DOCSLIB.ORG

Type 3 Innate Lymphoid Cells a Stromal Cell Niche for Human and Mouse

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Type 3 Innate Lymphoid Cells a Stromal Cell Niche for Human and Mouse A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells Kerim Hoorweg, Priyanka Narang, Zhi Li, Anne Thuery, Natalie Papazian, David R. Withers, Mark C. Coles and Tom This information is current as Cupedo of September 28, 2021. J Immunol 2015; 195:4257-4263; Prepublished online 16 September 2015; doi: 10.4049/jimmunol.1402584 http://www.jimmunol.org/content/195/9/4257 Downloaded from References This article cites 42 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/195/9/4257.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 28, 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells Kerim Hoorweg,*,1 Priyanka Narang,†,1 Zhi Li,† Anne Thuery,† Natalie Papazian,* David R. Withers,‡ Mark C. Coles,† and Tom Cupedo* Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stro- mal cells create and maintain specialized niches that support survival, activation, and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells. Moreover, both cell types are conserved from mice to humans and coloc- alize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to Downloaded from adult marginal reticular cells and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs. The Journal of Immunology, 2015, 195: 4257–4263. esenchymal stromal cells are essential for the devel- adaptive immunity, highlighting the essential role of stromal cell– opment of secondary lymphoid organs (reviewed in derived microenvironments in the immune system (9–13). + M Ref. 1). In adult mice, mesenchymal stromal cells Rorgt type 3 innate lymphoid cells (ILC3) are a part of a http://www.jimmunol.org/ maintain the specialized microenvironments in lymphoid tissues family of innate-like immune cells with important roles in barrier where T cells encounter their cognate Ag presented by dendritic immunity to enteric pathogens, cancer surveillance, and intestinal cells and B cells generate high-affinity Abs during germinal center homeostasis (reviewed in Ref. 14). Rorgt+ ILC3 reside in mucosal reactions (2). To date, several specialized subsets of stromal cells lymphoid and nonlymphoid tissues, where they are characterized have been identified. T zone fibroblastic reticular cells (TRCs) by expression of the natural cytotoxicity receptor NKp46 in mice provide structural support for the migration of T cells and deliver and NKp44 in humans (15–18). In addition, ILC3 are also found survival and recruitment signals to the migrating T cells in the in peripheral lymphoid organs as natural cytotoxicity receptor- form of IL-7 and CCL19/CCL21 (3). Follicular dendritic cells negative cells (15, 16). Even though ILC3 are found in most (FDCs) are located in B cell follicles and are essential for gen- lymphoid tissues, it has yet to be established whether ILC3 reside by guest on September 28, 2021 eration of high-affinity Abs by presenting immune complexes to in specialized microdomains, analogous to T and B cells. If so, this B cells and for supporting B cell migration and homeostasis would provide novel insights into ILC3 function and regulation. through expression of BAFF and nonclassical CD40 ligands (4–8). During murine embryogenesis, a specialized population of stro- Functional deficiency of either TRC or FDC severely impacts mal cells termed lymphoid tissue organizer (LTo) cells interacts with a subset of ILC3 also known as lymphoid tissue inducer (LTi) cells, at prospective lymph node (LN) anlagen (19–22). This in- *Department of Hematology, Erasmus University Medical Center, 3000 CA Rotter- dam, the Netherlands; †Department of Biology, Centre for Immunology and Infec- teraction induces activation of LTo cells through lymphotoxin-b tion, Hull York Medical School, University of York, York YO10 5DD, United receptor (LTbR) and TNFR signaling (22). Activated LTo cells ‡ Kingdom; and Medical Research Council Centre for Immune Regulation, College express ICAM-1, VCAM-1, and mucosal addressin cell adhesion of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom molecule-1 (MAdCAM-1), and secrete the three homeostatic 1K.H. and P.N. contributed equally to this study. chemokines, CXCL13, CCL21, and CCL19, that are essential for Received for publication October 10, 2014. Accepted for publication August 22, stromal cell–driven organization of the developing LN. Whereas 2015. LTi cell–LTo cell interactions are crucial for mouse LN and This work was supported by an Erasmus Medical Center grant (to T.C.), ZenithII Peyer’s patch development, splenic white pulp development is LTi Grant 93512004 awarded by the Netherlands Genomics Initiative (to T.C.), Medical cell independent (23–25). Research Council Grant G0601156 (to M.C.C.), Human Frontier Science Program Grant RGP0006/2009-C (to T.C. and M.C.C.), and the People Programme (Marie In adult LNs, a stromal cell population exists that phenotypically Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007- resembles fetal stromal LTo cells (26, 27). These marginal reticular 2013 under Research Executive Agency Grant Agreement 289720. cells (MRC) express VCAM-1, ICAM-1, and MAdCAM-1 (26), Address correspondence and reprint requests to Dr. Mark C. Coles or Dr. Tom and cell lines generated from MRC produce CXCL13 upon LTbR Cupedo, Department of Biology, Centre for Immunology and Infection, Wentworth Way, University of York, York YO10 5DD, U.K. (M.C.C.) or Erasmus Medical stimulation (28). In vivo, MRC can differentiate into FDC after Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands (T.C.). E-mail ad- immune activation (29). Due to their phenotypic resemblance to dresses: [email protected] (M.C.C.) or [email protected] (T.C.) fetal LTo cells, it was postulated that MRC represent direct Abbreviations used in this article: E, embryonic day; FDC, follicular dendritic cell; descendants of the fetal stromal organizer cells (30). However, ILC, innate lymphoid cell; LN, lymph node; LTi, lymphoid tissue inducer; LTo, lymphoid tissue organizer; LTbR, lymphotoxin-b receptor; MAdCAM-1, mucosal stromal cell lineage relationships between LTo and MRC remain addressin cell adhesion molecule-1; MRC, marginal reticular cell; qPCR, quantitative experimentally unaddressed. PCR; RANKL, receptor activator for NF-kB ligand; TRC, T cell zone fibroblastic In this study, we set out to identify and characterize a specialized reticular cell. stromal cell niche for ILC3 in human and mouse secondary Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 lymphoid organs. We show that LTo and MRC are conserved from www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402584 4258 STROMAL NICHE FOR LYMPH NODE ILC3 mice to humans and that they colocalize with ILC3. Using a novel RNA from human tissues was extracted using the RNA-XS kit (Machery lineage-tracing approach, we provide evidence that a subset of Nagel), followed by reverse transcription with random hexamer primers. A fetal LTo cells gives rise exclusively to MRC, suggesting that the Neviti Thermal Cycler (Applied Biosystems) and DyNAmo Flash SYBR Green qPCR kit (Finnzymes) were used for quantitative PCR, with the LTo–MRC lineage provides a lifelong stromal framework for addition of MgCl2 to a final concentration of 4 mM. All reactions were human and mouse ILC3. done in duplicate and are normalized to the expression of GAPDH. Rel- ative expression was calculated by the cycling threshold method as 22Δt. Materials and Methods Statistical analysis Mice Significance values were calculated using an unpaired two-tailed Student Il7Cre (31), and Rosa26 eYFP mice were bred and maintained in a specific t test. The p values , 0.05 were considered statistically significant. pathogen-free facility at the University of York under Home Office license. All animal research was approved by the University of York Ethical Re- view Process and conducted in accordance with ARRIVE guidelines. Results Superovulated female Rosa26eYFP mice were mated with IL-7 Cre males, Identification of human fetal stromal organizer cells and day
Load more

Recommended publications
  • RUTH FAIR-MÄKELÄ: Lymphatic Endothelial Cells Regulate Traffic in Lymph Nodes Doctoral Dissertation, 180 Pp
    ANNALES UNIVERSITATIS TURKUENSIS UNIVERSITATIS ANNALES D 1507 D Ruth Fair-Mäkelä Ruth LYMPHATIC ENDOTHELIAL CELLS REGULATE TRAFFIC INTO LYMPH NODES Ruth Fair-Mäkelä Painosalama Oy, Turku, Finland 2020 Finland Turku, Oy, Painosalama ISBN 978-951-29-8175-5 (PRINT) – ISBN 978-951-29-8176-2 (PDF) TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS ISSN 0355-9483 (Print) SARJA - SER. D OSA - TOM. 1507 | MEDICA - ODONTOLOGICA | TURKU 2020 ISSN 2343-3213 (Online) LYMPHATIC ENDOTHELIAL CELLS REGULATE TRAFFIC IN LYMPH NODES Ruth Fair-Mäkelä TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS SARJA - SER. D OSA – TOM. 1507 | MEDICA – ODONTOLOGICA | TURKU 2020 University of Turku Faculty of Medicine Institute of Biomedicine Medical Microbiology and Immunology Turku Doctoral Programme of Molecular Medicine Supervised by Academician Sirpa Jalkanen, MD, PhD Professor Masayuki Miyasaka, MD, PhD Medicity Research Laboratory Medicity Research Laboratory Medical Microbiology and Immunology Medical Microbiology and Immunology University of Turku University of Turku Turku, Finland Turku, Finland Adjunct Professor Kati Elima, MD, PhD Medicity Research Laboratory Medical Biochemistry and Genetics University of Turku Turku, Finland Reviewed by Professor Lena Claesson-Welsh, BD, PhD Adjunct Professor Marko Pesu, MD, PhD Rudbeck Laboratory and Science for Laboratory of Immunoregulation Life Laboratory Faculty of Medicine and Health Department of Immunology, Technology Genetics and Pathology Tampere University Uppsala University Tampere, Finland
    [Show full text]
  • Visualizing B Cell Development: Creating an Immunology Video Game
    VISUALIZING B CELL DEVELOPMENT: CREATING AN IMMUNOLOGY VIDEO GAME By Emily Lunhui Ling A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Master of Arts Baltimore, Maryland March, 2016 © 2016 Emily L. Ling All Rights Reserved ABSTRACT e foundational immunology concepts of lymphocyte development are important for beginning science students to comprehend. Video games oer the potential for a novel approach to teaching this complex subject matter by more eectively engaging students in this material. However, currently available educational video games intended to teach immunology have distinct limitations such as a lack of explicit demonstrations of the stages of lymphocyte development and clonal selection. is project identies the content focus and gameplay mechanics of currently available immunology video games. Using this as a basis, a novel approach for developing an immunology video game was outlined with the primary goal of improving integration of educational content. A proof of concept was developed for the B lymphocyte development portion of the game content and a partial prototype was developed in Unity 5 3D. e important contribution of this thesis was the development of a new approach to designing a more eective educational video game specically for immunology. Outcomes of this research will serve to inform future biomedical communicators on how to develop content for active learning games in immunology and provide a guide for designing full length educational video games featuring novel gameplay mechanics such as those identied through this project. Emily L. Ling ii CHAIRPERSONS OF THE SUPERVISORY COMMITTEE esis Preceptor Mark J. Soloski, Ph.D., Professor of Medicine Departments of Medicine, Pathology, Molecular Biology and Genetics, and Molecular Microbiology and Immunology Director, Immunology Training Program e Johns Hopkins University School of Medicine Departmental Advisor David A.
    [Show full text]
  • Review Article Mesenchymal Stromal Cells Affect Disease Outcomes Via Macrophage Polarization
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi Publishing Corporation Stem Cells International Volume 2015, Article ID 989473, 11 pages http://dx.doi.org/10.1155/2015/989473 Review Article Mesenchymal Stromal Cells Affect Disease Outcomes via Macrophage Polarization Guoping Zheng,1 Menghua Ge,1 Guanguan Qiu,1 Qiang Shu,2 and Jianguo Xu1,3 1 Shaoxing Second Hospital, Shaoxing, Zhejiang 312000, China 2The Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China 3The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China Correspondence should be addressed to Jianguo Xu; [email protected] Received 18 May 2015; Accepted 30 June 2015 Academic Editor: Armand Keating Copyright © 2015 Guoping Zheng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mesenchymal stromal cells (MSCs) are multipotent and self-renewable cells that reside in almost all postnatal tissues. In recent years, many studies have reported the effect of MSCs on the innate and adaptive immune systems. MSCs regulate the proliferation, activation, and effector function of T lymphocytes, professional antigen presenting cells (dendritic cells, macrophages, and B lymphocytes), and NK cells via direct cell-to-cell contact or production of soluble factors including indoleamine 2,3-dioxygenase, prostaglandin E2, tumor necrosis factor- stimulated gene/protein 6, nitric oxide, and IL-10. MSCs are also able to reprogram macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype capable of regulating immune response.
    [Show full text]
  • Tumor Microenvironment Consortium
    Tumor Microenvironment Network (TMEN) Dinah Singer, Ph.D. Director Suresh Mohla, Ph.D. TMEN Program Director Division of Cancer Biology TMEN 2006-2011: Goals – Generate a comprehensive understanding of the composition of the normal stroma and the role of the stroma in tumor initiation, progression and metastasis – Develop resources and infrastructure critical to the broader research community to advance understanding of the tumor microenvironment (TME) TMEN 2006-2011: Current Program •Nine interdisciplinary groups characterizing the TME in major cancer sites, emphasizing human samples •Identifying and translating promising leads •Collaboratively addressing the complexity of TME by assessing: • The co-evolution of tumor-associated stromal cell types and the tumor •Stromal cell interactions with each other and with tumor cells •Generating novel reagents, models and technologies for the research community TMEN 2006-2011: Areas of Emphasis Microenvironment Initiation Progression Metastasis – Tumor initiating cells – Tumor heterogeneity – Stromal cell types and cellular processes – Complex signaling pathways – Genes and genetics TMEN 2006-2011: Scientific Accomplishments Tumor Initiating Cells: • Combined invasive gene signatures in tumor initiating cells and stromal wound repair response genes robustly predict metastasis-free and overall survival in breast, medulloblastoma, lung and prostate cancer patients • New therapeutic approaches to circumvent the chemo- and radio-resistance of tumor initiating cells Stromal Cells: • Delineation of mechanisms
    [Show full text]
  • Essential Role of Canonical NF-Κb Activity in the Development of Stromal Cell Subsets in Secondary Lymphoid Organs
    Essential Role of Canonical NF-κB Activity in the Development of Stromal Cell Subsets in Secondary Lymphoid Organs This information is current as Dana Bogdanova, Arata Takeuchi, Madoka Ozawa, of September 24, 2021. Yasuhiro Kanda, M. Azizur Rahman, Burkhard Ludewig, Tatsuo Kinashi and Tomoya Katakai J Immunol published online 5 November 2018 http://www.jimmunol.org/content/early/2018/11/02/jimmun ol.1800539 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/11/03/jimmunol.180053 Material 9.DCSupplemental 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 24, 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 5, 2018, doi:10.4049/jimmunol.1800539 The Journal of Immunology Essential Role of Canonical NF-kB Activity in the Development of Stromal Cell Subsets in Secondary Lymphoid Organs Dana Bogdanova,* Arata Takeuchi,* Madoka Ozawa,* Yasuhiro Kanda,* M. Azizur Rahman,* Burkhard Ludewig,† Tatsuo Kinashi,‡ and Tomoya Katakai* Organized tissue structure in the secondary lymphoid organs (SLOs) tightly depends on the development of fibroblastic stromal cells (FSCs) of mesenchymal origin; however, the mechanisms of this relationship are poorly understood.
    [Show full text]
  • Lymphatic Tissue Engineering and Regeneration Laura Alderfer1, Alicia Wei1 and Donny Hanjaya-Putra1,2,3,4,5,6*
    Alderfer et al. Journal of Biological Engineering (2018) 12:32 https://doi.org/10.1186/s13036-018-0122-7 REVIEW Open Access Lymphatic Tissue Engineering and Regeneration Laura Alderfer1, Alicia Wei1 and Donny Hanjaya-Putra1,2,3,4,5,6* Abstract The lymphatic system is a major circulatory system within the body, responsible for the transport of interstitial fluid, waste products, immune cells, and proteins. Compared to other physiological systems, the molecular mechanisms and underlying disease pathology largely remain to be understood which has hindered advancements in therapeutic options for lymphatic disorders. Dysfunction of the lymphatic system is associated with a wide range of disease phenotypes and has also been speculated as a route to rescue healthy phenotypes in areas including cardiovascular disease, metabolic syndrome, and neurological conditions. This review will discuss lymphatic system functions and structure, cell sources for regenerating lymphatic vessels, current approaches for engineering lymphatic vessels, and specific therapeutic areas that would benefit from advances in lymphatic tissue engineering and regeneration. Keywords: Lymphangiogenesis, Tissue Engineering, Disease Modeling, Wound Healing, Lymphedema, Stem Cells, Biomaterials, Interstitial Fluid, Regeneration I. Introduction to the Lymphatic System and its role Interstitial fluid (IF) is a plasma filtrate that is generated Function by transcapillary filtration and is governed by Starling The lymphatic system is nearly ubiquitous in the human forces, the net difference between hydrostatic and body, present in all tissues except the epidermis, cartil- osmotic pressures, at the microcirculatory level [9]. In age, eye lens, cornea, retina, and bone marrow [1, 2]. order to maintain fluid homeostasis, lymph formation in The main functions of the lymphatic system include the initial lymphatic vessels must be balanced by the net fluid homeostasis and interstitial fluid drainage, immune flux of plasma being filtered out [4].
    [Show full text]
  • Are Mesenchymal Stromal Cells Immune Cells? Martin J Hoogduijn
    Hoogduijn Arthritis Research & Therapy (2015) 17:88 DOI 10.1186/s13075-015-0596-3 REVIEW Open Access Are mesenchymal stromal cells immune cells? Martin J Hoogduijn however, covers various subsets of MSCs with different Abstract phenotypes and different functions [4,5]. Cell isolation Mesenchymal stromal cells (MSCs) are considered to be procedures can, therefore, affect the cellular compos- promising agents for the treatment of immunological ition of MSC cultures. Culture conditions can have a disease. Although originally identified as precursor cells further impact on the phenotype and function of MSCs for mesenchymal lineages, in vitro studies have [6]. This may affect study outcomes. Therefore, some demonstrated that MSCs possess diverse immune care should be taken in comparing the results of studies regulatory capacities. Pre-clinical models have shown using different MSC isolation and culture procedures. beneficial effects of MSCs in multiple immunological In the bone marrow, MSCs have a supportive function diseases and a number of phase 1/2 clinical trials carried for the haematopoietic system and provide a niche for out so far have reported signs of immune modulation haematopoietic progenitor cells to mature. The presence after MSC infusion. These data indicate that MSCs play a of MSCs is not limited, however, to the bone marrow central role in the immune response. This raises the and in other tissues, such as adipose tissue, muscle and academic question whether MSCs are immune cells multiple organs, they provide support for tissue cells by or whether they are tissue precursor cells with producing growth factors and matrix proteins. In immunoregulatory capacity. Correct understanding addition to their differentiation and tissue supportive of the immunological properties and origin of MSCs functions, MSCs have a well-established immune modu- will aid in the appropriate and safe use of the latory function.
    [Show full text]
  • Innate Lymphoid Cells (Ilcs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis
    Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Innate Lymphoid Cells (ILCs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis Maho Nagasawa, Hergen Spits, and Xavier Romero Ros Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, 1105 BA Amsterdam, Netherlands Correspondence: [email protected] Innate lymphoid cells (ILCs) have emerged as an expanding family of effector cells particu- larly enriched in the mucosal barriers. ILCs are promptly activated by stress signals and multiple epithelial- and myeloid-cell-derived cytokines. In response, ILCs rapidly secrete effector cytokines, which allow them to survey and maintain the mucosal integrity. Uncontrolled action of ILCs might contribute to tissue damage, chronic inflammation, met- abolic diseases, autoimmunity, and cancer. Here we discuss the recent advances in our understanding of the cytokine network that modulate ILC immune responses: stimulating cytokines, signature cytokines secreted by ILC subsets, autocrine cytokines, and cytokines that induce cell plasticity. nnate lymphoid cells (ILCs) are innate lym- Klose et al. 2014; Gasteiger et al. 2015). ILCs Iphocytes that play important roles in immune cross talk with the resident tissue by sensing defense against microbes, regulation of adaptive the cytokines present in their microenviron- immunity, tissue remodeling, and repair and ments and subsequently secreting a plethora homeostasis of hematopoietic and nonhemato- of cytokines that regulate innate immunity poietic cell types. ILCs are present in all tissues, and homeostasis of hematopoietic and nonhe- but they are particularly enriched in mucosal matopoietic cells in the tissues (Artis and Spits surfaces. Unlike adaptive lymphocytes, ILCs 2015).
    [Show full text]
  • Tumor-Associated Stromal Cells As Key Contributors to the Tumor Microenvironment Karen M
    Bussard et al. Breast Cancer Research (2016) 18:84 DOI 10.1186/s13058-016-0740-2 REVIEW Open Access Tumor-associated stromal cells as key contributors to the tumor microenvironment Karen M. Bussard1,2, Lysette Mutkus3, Kristina Stumpf3, Candelaria Gomez-Manzano4 and Frank C. Marini1,3* Abstract The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.
    [Show full text]
  • Visualizing Stromal Cell Dynamics in Different Tumor Microenvironments by Spinning Disk Confocal Microscopy
    Disease Models & Mechanisms 1, 155-167 (2008) doi:10.1242/dmm.000596 RESEARCH ARTICLE Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy Mikala Egeblad1,*,‡, Andrew J. Ewald1,‡, Hanne A. Askautrud1,2, Morgan L. Truitt1, Bryan E. Welm1,5, Emma Bainbridge1, George Peeters3, Matthew F. Krummel4 and Zena Werb1,* SUMMARY The tumor microenvironment consists of stromal cells and extracellular factors that evolve in parallel with carcinoma cells. To gain insights into the activities of stromal cell populations, we developed and applied multicolor imaging techniques to analyze the behavior of these cells within different tumor microenvironments in the same live mouse. We found that regulatory T-lymphocytes (Tregs) migrated in proximity to blood vessels. Dendritic- like cells, myeloid cells and carcinoma-associated fibroblasts all exhibited higher motility in the microenvironment at the tumor periphery than within the tumor mass. Since oxygen levels differ between tumor microenvironments, we tested if acute hypoxia could account for the differences in cell migration. Direct visualization revealed that Tregs ceased migration under acute systemic hypoxia, whereas myeloid cells continued migrating. In the same mouse and microenvironment, we experimentally subdivided the myeloid cell population and revealed that uptake of fluorescent dextran defined a low-motility subpopulation expressing markers of tumor-promoting, alternatively activated macrophages. In contrast, fluorescent anti-Gr1 antibodies marked myeloid cells patrolling inside tumor vessels and in the stroma. Our techniques allow real-time combinatorial analysis DMM of cell populations based on spatial location, gene expression, behavior and cell surface molecules within intact tumors. The techniques are not limited to investigations in cancer, but could give new insights into cell behavior more broadly in development and disease.
    [Show full text]
  • Characterization of Lymph Node Stromal Cells During Treg-Mediated Tolerance
    Characterization of lymph node stromal cells during Treg-mediated tolerance Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Maria Anna Sofia Broggi aus Mailand, Italien Basel, 2013 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Ed Palmer Prof. Dr. Daniela Finke Basel, den 26. Februar 2013 Prof. Dr Jörg Schibler, Dekan Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz“ lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licences/by-nc-nd/2.5/cheingesehen werden. Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz Sie dürfen: das Werk vervielfältigen, verbreiten und öffentlich zugänglich machen Zu den folgenden Bedingungen: Namensnennung. Sie müssen den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen (wodurch aber nicht der Eindruck entstehen darf, Sie oder die Nutzung des Werkes durch Sie würden entlohnt). Keine kommerzielle Nutzung. Dieses Werk darf nicht für kommerzielle Zwecke verwendet werden. Keine Bearbeitung. Dieses Werk darf nicht bearbeitet oder in anderer Weise verändert werden. • Im Falle einer Verbreitung müssen Sie anderen die Lizenzbedingungen, unter welche dieses Werk fällt, mitteilen. Am Einfachsten ist es, einen Link auf diese Seite einzubinden. • Jede der vorgenannten Bedingungen kann aufgehoben werden, sofern Sie die Einwilligung des Rechteinhabers dazu erhalten. • Diese Lizenz lässt die Urheberpersönlichkeitsrechte unberührt. Die gesetzlichen Schranken des Urheberrechts bleiben hiervon unberührt. Die Commons Deed ist eine Zusammenfassung des Lizenzvertrags in allgemeinverständlicher Sprache: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/legalcode.de Haftungsausschluss: Die Commons Deed ist kein Lizenzvertrag.
    [Show full text]
  • Application of Tissue Engineering to the Immune System: Development of Artificial Lymph Nodes
    MINI REVIEW ARTICLE published: 16 November 2012 doi: 10.3389/fimmu.2012.00343 Application of tissue engineering to the immune system: development of artificial lymph nodes Tom Cupedo1*, Abraham Stroock2 and Mark Coles3* 1 Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands 2 School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA 3 Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York,York, UK Edited by: The goal of tissue engineering and regenerative medicine is to develop synthetic versions Burkhard Ludewig, Cantonal Hospital of human organs for transplantation, in vitro toxicology testing and to understand basic St. Gallen, Switzerland mechanisms of organ function. A variety of different approaches have been utilized to repli- Reviewed by: cate the microenvironments found in lymph nodes including the use of a variety of different Joern Dengjel, Albert-Ludwigs-Universität Freiburg, bio-materials, culture systems, and the application of different cell types to replicate stro- Germany mal networks found in vivo. Although no system engineered so far can fully replicate lymph Henrique Veiga-Fernandes, Instituto node function, progress has been made in the development of microenvironments that can de Medicina Molecular, Portugal promote the initiation of protective immune responses. In this review we will explore the *Correspondence: different approaches utilized to recreate lymph node microenvironments and the technical Mark Coles, Centre for Immunology and Infection, Department of Biology challenges required to recreate a fully functional immune system in vitro. and Hull York Medical School, Keywords: lymph node, tissue engineering, stroma, bio-materials, extracellular matrix University of York,YorkYO10 5DD, UK.
    [Show full text]