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The Evolving Cardiac Lymphatic Vasculature in Development, Repair and Regeneration
REVIEWS The evolving cardiac lymphatic vasculature in development, repair and regeneration Konstantinos Klaourakis 1,2, Joaquim M. Vieira 1,2,3 ✉ and Paul R. Riley 1,2,3 ✉ Abstract | The lymphatic vasculature has an essential role in maintaining normal fluid balance in tissues and modulating the inflammatory response to injury or pathogens. Disruption of normal development or function of lymphatic vessels can have severe consequences. In the heart, reduced lymphatic function can lead to myocardial oedema and persistent inflammation. Macrophages, which are phagocytic cells of the innate immune system, contribute to cardiac development and to fibrotic repair and regeneration of cardiac tissue after myocardial infarction. In this Review, we discuss the cardiac lymphatic vasculature with a focus on developments over the past 5 years arising from the study of mammalian and zebrafish model organisms. In addition, we examine the interplay between the cardiac lymphatics and macrophages during fibrotic repair and regeneration after myocardial infarction. Finally, we discuss the therapeutic potential of targeting the cardiac lymphatic network to regulate immune cell content and alleviate inflammation in patients with ischaemic heart disease. The circulatory system of vertebrates is composed of two after MI. In this Review, we summarize the current complementary vasculatures, the blood and lymphatic knowledge on the development, structure and function vascular systems1. The blood vasculature is a closed sys- of the cardiac lymphatic vasculature, with an emphasis tem responsible for transporting gases, fluids, nutrients, on breakthroughs over the past 5 years in the study of metabolites and cells to the tissues2. This extravasation of cardiac lymphatic heterogeneity in mice and zebrafish. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Isolation and Characterisation of Lymphatic Endothelial Cells From
www.nature.com/scientificreports OPEN Isolation and characterisation of lymphatic endothelial cells from lung tissues afected by lymphangioleiomyomatosis Koichi Nishino1,2*, Yasuhiro Yoshimatsu3,4, Tomoki Muramatsu5, Yasuhito Sekimoto1,2, Keiko Mitani1,2, Etsuko Kobayashi1,2, Shouichi Okamoto1,2, Hiroki Ebana1,2,6,7, Yoshinori Okada8, Masatoshi Kurihara2,6, Kenji Suzuki9, Johji Inazawa5, Kazuhisa Takahashi1, Tetsuro Watabe3 & Kuniaki Seyama1,2 Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-afected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fuorescence-activated cell sorting (FACS). We found that LAM-LECs had signifcantly higher ability of proliferation and migration compared to control LECs. VEGF-D signifcantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis. -
The Role of SOX Family Members in Solid Tumours and Metastasis
Seminars in Cancer Biology 67 (2020) 122–153 Contents lists available at ScienceDirect Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer Review The role of SOX family members in solid tumours and metastasis T ⁎ Daniela Grimma,b,c, , Johann Bauerd, Petra Wisee, Marcus Krügerb, Ulf Simonsena, Markus Wehlandb, Manfred Infangerb, Thomas J. Corydona,f a Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, Denmark b Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University of Magdeburg, Leipziger Str. 44, D-39120, Magdeburg, Germany c Gravitational Biology and Translational Regenerative Medicine, Faculty of Medicine and Mechanical Engineering, Otto von Guericke University of Magdeburg, Leipziger Str. 44, D-39120, Magdeburg, Germany d Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany e Charles R. Drew University of Medicine and Science, 1731 E. 120th St., Los Angeles, CA 90059, USA f Department of Ophthalmology, Aarhus University Hospital, DK-8200 Aarhus C, Denmark ARTICLE INFO ABSTRACT Keywords: Cancer is a heavy burden for humans across the world with high morbidity and mortality. Transcription factors SOX family including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are thought to Tumorigenesis be involved in the regulation of specific biological processes. The deregulation of gene expression programs can Cancer lead to cancer development. Here, we review the role of the SOX family in breast cancer, prostate cancer, renal Metastasis cell carcinoma, thyroid cancer, brain tumours, gastrointestinal and lung tumours as well as the entailing ther- Targets apeutic implications. The SOX family consists of more than 20 members that mediate DNA binding by the HMG domain and have regulatory functions in development, cell-fate decision, and differentiation. -
Prognostic Significance of SOX18 Expression in Non-Small Cell Lung Cancer
INTERNATIONAL JOURNAL OF ONCOLOGY 46: 123-132, 2015 Prognostic significance of SOX18 expression in non-small cell lung cancer AlekSANDRA JeTHON1,2, BartosZ PULA1,2, MateusZ OLBROMSKI1,2, BOZENA Werynska3, Beata MuSzCzyNSkA-BeRNHARD4, WOJCIECH WITKIEWICZ1, PIOTR DzIeGIel1,2,5 and MARzeNA PODHORSkA-OkOlOw1,2 1Regional Specialist Hospital, Research and Development Centre, 51-124 wroclaw; 2Department of Histology and embryology, Medical university, 50-368 wroclaw; 3Department of Pulmonology and Pulmonary Tumours, Medical university, 53-439 wroclaw; 4Laboratory of Histopathology, lower Silesian Centre for Pulmonary Diseases, 53-439 wroclaw; 5Department of Physiotherapy, wrocław university School of Physical education, 51-612 wroclaw, Poland Received July 31, 2014; Accepted September 9, 2014 DOI: 10.3892/ijo.2014.2698 Abstract. Recent studies have demonstrated the involvement Introduction of SOX18 transcription factor in blood and lymphatic vessel development, as well as in wound healing processes. SOX18 Lung cancer is the most common malignancy worldwide expression has been noted in cancer cells of various tumours, (accounting for ~12% of cancers) in terms of both incidence and including lung cancer. However, the exact role of SOX18 mortality. In addition, a tendency toward increased incidence expression in non-small cell lung cancer (NSCLC) remains is estimated (1). More than 80% of diagnosed lung cancers to be determined. The present study, therefore, assessed its belong to the group of non-small cell carcinomas (NSCLC), expression in 198 cases of NSCLC, consisting of 94 adeno- and the majority of these cases are diagnosed in advanced carcinomas (AC), 89 squamous cell carcinomas (SQC) and disease stages (2). In view of these facts, the discovery of new 15 large cell carcinomas (LCC). -
SOX7 Is Down-Regulated in Lung Cancer
Hayano et al. Journal of Experimental & Clinical Cancer Research 2013, 32:17 http://www.jeccr.com/content/32/1/17 RESEARCH Open Access SOX7 is down-regulated in lung cancer Takahide Hayano1, Manoj Garg1*, Dong Yin2, Makoto Sudo1, Norihiko Kawamata2, Shuo Shi3, Wenwen Chien1, Ling-wen Ding1, Geraldine Leong1, Seiichi Mori4, Dong Xie3, Patrick Tan1,5 and H Phillip Koeffler1,2,6 Abstract Background: SOX7 is a transcription factor belonging to the SOX family. Its role in lung cancer is unknown. Methods: In this study, whole genomic copy number analysis was performed on a series of non-small cell lung cancer (NSCLC) cell lines and samples from individuals with epidermal growth factor receptor (EGFR) mutations using a SNP-Chip platform. SOX7 was measured in NSCLC samples and cell lines, and forced expressed in one of these lines. Results: A notable surprise was that the numerous copy number (CN) changes observed in samples of Asian, non-smoking EGFR mutant NSCLC were nearly the same as those CN alterations seen in a large collection of NSCLC from The Cancer Genome Atlas which is presumably composed of predominantly Caucasians who often smoked. However, four regions had CN changes fairly unique to the Asian EGFR mutant group. We also examined CN changes in NSCLC lines. The SOX7 gene was homozygously deleted in one (HCC2935) of 10 NSCLC cell lines and heterozygously deleted in two other NSCLC lines. Expression of SOX7 was significantly downregulated in NSCLC cell lines (8/10, 80%) and a large collection of NSCLC samples compared to matched normal lung (57/62, 92%, p= 0.0006). -
SOX18 Expression in Non-Melanoma Skin Cancer
ANTICANCER RESEARCH 36: 2379-2384 (2016) SOX18 Expression in Non-melanoma Skin Cancer MACIEJ ORNAT1, CHRISTOPHER KOBIERZYCKI1, JEDRZEJ GRZEGRZOLKA1, BARTOSZ PULA1, ALEKSANDRA ZAMIRSKA2, ANDRZEJ BIENIEK2, JACEK C. SZEPIETOWSKI2, PIOTR DZIEGIEL1,3 and MARZENNA PODHORSKA OKOLOW1 Departments of 1Histology and Embryology, and 2Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland; 3Department of Physiotherapy, University School of Physical Education, Wroclaw, Poland Abstract. Background/aim: SRY-related HMG box protein Classification of Tumours, the most common malignant skin 18 (SOX18) is a transcription factor involved in a range of tumours are: basal cell carcinoma (BCC), squamous cell physiological processes, including differentiation of carcinoma (SCC) and melanoma malignum (1). BCC and endothelial cells during new vessel formation. Numerous SCC are jointly referred to as non-melanoma skin cancers studies are being conducted to determine its role in (NMSCs) and originating from stratified squamous carcinogenesis. Materials and Methods: Thirty-five cases of epithelium cells, as in contrast to melanoma, which is of squamous cell carcinoma (SCC), 61 cases of basal cell neuroectodermal origin (1, 2). In 2012, there were 5.4 million carcinoma (BCC), 15 cases of actinic keratosis (AK) and 15 NMSC cases, including 3.3 million of BCC and SCC (3). normal skin (NS) cases were examined in the study. Actinic keratosis (AK) is a common intraepithelial Expression of SOX18 was investigated with immuno - proliferative lesion classified as a preinvasive cancer (4). Up histochemistry and light optic microscopy. The obtained to 20% of all AK have a tendency towards transformation results were subjected to statistical analysis including into SCC and for patients diagnosed with at least 10 AK available clinicopathological data. -
Specification of the Hair Follicle Niche Occurs Prior to Its Formation and Is Progenitor Dependent
bioRxiv preprint doi: https://doi.org/10.1101/414839; this version posted September 12, 2018. 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. Mok, Saxena, Heitman et al., 2018 Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent Ka-Wai Mok,1,2,9 Nivedita Saxena,1,2,3,9 Nicholas Heitman,1,2,3,9 Laura Grisanti,1,2 Devika Srivastava,1,2 Mauro Muraro,4 Tina Jacob,5 Rachel Sennett,1,2 Zichen Wang,6 Yutao Su,7 Lu M. Yang,7 Avi Ma’ayan,6 David M. Ornitz7, Maria Kasper,5 and Michael Rendl1,2,3,8,10,* 1Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, Atran Building AB7-10C, Box 1020; 1428 Madison Ave, New York, NY 10029, USA 2Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Atran Building AB7-10C, Box 1020; 1428 Madison Ave, New York, NY 10029, USA 3Graduate School of Biomedical Sciences; Icahn School of Medicine at Mount Sinai, Atran Building AB7-10C, Box 1020; 1428 Madison Ave, New York, NY 10029, USA 4Oncode Institute, Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands 5Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet. 141 83 Huddinge, Sweden 6Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, BD2K-LINCS Data Coordination and Integration Center, Knowledge Management Center for Illuminating the Druggable Genome (KMC-IDG), Icahn School of Medicine at Mount Sinai, One Gustave L. -
A Molecular Map of Murine Lymph Node Blood Vascular Endothelium at Single Cell Resolution
ARTICLE https://doi.org/10.1038/s41467-020-17291-5 OPEN A molecular map of murine lymph node blood vascular endothelium at single cell resolution Kevin Brulois1,13, Anusha Rajaraman1,2,3,13, Agata Szade 1,4,13,Sofia Nordling1,13, Ania Bogoslowski 5,6, Denis Dermadi 1, Milladur Rahman 1, Helena Kiefel1, Edward O’Hara1, Jasper J. Koning3, Hiroto Kawashima7, Bin Zhou 8, Dietmar Vestweber 9, Kristy Red-Horse10, Reina E. Mebius3, Ralf H. Adams 11, ✉ Paul Kubes 5,6, Junliang Pan1,2 & Eugene C. Butcher1,2,12 1234567890():,; Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicro- scopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis. 1 Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. -
A Novel Tumor Suppressor Through the Wnt/Β-Catenin Signaling Pathway
Liu et al. Journal of Ovarian Research 2014, 7:87 http://www.ovarianresearch.com/content/7/1/87 RESEARCH Open Access Reduced expression of SOX7 in ovarian cancer: a novel tumor suppressor through the Wnt/β-catenin signaling pathway Huidi Liu1,2,4, Zi-Qiao Yan1, Bailiang Li1, Si-Yuan Yin1, Qiang Sun1, Jun-Jie Kou1, Dan Ye1, Kelsey Ferns1,5, Hong-Yu Liu3 and Shu-Lin Liu1,2,4* Abstract Background: Products of the SOX gene family play important roles in the life process. One of the members, SOX7, is associated with the development of a variety of cancers as a tumor suppression factor, but its relevance with ovarian cancer was unclear. In this study, we investigated the involvement of SOX7 in the progression and prognosis of epithelial ovarian cancer (EOC) and the involved mechanisms. Methods: Expression profiles in two independent microarray data sets were analyzed for SOX7 between malignant and normal tissues. The expression levels of SOX7 in EOC, borderline ovarian tumors and normal ovarian tissues were measured by immunohistochemistry. We also measured levels of COX2 and cyclin-D1 to examine their possible involvement in the same signal transduction pathway as SOX7. Results: The expression of SOX7 was significantly reduced in ovarian cancer tissues compared with normal controls, strongly indicating that SOX7 might be a negative regulator in the Wnt/β-catenin pathway in ovarian cancer. By immunohistochemistry staining, the protein expression of SOX7 showed a consistent trend with that of the gene expression microarray analysis. By contrast, the protein expression level of COX2 and cyclin-D1 increased as the tumor malignancy progressed, suggesting that SOX7 may function through the Wnt/β-catenin signaling pathway as a tumor suppressor. -
Analysis of Dll4 Regulation Reveals a Combinatorial Role for Sox and Notch in Arterial Development
Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development Natalia Sacilottoa, Rui Monteirob, Martin Fritzschea, Philipp W. Beckera, Luis Sanchez-del-Campoa, Ke Liuc, Philip Pinheirob, Indrika Ratnayakaa, Benjamin Daviesd, Colin R. Godinga, Roger Patientb, George Bou-Ghariosc, and Sarah De Vala,1 aLudwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; bMolecular Haematology Unit and British Heart Foundation Centre of Research Excellence, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom; cKennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7DQ, United Kingdom; and dWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved June 4, 2013 (received for review January 14, 2013) The mechanisms by which arterial fate is established and main- DNA-binding factor RBPJ (CSL) and coactivator Mastermind tained are not clearly understood. Although a number of signaling to form an activation complex (10). Loss of Notch signaling in pathways and transcriptional regulators have been implicated in zebrafish results in defective arterial-venous differentiation al- arterio-venous differentiation, none are essential for arterial though a distinct dorsal aorta still forms, and some arterial- formation, and the manner in which widely expressed factors specific genes are expressed (10). Mice null for the Notch1 and may achieve arterial-specific gene regulation is unclear. Using both -4 receptors also display severe vascular remodeling defects, as mouse and zebrafish models, we demonstrate here that arterial do those lacking Rbpj and Delta-like ligand 4 (Dll4), the arte- specification is regulated combinatorially by Notch signaling and rial-specific Notch ligand (12–14). -
Regulation of Extra-Embryonic Endoderm Stem Cell Differentiation by Nodal and Cripto Signaling Marianna Kruithof-De Julio1,2, Mariano J
DEVELOPMENT AND STEM CELLS RESEARCH ARTICLE 3885 Development 138, 3885-3895 (2011) doi:10.1242/dev.065656 © 2011. Published by The Company of Biologists Ltd Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling Marianna Kruithof-de Julio1,2, Mariano J. Alvarez2,3, Antonella Galli1,2, Jianhua Chu1,2, Sandy M. Price4, Andrea Califano2,3 and Michael M. Shen1,2,* SUMMARY The signaling pathway for Nodal, a ligand of the TGF superfamily, plays a central role in regulating the differentiation and/or maintenance of stem cell types that can be derived from the peri-implantation mouse embryo. Extra-embryonic endoderm stem (XEN) cells resemble the primitive endoderm of the blastocyst, which normally gives rise to the parietal and the visceral endoderm in vivo, but XEN cells do not contribute efficiently to the visceral endoderm in chimeric embryos. We have found that XEN cells treated with Nodal or Cripto (Tdgf1), an EGF-CFC co-receptor for Nodal, display upregulation of markers for visceral endoderm as well as anterior visceral endoderm (AVE), and can contribute to visceral endoderm and AVE in chimeric embryos. In culture, XEN cells do not express Cripto, but do express the related EGF-CFC co-receptor Cryptic (Cfc1), and require Cryptic for Nodal signaling. Notably, the response to Nodal is inhibited by the Alk4/Alk5/Alk7 inhibitor SB431542, but the response to Cripto is unaffected, suggesting that the activity of Cripto is at least partially independent of type I receptor kinase activity. Gene set enrichment analysis of genome-wide expression signatures generated from XEN cells under these treatment conditions confirmed the differing responses of Nodal- and Cripto-treated XEN cells to SB431542.