, Shunsuke Saito4, Kazutoshi Mori4, Osamu Hori1* 8 9 10 1.Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa 11 University, Kanazawa, Japan 12 2.Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive 13 Medical Sciences, Kanazawa University, Kanazawa, Japan 14 3.Division of Molecular Biology, Institute for Genome Research, Institute of Advanced 15 Medical Sciences, Tokushima University, Tokushima, Japan 16 4.Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan 17 18 19 Running title: Neuroprotective role of the ATF6β-calreticulin axis 20 21 22 23 24 25 26 * Corresponding author: 27 Dr. Osamu Hori 28 Department of Neuroanatomy, Kanazawa University Graduate School of Medical 29 Sciences, 30 13-1 Takara-Machi, Kanazawa City, 31 Ishikawa 920-8640, Japan 32 Tel: +81-76-265-2162 33 Fax: +81-76-234-4222 34 E-mail: [email protected] 35 36 37 38 39 Key words: neurodegeneration, Ca2+ homeostasis, ER stress 40 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.01.429116; this version posted February 2, 2021.
    [Show full text]
  • Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance As a Prognostic Biomarker in Ovarian
    cells Review Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients Michal Kielbik *, Izabela Szulc-Kielbik and Magdalena Klink Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland; [email protected] (I.S.-K.); [email protected] (M.K.) * Correspondence: [email protected]; Tel.: +48-42-27-23-636 Abstract: Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant dis- ease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.
    [Show full text]
  • Steroid-Dependent Regulation of the Oviduct: a Cross-Species Transcriptomal Analysis
    University of Kentucky UKnowledge Theses and Dissertations--Animal and Food Sciences Animal and Food Sciences 2015 Steroid-dependent regulation of the oviduct: A cross-species transcriptomal analysis Katheryn L. Cerny University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Cerny, Katheryn L., "Steroid-dependent regulation of the oviduct: A cross-species transcriptomal analysis" (2015). Theses and Dissertations--Animal and Food Sciences. 49. https://uknowledge.uky.edu/animalsci_etds/49 This Doctoral Dissertation is brought to you for free and open access by the Animal and Food Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Animal and Food Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Comparative Analysis of a Teleost Skeleton Transcriptome Provides Insight Into Its Regulation
    Accepted Manuscript Comparative analysis of a teleost skeleton transcriptome provides insight into its regulation Florbela A. Vieira, M.A.S. Thorne, K. Stueber, M. Darias, R. Reinhardt, M.S. Clark, E. Gisbert, D.M. Power PII: S0016-6480(13)00264-5 DOI: http://dx.doi.org/10.1016/j.ygcen.2013.05.025 Reference: YGCEN 11541 To appear in: General and Comparative Endocrinology Please cite this article as: Vieira, F.A., Thorne, M.A.S., Stueber, K., Darias, M., Reinhardt, R., Clark, M.S., Gisbert, E., Power, D.M., Comparative analysis of a teleost skeleton transcriptome provides insight into its regulation, General and Comparative Endocrinology (2013), doi: http://dx.doi.org/10.1016/j.ygcen.2013.05.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Comparative analysis of a teleost skeleton transcriptome 2 provides insight into its regulation 3 4 Florbela A. Vieira1§, M. A. S. Thorne2, K. Stueber3, M. Darias4,5, R. Reinhardt3, M. 5 S. Clark2, E. Gisbert4 and D. M. Power1 6 7 1Center of Marine Sciences, Universidade do Algarve, Faro, Portugal. 8 2British Antarctic Survey – Natural Environment Research Council, High Cross, 9 Madingley Road, Cambridge, CB3 0ET, UK.
    [Show full text]
  • Supplemental Table 3 - Male Genes Differentially Expressed > 1.5-Fold Among Strains in E11.5 XY Gonads
    Supplemental Table 3 - Male genes differentially expressed > 1.5-fold among strains in E11.5 XY gonads. Male genes differentially expressed between C57BL/6J and 129S1/SvImJ. Note: Positive fold values reflect male genes that are up regulated in C57BL/6J relative to 129S1/SvImJ. Fold Diff Gene symbol Genbank acc Description 10.77 Gcnt1 NM_173442 Mus musculus glucosaminyl (N-acetyl) transferase 1, core 2 (Gcnt1), mRNA [NM_173442] 5.50 Afp NM_007423 Mus musculus alpha fetoprotein (Afp), mRNA [NM_007423] 4.95 Hnf4a NM_008261 Mus musculus hepatic nuclear factor 4, alpha (Hnf4a), mRNA [NM_008261] 4.71 Ppp1r14c AK082372 Mus musculus 0 day neonate cerebellum cDNA, RIKEN full-length enriched library, clone:C230042N14 product:hypothetical protein, full insert sequence. [AK082372] 4.41 Gorasp2 AK020521 Mus musculus 12 days embryo embryonic body between diaphragm region and neck cDNA, RIKEN full-length enriched library, clone:9430094F20 product:inferred: golgi reassembly stacking protein 2, full insert sequence. [AK020521] 3.69 Tmc7 NM_172476 Mus musculus transmembrane channel-like gene family 7 (Tmc7), mRNA [NM_172476] 2.97 Mt2 NM_008630 Mus musculus metallothionein 2 (Mt2), mRNA [NM_008630] 2.62 Gstm6 NM_008184 Mus musculus glutathione S-transferase, mu 6 (Gstm6), mRNA [NM_008184] 2.43 Adhfe1 NM_175236 Mus musculus alcohol dehydrogenase, iron containing, 1 (Adhfe1), mRNA [NM_175236] 2.38 Txndc2 NM_153519 Mus musculus thioredoxin domain containing 2 (spermatozoa) (Txndc2), mRNA [NM_153519] 2.30 C030038J10Rik AK173336 Mus musculus mRNA for mKIAA2027
    [Show full text]
  • Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment
    cells Article Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors Nunzia Novizio 1, Raffaella Belvedere 1 , Emanuela Pessolano 1,2 , Alessandra Tosco 1 , Amalia Porta 1 , Mauro Perretti 2, Pietro Campiglia 1 , Amelia Filippelli 3 and Antonello Petrella 1,* 1 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; [email protected] (N.N.); [email protected] (R.B.); [email protected] (E.P.); [email protected] (A.T.); [email protected] (A.P.); [email protected] (P.C.) 2 The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; [email protected] 3 Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende 43, 84081 Baronissi, Italy; afi[email protected] * Correspondence: [email protected]; Tel.: +39-089-969-762; Fax: +39-089-969-602 Received: 17 November 2020; Accepted: 17 December 2020; Published: 18 December 2020 Abstract: Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones.
    [Show full text]
  • Characterization of Glomerular Extracellular Matrix in Iga Nephropathy by Proteomic Analysis of Laser-Captured Microdissected Gl
    Paunas et al. BMC Nephrology (2019) 20:410 https://doi.org/10.1186/s12882-019-1598-1 RESEARCH ARTICLE Open Access Characterization of glomerular extracellular matrix in IgA nephropathy by proteomic analysis of laser-captured microdissected glomeruli Flavia Teodora Ioana Paunas1,2* , Kenneth Finne2, Sabine Leh2,3, Tarig Al-Hadi Osman2, Hans-Peter Marti2,4, Frode Berven5 and Bjørn Egil Vikse1,2 Abstract Background: IgA nephropathy (IgAN) involves mesangial matrix expansion, but the proteomic composition of this matrix is unknown. The present study aimed to characterize changes in extracellular matrix in IgAN. Methods: In the present study we used mass spectrometry-based proteomics in order to quantitatively compare protein abundance between glomeruli of patients with IgAN (n = 25) and controls with normal biopsy findings (n = 15). Results: Using a previously published paper by Lennon et al. and cross-referencing with the Matrisome database we identified 179 extracellular matrix proteins. In the comparison between IgAN and controls, IgAN glomeruli showed significantly higher abundance of extracellular matrix structural proteins (e.g periostin, vitronectin, and extracellular matrix protein 1) and extracellular matrix associated proteins (e.g. azurocidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase-9 and matrix metalloproteinase 2). Periostin (fold change 3.3) and azurocidin (3.0) had the strongest fold change between IgAN and controls; periostin was also higher in IgAN patients who progressed to ESRD as compared to patients who did not. Conclusion: IgAN is associated with widespread changes of the glomerular extracellular matrix proteome. Proteins important in glomerular sclerosis or inflammation seem to be most strongly increased and periostin might be an important marker of glomerular damage in IgAN.
    [Show full text]
  • Methylome and Transcriptome Maps of Human Visceral and Subcutaneous
    www.nature.com/scientificreports OPEN Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal Received: 9 April 2019 Accepted: 11 June 2019 key epigenetic diferences at Published: xx xx xxxx developmental genes Stephen T. Bradford1,2,3, Shalima S. Nair1,3, Aaron L. Statham1, Susan J. van Dijk2, Timothy J. Peters 1,3,4, Firoz Anwar 2, Hugh J. French 1, Julius Z. H. von Martels1, Brodie Sutclife2, Madhavi P. Maddugoda1, Michelle Peranec1, Hilal Varinli1,2,5, Rosanna Arnoldy1, Michael Buckley1,4, Jason P. Ross2, Elena Zotenko1,3, Jenny Z. Song1, Clare Stirzaker1,3, Denis C. Bauer2, Wenjia Qu1, Michael M. Swarbrick6, Helen L. Lutgers1,7, Reginald V. Lord8, Katherine Samaras9,10, Peter L. Molloy 2 & Susan J. Clark 1,3 Adipocytes support key metabolic and endocrine functions of adipose tissue. Lipid is stored in two major classes of depots, namely visceral adipose (VA) and subcutaneous adipose (SA) depots. Increased visceral adiposity is associated with adverse health outcomes, whereas the impact of SA tissue is relatively metabolically benign. The precise molecular features associated with the functional diferences between the adipose depots are still not well understood. Here, we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic diferences and their contribution to cell type and depot-specifc function. We found that DNA methylomes were notably distinct between diferent adipocyte depots and were associated with diferential gene expression within pathways fundamental to adipocyte function. Most striking diferential methylation was found at transcription factor and developmental genes. Our fndings highlight the importance of developmental origins in the function of diferent fat depots.
    [Show full text]