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Li G, Gao J, Ding P, Gao Y. The role of endothelial cell-pericyte interactions in vascularization and diseases. J Adv Res 2025; 67:269-288. [PMID: 38246244 PMCID: PMC11725166 DOI: 10.1016/j.jare.2024.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Endothelial cells (ECs) and pericytes (PCs) are crucial components of the vascular system, with ECs lining the inner layer of blood vessels and PCs surrounding capillaries to regulate blood flow and angiogenesis. Intercellular communication between ECs and PCs is vital for the formation, stability, and function of blood vessels. Various signaling pathways, such as the vascular endothelial growth factor/vascular endothelial growth factor receptor pathway and the platelet-derived growth factor-B/platelet-derived growth factor receptor-β pathway, play roles in communication between ECs and PCs. Dysfunctional communication between these cells is associated with various diseases, including vascular diseases, central nervous system disorders, and certain types of cancers. AIM OF REVIEW This review aimed to explore the diverse roles of ECs and PCs in the formation and reshaping of blood vessels. This review focused on the essential signaling pathways that facilitate communication between these cells and investigated how disruptions in these pathways may contribute to disease. Additionally, the review explored potential therapeutic targets, future research directions, and innovative approaches, such as investigating the impact of EC-PCs in novel systemic diseases, addressing resistance to antiangiogenic drugs, and developing novel antiangiogenic medications to enhance therapeutic efficacy. KEY SCIENTIFIC CONCEPTS OF REVIEW Disordered EC-PC intercellular signaling plays a role in abnormal blood vessel formation, thus contributing to the progression of various diseases and the development of resistance to antiangiogenic drugs. Therefore, studies on EC-PC intercellular interactions have high clinical relevance.
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Affiliation(s)
- Gan Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Shanghai Sixth People's Hospital Fujian, No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, China
| | - Peng Ding
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Youshui Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
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2
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DeBose-Scarlett E, Ressler AK, Gallione CJ, Sapisochin Cantis G, Friday C, Weinsheimer S, Schimmel K, Spiekerkoetter E, Kim H, Gossage JR, Faughnan ME, Marchuk DA. Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis. Am J Hum Genet 2024; 111:2283-2298. [PMID: 39299239 PMCID: PMC11480799 DOI: 10.1016/j.ajhg.2024.08.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/22/2024] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations.
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Affiliation(s)
- Evon DeBose-Scarlett
- Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Andrew K Ressler
- Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Carol J Gallione
- Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Gonzalo Sapisochin Cantis
- Abdominal Transplant and HPB Surgical Oncology, Toronto General Hospital and Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, ON PMB-11-175, Canada
| | | | - Shantel Weinsheimer
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA
| | - Katharina Schimmel
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University, Stanford, CA 94305, USA
| | - Edda Spiekerkoetter
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University, Stanford, CA 94305, USA
| | - Helen Kim
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA
| | - James R Gossage
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Marie E Faughnan
- Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada; Toronto HHT Centre, St. Michael's Hospital and Li Ka Shing Knowledge Institute, Toronto, ON M5B 1W8, Canada
| | - Douglas A Marchuk
- Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
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Ricciardelli AR, Robledo A, Fish JE, Kan PT, Harris TH, Wythe JD. The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations. Biomedicines 2023; 11:2876. [PMID: 38001877 PMCID: PMC10669898 DOI: 10.3390/biomedicines11112876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 11/26/2023] Open
Abstract
Brain arteriovenous malformations (bAVMs) are focal vascular lesions composed of abnormal vascular channels without an intervening capillary network. As a result, high-pressure arterial blood shunts directly into the venous outflow system. These high-flow, low-resistance shunts are composed of dilated, tortuous, and fragile vessels, which are prone to rupture. BAVMs are a leading cause of hemorrhagic stroke in children and young adults. Current treatments for bAVMs are limited to surgery, embolization, and radiosurgery, although even these options are not viable for ~20% of AVM patients due to excessive risk. Critically, inflammation has been suggested to contribute to lesion progression. Here we summarize the current literature discussing the role of the immune system in bAVM pathogenesis and lesion progression, as well as the potential for targeting inflammation to prevent bAVM rupture and intracranial hemorrhage. We conclude by proposing that a dysfunctional endothelium, which harbors the somatic mutations that have been shown to give rise to sporadic bAVMs, may drive disease development and progression by altering the immune status of the brain.
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Affiliation(s)
- Ashley R. Ricciardelli
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ariadna Robledo
- Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX 77555, USA; (A.R.)
| | - Jason E. Fish
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada;
- Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2N2, Canada
| | - Peter T. Kan
- Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX 77555, USA; (A.R.)
| | - Tajie H. Harris
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA;
- Brain, Immunology, and Glia (BIG) Center, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Joshua D. Wythe
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA;
- Brain, Immunology, and Glia (BIG) Center, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
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Sánchez-Duffhues G, Hiepen C. Human iPSCs as Model Systems for BMP-Related Rare Diseases. Cells 2023; 12:2200. [PMID: 37681932 PMCID: PMC10487005 DOI: 10.3390/cells12172200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/17/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
Disturbances in bone morphogenetic protein (BMP) signalling contribute to onset and development of a number of rare genetic diseases, including Fibrodysplasia ossificans progressiva (FOP), Pulmonary arterial hypertension (PAH), and Hereditary haemorrhagic telangiectasia (HHT). After decades of animal research to build a solid foundation in understanding the underlying molecular mechanisms, the progressive implementation of iPSC-based patient-derived models will improve drug development by addressing drug efficacy, specificity, and toxicity in a complex humanized environment. We will review the current state of literature on iPSC-derived model systems in this field, with special emphasis on the access to patient source material and the complications that may come with it. Given the essential role of BMPs during embryonic development and stem cell differentiation, gain- or loss-of-function mutations in the BMP signalling pathway may compromise iPSC generation, maintenance, and differentiation procedures. This review highlights the need for careful optimization of the protocols used. Finally, we will discuss recent developments towards complex in vitro culture models aiming to resemble specific tissue microenvironments with multi-faceted cellular inputs, such as cell mechanics and ECM together with organoids, organ-on-chip, and microfluidic technologies.
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Affiliation(s)
- Gonzalo Sánchez-Duffhues
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), ISPA-HUCA, Avda. de Roma, s/n, 33011 Oviedo, Spain
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
| | - Christian Hiepen
- Department of Engineering and Natural Sciences, Westphalian University of Applied Sciences, August-Schmidt-Ring 10, 45665 Recklinghausen, Germany
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5
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Rossi E, Bernabeu C. Novel vascular roles of human endoglin in pathophysiology. J Thromb Haemost 2023; 21:2327-2338. [PMID: 37315795 DOI: 10.1016/j.jtha.2023.06.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/19/2023] [Accepted: 06/02/2023] [Indexed: 06/16/2023]
Abstract
Endoglin, alias CD105, is a human membrane glycoprotein highly expressed in vascular endothelial cells. It is involved in angiogenesis and angiogenesis-related diseases, including the rare vascular pathology known as hereditary hemorrhagic telangiectasia type 1. Although endoglin acts as an accessory receptor for members of the transforming growth factor-β family, in recent years, emerging evidence has shown a novel functional role for this protein beyond the transforming growth factor-β system. In fact, endoglin has been found to be an integrin counterreceptor involved in endothelial cell adhesion processes during pathological inflammatory conditions and primary hemostasis. Furthermore, a circulating form of endoglin, also named as soluble endoglin, whose levels are abnormally increased in different pathological conditions, such as preeclampsia, seems to act as an antagonist of membrane-bound endoglin and as a competitor of the fibrinogen-integrin interaction in platelet-dependent thrombus formation. These studies suggest that membrane-bound endoglin and circulating endoglin are important components involved in vascular homeostasis and hemostasis.
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Affiliation(s)
- Elisa Rossi
- Université Paris Cité, INSERM U1140, Innovative Therapies in Haemostasis, Paris, France.
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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6
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Abstract
The vasculature consists of vessels of different sizes that are arranged in a hierarchical pattern. Two cell populations work in concert to establish this pattern during embryonic development and adopt it to changes in blood flow demand later in life: endothelial cells that line the inner surface of blood vessels, and adjacent vascular mural cells, including smooth muscle cells and pericytes. Despite recent progress in elucidating the signalling pathways controlling their crosstalk, much debate remains with regard to how mural cells influence endothelial cell biology and thereby contribute to the regulation of blood vessel formation and diameters. In this Review, I discuss mural cell functions and their interactions with endothelial cells, focusing on how these interactions ensure optimal blood flow patterns. Subsequently, I introduce the signalling pathways controlling mural cell development followed by an overview of mural cell ontogeny with an emphasis on the distinguishing features of mural cells located on different types of blood vessels. Ultimately, I explore therapeutic strategies involving mural cells to alleviate tissue ischemia and improve vascular efficiency in a variety of diseases.
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Affiliation(s)
- Arndt F. Siekmann
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, 1114 Biomedical Research Building, 421 Curie Boulevard, Philadelphia, PA 19104, USA
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Mesenchymal stem cells support human vascular endothelial cells to form vascular sprouts in human platelet lysate-based matrices. PLoS One 2022; 17:e0278895. [PMID: 36520838 PMCID: PMC9754269 DOI: 10.1371/journal.pone.0278895] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 11/24/2022] [Indexed: 12/23/2022] Open
Abstract
During tissue regeneration, mesenchymal stem cells can support endothelial cells in the process of new vessel formation. For a functional interaction of endothelial cells with mesenchymal stem cells a vascular inductive microenvironment is required. Using a cellular model for neo-vessel formation, we could show that newly formed vascular structures emanated from the embedded aggregates, consisting of mesenchymal stem cells co-cultured with autologous human umbilical vein endothelial cells, into avascular human platelet lysate-based matrices, bridging distances up to 5 mm to join with adjacent aggregates with the same morphology forming an interconnected network. These newly formed vascular sprouts showed branch points and generated a lumen, as sign of mature vascular development. In two-dimensional culture, we detected binding of mesenchymal stem cells to laser-damaged endothelial cells under flow conditions, mimicking the dynamics in blood vessels. In conclusion, we observed that mesenchymal stem cells can support human umbilical vein endothelial cells in their vitality and functionality. In xeno-free human platelet lysate-based matrices, endothelial cells form complex vascular networks in a primarily avascular scaffold with the aid of mesenchymal stem cells, when co-cultured in three-dimensional spherical aggregates. Under dynamic conditions, representing the flow rate of venous vessel, mesenchymal stem cells preferably bind to damaged endothelial cells presumably assisting in the healing process.
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8
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Arthur HM, Roman BL. An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms. Front Med (Lausanne) 2022; 9:973964. [PMID: 36250069 PMCID: PMC9556665 DOI: 10.3389/fmed.2022.973964] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Endoglin (ENG) is expressed on the surface of endothelial cells (ECs) where it efficiently binds circulating BMP9 and BMP10 ligands to initiate activin A receptor like type 1 (ALK1) protein signalling to protect the vascular architecture. Patients heterozygous for ENG or ALK1 mutations develop the vascular disorder known as hereditary haemorrhagic telangiectasia (HHT). Many patients with this disorder suffer from anaemia, and are also at increased risk of stroke and high output heart failure. Recent work using animal models of HHT has revealed new insights into cellular and molecular mechanisms causing this disease. Loss of the ENG (HHT1) or ALK1 (HHT2) gene in ECs leads to aberrant arteriovenous connections or malformations (AVMs) in developing blood vessels. Similar phenotypes develop following combined EC specific loss of SMAD1 and 5, or EC loss of SMAD4. Taken together these data point to the essential role of the BMP9/10-ENG-ALK1-SMAD1/5-SMAD4 pathway in protecting the vasculature from AVMs. Altered directional migration of ECs in response to shear stress and increased EC proliferation are now recognised as critical factors driving AVM formation. Disruption of the ENG/ALK1 signalling pathway also affects EC responses to vascular endothelial growth factor (VEGF) and crosstalk between ECs and vascular smooth muscle cells. It is striking that the vascular lesions in HHT are both localised and tissue specific. Increasing evidence points to the importance of a second genetic hit to generate biallelic mutations, and the sporadic nature of such somatic mutations would explain the localised formation of vascular lesions. In addition, different pro-angiogenic drivers of AVM formation are likely to be at play during the patient’s life course. For example, inflammation is a key driver of vessel remodelling in postnatal life, and may turn out to be an important driver of HHT disease. The current wealth of preclinical models of HHT has led to increased understanding of AVM development and revealed new therapeutic approaches to treat AVMs, and form the topic of this review.
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Affiliation(s)
- Helen M. Arthur
- Biosciences Institute, Centre for Life, University of Newcastle, Newcastle, United Kingdom
- *Correspondence: Helen M. Arthur,
| | - Beth L. Roman
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States
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Orlova VV, Nahon DM, Cochrane A, Cao X, Freund C, van den Hil F, Westermann CJJ, Snijder RJ, Ploos van Amstel JK, Ten Dijke P, Lebrin F, Mager HJ, Mummery CL. Vascular defects associated with hereditary hemorrhagic telangiectasia revealed in patient-derived isogenic iPSCs in 3D vessels on chip. Stem Cell Reports 2022; 17:1536-1545. [PMID: 35777360 PMCID: PMC9287680 DOI: 10.1016/j.stemcr.2022.05.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 11/30/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent stem cells (hiPSCs) from a patient with rare mosaic HHT1 with tissues containing both mutant (ENGc.1678C>T) and normal cells, enabling derivation of isogenic diseased and healthy hiPSCs, respectively. We showed reduced ENG expression in HHT1 endothelial cells (HHT1-hiPSC-ECs), reflecting haploinsufficiency. HHT1c.1678C>T-hiPSC-ECs and the healthy isogenic control behaved similarly in two-dimensional (2D) culture, forming functionally indistinguishable vascular networks. However, when grown in 3D organ-on-chip devices under microfluidic flow, lumenized vessels formed in which defective vascular organization was evident: interaction between inner ECs and surrounding pericytes was decreased, and there was evidence for vascular leakage. Organs on chip thus revealed features of HHT in hiPSC-derived blood vessels that were not evident in conventional 2D assays.
Vessels from isogenic hiPSCs from HHT1 patients compared HHT1-hiPSC-ECs show defective vascular organization in 3D microfluidic chips HHT1-hiPSC-ECs show defective EC-pericyte interaction
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Affiliation(s)
- Valeria V Orlova
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.
| | - Dennis M Nahon
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Amy Cochrane
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Xu Cao
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Christian Freund
- Department of Anatomy and Embryology and Human iPSC Hotel, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Francijna van den Hil
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | | | | | | | - Peter Ten Dijke
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Franck Lebrin
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands; INSERM U1273, ESPCI, CNRS FRE 2031, Paris, France
| | | | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Department of Anatomy and Embryology and Human iPSC Hotel, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.
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10
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Sacnun JM, Herzog R, Kratochwill K. Proteomic study of mesothelial and endothelial cross-talk: key lessons. Expert Rev Proteomics 2022; 19:289-296. [PMID: 36714918 DOI: 10.1080/14789450.2023.2174851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The peritoneum, pleura, and pericardium are yet understudied multicellular systems where mesothelial cells (MCs) and endothelial cells (ECs) are in close proximity. Crosstalk between these cell types likely plays role in molecular transport, immunological reactions, and metabolic processes in health, disease, and therapeutic intervention. AREAS COVERED In this review, we discuss recent proteomic efforts to characterize the crosstalk between MC and EC. We describe the proteomic methods necessary for investigation of crosstalk between MC and EC, as well as the in-vitro models that can be employed. Potential experimental approaches range from conditioned medium, via co-culture on semi-permeable membranes, to 3D cell culture based organoid models. While the biological and clinical relevance of the models may increase with their ability to mimic close cell communication, the practicality of these complex experiments corresponds vice versa, making standardization more difficult and expensive. EXPERT OPINION Currently, data and reports on mesothelial-to-endothelial crosstalk are still very scarce. In our opinion, the in-vitro model using semi-permeable cell culture inserts will allow to establish a basic understanding of cellular crosstalk that may occur between those cell types. Later-on, more sophisticated 3D cell cultures may be better able to simulate the transport dynamics within the peritoneal membrane.
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Affiliation(s)
- Juan Manuel Sacnun
- Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.,Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Rebecca Herzog
- Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.,Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Klaus Kratochwill
- Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.,Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
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11
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Kilari S, Wang Y, Singh A, Graham RP, Iyer V, Thompson SM, Torbenson MS, Mukhopadhyay D, Misra S. Neuropilin-1 deficiency in vascular smooth muscle cells is associated with hereditary hemorrhagic telangiectasia arteriovenous malformations. JCI Insight 2022; 7:155565. [PMID: 35380991 PMCID: PMC9090252 DOI: 10.1172/jci.insight.155565] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 03/30/2022] [Indexed: 11/25/2022] Open
Abstract
Patients with hereditary hemorrhagic telangiectasia (HHT) have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent studies have shown that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with a decrease in SMCs, and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung arteriovenous fistulas (AVFs) with enlarged liver vessels. Evaluation of the retina vessels at P5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO versus WT mice, there was a significant decrease in Tgfb1, Eng, and Alk1 expression and phosphorylated SMAD1/5/8 (pSMAD1/5/8), with an increase in apoptosis. TGF-β1–stimulated aortic SMCs from Nrp1SM22KO versus WT mice have decreased pSMAD1/5/8 and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In summary, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, and pSMAD1/5/8 signaling and reduced cell death associated with AVM formation.
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Affiliation(s)
| | - Ying Wang
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States of America
| | - Avishek Singh
- Department of Radiology, Mayo Clinic, Rochester, United States of America
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America
| | - Vivek Iyer
- Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, United States of America
| | - Scott M Thompson
- Department of Radiology, Mayo Clinic, Rochester, United States of America
| | - Michael S Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States of America
| | - Sanjay Misra
- Department of Radiology, Mayo Clinic, Rochester, United States of America
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12
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Lu CL, Ortmeier S, Brudvig J, Moretti T, Cain J, Boyadjiev SA, Weimer JM, Kim J. Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum. Traffic 2022; 23:81-93. [PMID: 34761479 PMCID: PMC8692420 DOI: 10.1111/tra.12826] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 01/03/2023]
Abstract
SEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A-D) in vertebrates, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations in SEC24D cause osteogenesis imperfecta with craniofacial dysplasia in humans. sec24d mutant fish also recapitulate the phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient-derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. Using Sec24d KO mice and cultured cells, we show that SEC24A and SEC24B also contribute to endoplasmic reticulum (ER) export of procollagen. In contrast, fibronectin 1 requires either SEC24C or SEC24D for ER export. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency.
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Affiliation(s)
- Chung-Ling Lu
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, 50011, USA
| | - Steven Ortmeier
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Jon Brudvig
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Tamara Moretti
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, 50011, USA
| | - Jacob Cain
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Simeon A. Boyadjiev
- Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Jill M. Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Jinoh Kim
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, 50011, USA,To who correspondence should be addressed: Jinoh Kim, 2086 Vet Med, 1800 Christensen Drive, Iowa State University, Ames, IA 50011, , Tel: 515-294-3401
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Kemp SS, Lin PK, Sun Z, Castaño MA, Yrigoin K, Penn MR, Davis GE. Molecular basis for pericyte-induced capillary tube network assembly and maturation. Front Cell Dev Biol 2022; 10:943533. [PMID: 36072343 PMCID: PMC9441561 DOI: 10.3389/fcell.2022.943533] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Here we address the functional importance and role of pericytes in capillary tube network assembly, an essential process that is required for vascularized tissue development, maintenance, and health. Healthy capillaries may be directly capable of suppressing human disease. Considerable advances have occurred in our understanding of the molecular and signaling requirements controlling EC lumen and tube formation in 3D extracellular matrices. A combination of SCF, IL-3, SDF-1α, FGF-2 and insulin ("Factors") in conjunction with integrin- and MT1-MMP-induced signaling are required for EC sprouting behavior and tube formation under serum-free defined conditions. Pericyte recruitment to the abluminal EC tube surface results in elongated and narrow tube diameters and deposition of the vascular basement membrane. In contrast, EC tubes in the absence of pericytes continue to widen and shorten over time and fail to deposit basement membranes. Pericyte invasion, recruitment and proliferation in 3D matrices requires the presence of ECs. A detailed analysis identified that EC-derived PDGF-BB, PDGF-DD, ET-1, HB-EGF, and TGFβ1 are necessary for pericyte recruitment, proliferation, and basement membrane deposition. Blockade of these individual factors causes significant pericyte inhibition, but combined blockade profoundly interferes with these events, resulting in markedly widened EC tubes without basement membranes, like when pericytes are absent.
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Affiliation(s)
- Scott S Kemp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Prisca K Lin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Zheying Sun
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Maria A Castaño
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Ksenia Yrigoin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Marlena R Penn
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - George E Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
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Bakker W, Dingenouts CKE, Lodder K, Wiesmeijer KC, de Jong A, Kurakula K, Mager HJJ, Smits AM, de Vries MR, Quax PHA, Goumans MJTH. BMP Receptor Inhibition Enhances Tissue Repair in Endoglin Heterozygous Mice. Int J Mol Sci 2021; 22:2010. [PMID: 33670533 PMCID: PMC7922601 DOI: 10.3390/ijms22042010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/02/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a severe vascular disorder caused by mutations in the TGFβ/BMP co-receptor endoglin. Endoglin haploinsufficiency results in vascular malformations and impaired neoangiogenesis. Furthermore, HHT1 patients display an impaired immune response. To date it is not fully understood how endoglin haploinsufficient immune cells contribute to HHT1 pathology. Therefore, we investigated the immune response during tissue repair in Eng+/- mice, a model for HHT1. Eng+/- mice exhibited prolonged infiltration of macrophages after experimentally induced myocardial infarction. Moreover, there was an increased number of inflammatory M1-like macrophages (Ly6Chigh/CD206-) at the expense of reparative M2-like macrophages (Ly6Clow/CD206+). Interestingly, HHT1 patients also showed an increased number of inflammatory macrophages. In vitro analysis revealed that TGFβ-induced differentiation of Eng+/- monocytes into M2-like macrophages was blunted. Inhibiting BMP signaling by treating monocytes with LDN-193189 normalized their differentiation. Finally, LDN treatment improved heart function after MI and enhanced vascularization in both wild type and Eng+/- mice. The beneficial effect of LDN was also observed in the hind limb ischemia model. While blood flow recovery was hampered in vehicle-treated animals, LDN treatment improved tissue perfusion recovery in Eng+/- mice. In conclusion, BMPR kinase inhibition restored HHT1 macrophage imbalance in vitro and improved tissue repair after ischemic injury in Eng+/- mice.
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Affiliation(s)
- Wineke Bakker
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Calinda K. E. Dingenouts
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Kirsten Lodder
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Karien C. Wiesmeijer
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Alwin de Jong
- Department of Surgery, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (A.d.J.); (M.R.d.V.); (P.H.A.Q.)
| | - Kondababu Kurakula
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | | | - Anke M. Smits
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Margreet R. de Vries
- Department of Surgery, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (A.d.J.); (M.R.d.V.); (P.H.A.Q.)
| | - Paul H. A. Quax
- Department of Surgery, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (A.d.J.); (M.R.d.V.); (P.H.A.Q.)
| | - Marie José T. H. Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
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15
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Snodgrass RO, Chico TJA, Arthur HM. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes (Basel) 2021; 12:174. [PMID: 33513792 PMCID: PMC7911152 DOI: 10.3390/genes12020174] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies.
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Affiliation(s)
- Ryan O. Snodgrass
- Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK; (R.O.S.); (T.J.A.C.)
| | - Timothy J. A. Chico
- Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK; (R.O.S.); (T.J.A.C.)
| | - Helen M. Arthur
- Biosciences Institute, Centre for Life, Newcastle University, Newcastle NE1 3BZ, UK
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16
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White SJ, Chong JJH. Mesenchymal Stem Cells in Cardiac Repair: Effects on Myocytes, Vasculature, and Fibroblasts. Clin Ther 2020; 42:1880-1891. [PMID: 32938532 DOI: 10.1016/j.clinthera.2020.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/09/2020] [Accepted: 08/17/2020] [Indexed: 12/31/2022]
Abstract
PURPOSE Cardiac pathologies remain a dominant cause of morbidity and mortality within the community. The drive to develop therapies capable of repairing damaged heart tissue to achieve clinically significant restoration of function has motivated the pursuit of novel approaches such as cell therapy. To this end, evidence of therapeutic benefits achieved by using mesenchymal stem cells (MSCs) has captured considerable interest despite a relative lack of information regarding the mechanisms involved. This narrative review synthesizes and interprets the current literature describing mechanisms by which MSCs can elicit cardiac repair, thereby directing attention to avenues of further inquiry. METHODS OVID versions of MEDLINE and EMBASE were searched for studies describing the role of MSCs in mammalian cardiac repair. Additional studies were sourced from the reference lists of relevant articles and other personal files. FINDINGS MSCs elicit cardiac repair in a range of in vitro systems and animal models of diseases such as myocardial infarction and heart failure. Important mechanisms include the preservation of myocardial contractility, the promotion of angiogenesis, and the modulation of fibrosis. Exposing in vitro MSCs to a microenvironment reflective of that encountered in the injured heart seems to potentiate these therapeutic mechanisms. IMPLICATIONS Promising results in animal studies warrant continuation of clinical MSC cardiac therapy studies. Paracrine functions of MSCs seem to be the dominant mechanism of cardiac repair over direct cellular effects. Although integral, the MSC secretome remains poorly defined. In addition, most of the mechanistic data within the literature have been derived from animal MSC research, necessitating more human MSC-based work.
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Affiliation(s)
- Samuel J White
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
| | - James J H Chong
- Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia; Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia.
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17
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Klostranec JM, Chen L, Mathur S, McDonald J, Faughnan ME, Ratjen F, Krings T. A theory for polymicrogyria and brain arteriovenous malformations in HHT. Neurology 2019; 92:34-42. [PMID: 30584075 DOI: 10.1212/wnl.0000000000006686] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 08/14/2018] [Indexed: 01/11/2023] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow-related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.
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Affiliation(s)
- Jesse M Klostranec
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada
| | - Long Chen
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada
| | - Shobhit Mathur
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada
| | - Jamie McDonald
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada
| | - Marie E Faughnan
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada
| | - Felix Ratjen
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada
| | - Timo Krings
- From the Department of Medical Imaging (J.M.K., L.C., S.M., T.K.), Division of Respirology (M.E.F.) and Department of Paediatrics (F.R.), Department of Medicine, and Division of Neurosurgery (T.K.), Department of Surgery, University of Toronto; Division of Neuroradiology (J.M.K., L.C., S.M., T.K.), Toronto Western Hospital, University Health Network, Canada; Departments of Radiology and Pathology (J.M.), University of Utah School of Medicine, Salt Lake City; Toronto HHT Centre, Division of Respirology, Department of Medicine, and Li Ka Shing Knowledge Institute (M.E.F.), St. Michael's Hospital, Toronto; and Division of Respiratory Medicine (F.R.), the Hospital for Sick Children, Toronto, Canada.
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Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View. Int J Mol Sci 2019; 20:ijms20194941. [PMID: 31590461 PMCID: PMC6801733 DOI: 10.3390/ijms20194941] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/03/2019] [Accepted: 10/04/2019] [Indexed: 02/08/2023] Open
Abstract
Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.
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19
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Thalgott JH, Dos-Santos-Luis D, Hosman AE, Martin S, Lamandé N, Bracquart D, Srun S, Galaris G, de Boer HC, Tual-Chalot S, Kroon S, Arthur HM, Cao Y, Snijder RJ, Disch F, Mager JJ, Rabelink TJ, Mummery CL, Raymond K, Lebrin F. Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2. Circulation 2019; 138:2698-2712. [PMID: 30571259 DOI: 10.1161/circulationaha.117.033062] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. METHODS We took advantage of Acvrl1+/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1+/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. RESULTS Acvrl1+/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1+/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1+/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1+/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1+/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1+/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1+/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1+/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. CONCLUSIONS Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.
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Affiliation(s)
- Jérémy H Thalgott
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)
| | - Damien Dos-Santos-Luis
- CNRS UMR 7241, INSERM U1050, Collège de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
| | - Anna E Hosman
- St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)
| | - Sabrina Martin
- CNRS UMR 7241, INSERM U1050, Collège de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
| | - Noël Lamandé
- CNRS UMR 7241, INSERM U1050, Collège de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
| | - Diane Bracquart
- CNRS UMR 7241, INSERM U1050, Collège de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
| | - Samly Srun
- CNRS UMR 7241, INSERM U1050, Collège de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
| | - Georgios Galaris
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)
| | - Hetty C de Boer
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)
| | - Simon Tual-Chalot
- Institute of Genetic Medicine, Centre of Life, Newcastle University, United Kingdom (S.T.-C., H.M.A., )
| | - Steven Kroon
- St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)
| | - Helen M Arthur
- Institute of Genetic Medicine, Centre of Life, Newcastle University, United Kingdom (S.T.-C., H.M.A., )
| | - Yihai Cao
- Department of Microbiology, Tumor and cell Biology, Karolinska Institute, Stockholm, Sweden (Y.C.)
| | - Repke J Snijder
- St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)
| | - Frans Disch
- St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)
| | - Johannes J Mager
- St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)
| | - Ton J Rabelink
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, The Netherlands (C.L.M.)
| | - Karine Raymond
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)
- Sorbonne Université, UPMC Université Paris 06, INSERM UMR_S938, Centre de Recherche Saint-Antoine, France (K.R.)
| | - Franck Lebrin
- Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)
- CNRS UMR 7241, INSERM U1050, Collège de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)
- CNRS UMR 7587, INSERM U979, Institut Langevin, ESPCI, Paris, France (F.L.)
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20
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Nakazaki M, Sasaki M, Kataoka-Sasaki Y, Oka S, Suzuki J, Sasaki Y, Nagahama H, Hashi K, Kocsis JD, Honmou O. Intravenous infusion of mesenchymal stem cells improves impaired cognitive function in a cerebral small vessel disease model. Neuroscience 2019; 408:361-377. [DOI: 10.1016/j.neuroscience.2019.04.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 03/18/2019] [Accepted: 04/07/2019] [Indexed: 12/18/2022]
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21
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Galaris G, Thalgott JH, Lebrin FPG. Pericytes in Hereditary Hemorrhagic Telangiectasia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:215-246. [PMID: 31147880 DOI: 10.1007/978-3-030-16908-4_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-β and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT.
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Affiliation(s)
- Georgios Galaris
- Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jérémy H Thalgott
- Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Franck P G Lebrin
- Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
- Physics for Medicine, ESPCI, INSERM U1273, CNRS, Paris, France.
- MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France.
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22
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Sweeney M, Foldes G. It Takes Two: Endothelial-Perivascular Cell Cross-Talk in Vascular Development and Disease. Front Cardiovasc Med 2018; 5:154. [PMID: 30425990 PMCID: PMC6218412 DOI: 10.3389/fcvm.2018.00154] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 10/10/2018] [Indexed: 12/26/2022] Open
Abstract
The formation of new blood vessels is a crucial step in the development of any new tissue both during embryogenesis and in vitro models as without sufficient perfusion the tissue will be unable to grow beyond the size where nutrition and oxygenation can be managed by diffusion alone. Endothelial cells are the primary building block of blood vessels and are capable of forming tube like structures independently however they are unable to independently form functional vasculature which is capable of conducting blood flow. This requires support from other structures including supporting perivascular cells and the extracellular matrix. The crosstalk between endothelial cells and perivascular cells is vital in regulating vasculogenesis and angiogenesis and the consequences when this is disrupted can be seen in a variety of congenital and acquired disease states. This review details the mechanisms of vasculogenesis in vivo during embryogenesis and compares this to currently employed in vitro techniques. It also highlights clinical consequences of defects in the endothelial cell-pericyte cross-talk and highlights therapies which are being developed to target this pathway. Improving the understanding of the intricacies of endothelial-pericyte signaling will inform pathophysiology of multiple vascular diseases and allow the development of effective in vitro models to guide drug development and assist with approaches in tissue engineering to develop functional vasculature for regenerative medicine applications.
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Affiliation(s)
- Mark Sweeney
- Cardiovascular Division, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Gabor Foldes
- Cardiovascular Division, National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
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23
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Paauwe M, Schoonderwoerd MJA, Helderman RFCP, Harryvan TJ, Groenewoud A, van Pelt GW, Bor R, Hemmer DM, Versteeg HH, Snaar-Jagalska BE, Theuer CP, Hardwick JCH, Sier CFM, Ten Dijke P, Hawinkels LJAC. Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis. Clin Cancer Res 2018; 24:6331-6344. [PMID: 29945992 DOI: 10.1158/1078-0432.ccr-18-0329] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 05/23/2018] [Accepted: 06/18/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancer-associated fibroblasts (CAF) are a major component of the colorectal cancer tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through TGF-β signaling pathway. We investigated whether the TGF-β family coreceptor endoglin is involved in CAF-mediated invasion and metastasis. EXPERIMENTAL DESIGN CAF-specific endoglin expression was studied in colorectal cancer resection specimens using IHC and related to metastases-free survival. Endoglin-mediated invasion was assessed in vitro by transwell invasion, using primary colorectal cancer-derived CAFs. Effects of CAF-specific endoglin expression on tumor cell invasion were investigated in a colorectal cancer zebrafish model, whereas liver metastases were assessed in a mouse model. RESULTS CAFs specifically at invasive borders of colorectal cancer express endoglin and increased expression intensity correlated with increased disease stage. Endoglin-expressing CAFs were also detected in lymph node and liver metastases, suggesting a role in colorectal cancer metastasis formation. In stage II colorectal cancer, CAF-specific endoglin expression at invasive borders correlated with poor metastasis-free survival. In vitro experiments revealed that endoglin is indispensable for bone morphogenetic protein (BMP)-9-induced signaling and CAF survival. Targeting endoglin using the neutralizing antibody TRC105 inhibited CAF invasion in vitro. In zebrafish, endoglin-expressing fibroblasts enhanced colorectal tumor cell infiltration into the liver and decreased survival. Finally, CAF-specific endoglin targeting with TRC105 decreased metastatic spread of colorectal cancer cells to the mouse liver. CONCLUSIONS Endoglin-expressing CAFs contribute to colorectal cancer progression and metastasis. TRC105 treatment inhibits CAF invasion and tumor metastasis, indicating an additional target beyond the angiogenic endothelium, possibly contributing to beneficial effects reported during clinical evaluations.See related commentary by Becker and LeBleu, p. 6110.
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Affiliation(s)
- Madelon Paauwe
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands.,Department of Thrombosis & Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
| | - Mark J A Schoonderwoerd
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Roxan F C P Helderman
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Tom J Harryvan
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Arwin Groenewoud
- Institute of Biology, Leiden University, Leiden, the Netherlands
| | - Gabi W van Pelt
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Rosalie Bor
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Danielle M Hemmer
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Henri H Versteeg
- Department of Thrombosis & Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
| | | | | | - James C H Hardwick
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Cornelis F M Sier
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Peter Ten Dijke
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, the Netherlands
| | - Lukas J A C Hawinkels
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. .,Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands
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24
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Wang W, Feng Y, Aimaiti Y, Jin X, Mao X, Li D. TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1‐Notch‐Sox9 signaling axis. J Cell Physiol 2018; 233:5780-5791. [PMID: 29194611 DOI: 10.1002/jcp.26304] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/28/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Wei Wang
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingP. R. China
| | - Yuan Feng
- Department of Hepatobiliary SurgeryThe Second Clinical Medical College of North Sichuan Medical CollegeNanchong Central HospitalNanchongSichuanP. R. China
| | - Yasen Aimaiti
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingP. R. China
| | - Xin Jin
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingP. R. China
| | - Xixian Mao
- Department of Hepatobiliary SurgeryWest China‐Guang'an Hospital, Sichuan UniversityGuang'anSichuanP. R. China
| | - Dewei Li
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingP. R. China
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25
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Goumans MJ, Ten Dijke P. TGF-β Signaling in Control of Cardiovascular Function. Cold Spring Harb Perspect Biol 2018; 10:cshperspect.a022210. [PMID: 28348036 DOI: 10.1101/cshperspect.a022210] [Citation(s) in RCA: 247] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Genetic studies in animals and humans indicate that gene mutations that functionally perturb transforming growth factor β (TGF-β) signaling are linked to specific hereditary vascular syndromes, including Osler-Rendu-Weber disease or hereditary hemorrhagic telangiectasia and Marfan syndrome. Disturbed TGF-β signaling can also cause nonhereditary disorders like atherosclerosis and cardiac fibrosis. Accordingly, cell culture studies using endothelial cells or smooth muscle cells (SMCs), cultured alone or together in two- or three-dimensional cell culture assays, on plastic or embedded in matrix, have shown that TGF-β has a pivotal effect on endothelial and SMC proliferation, differentiation, migration, tube formation, and sprouting. Moreover, TGF-β can stimulate endothelial-to-mesenchymal transition, a process shown to be of key importance in heart valve cushion formation and in various pathological vascular processes. Here, we discuss the roles of TGF-β in vasculogenesis, angiogenesis, and lymphangiogenesis and the deregulation of TGF-β signaling in cardiovascular diseases.
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Affiliation(s)
- Marie-José Goumans
- Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Peter Ten Dijke
- Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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26
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Goumans MJ, Zwijsen A, Ten Dijke P, Bailly S. Bone Morphogenetic Proteins in Vascular Homeostasis and Disease. Cold Spring Harb Perspect Biol 2018; 10:cshperspect.a031989. [PMID: 28348038 DOI: 10.1101/cshperspect.a031989] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
It is well established that control of vascular morphogenesis and homeostasis is regulated by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Delta-like 4 (Dll4), angiopoietin, and ephrin signaling. It has become clear that signaling by bone morphogenetic proteins (BMPs), which have a long history of studies in bone and early heart development, are also essential for regulating vascular function. Indeed, mutations that cause deregulated BMP signaling are linked to two human vascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. These observations are corroborated by data obtained with vascular cells in cell culture and in mouse models. BMPs are required for normal endothelial cell differentiation and for venous/arterial and lymphatic specification. In adult life, BMP signaling orchestrates neo-angiogenesis as well as vascular inflammation, remodeling, and calcification responses to shear and oxidative stress. This review emphasizes the pivotal role of BMPs in the vascular system, based on studies of mouse models and human vascular disorders.
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Affiliation(s)
- Marie-José Goumans
- Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - An Zwijsen
- VIB Center for the Biology of Disease, 3000 Leuven, Belgium.,KU Leuven Department of Human Genetics, 3000 Leuven, Belgium
| | - Peter Ten Dijke
- Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.,Cancer Genomics Centre Netherlands, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Sabine Bailly
- Institut National de la Santé et de la Recherche Mécale (INSERM), U1036, 38000 Grenoble, France.,Laboratoire Biologie du Cancer et de l'Infection, Commissariat à l'Énergie Atomique et aux Energies Alternatives, Biosciences and Biotechnology Institute of Grenoble, 38000 Grenoble, France.,University of Grenoble Alpes, 38000 Grenoble, France
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27
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Zhang J, Zhang L, Lin Q, Ren W, Xu G. Prognostic value of endoglin-assessed microvessel density in cancer patients: a systematic review and meta-analysis. Oncotarget 2018; 9:7660-7671. [PMID: 29484142 PMCID: PMC5800934 DOI: 10.18632/oncotarget.23546] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 10/30/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Endoglin (ENG, CD105), an auxiliary receptor for several TGF-β superfamily ligands, is constitutively expressed in tumor microvessels. The prognostic value of ENG-assessed microvessel density (MVD) has not been systemically analyzed. This meta-analysis reviews and evaluates the association between ENG expression and prognosis in cancer patients. MATERIALS AND METHODS Thirty published studies involving in 3613 patients were included after searching of PubMed, Web of Science, and EMBASE. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were calculated using random-effects models. The publication bias was detected by a Begg's test and Egger's test. The outcome stability was verified by sensitivity analysis. RESULTS The high ENG-assessed MVD was significantly associated with poor OS (HR = 2.14, 95% CI 1.62-2.81; P < 0.001), DFS (HR = 3.23, 95% CI 2.10-4.95; P < 0.001), CSS (HR = 3.33, 95% CI 1.32-8.37; P < 0.001). Furthermore, subgroup analysis revealed that the association between the overexpression of ENG in tumor microvessels and the outcome endpoints (OS or DFS) were also significant in the Asians and Caucasians patients with different cancer types. CONCLUSIONS ENG of tumor microvessels is a predictor of poor OS, DFS and CSS and may be a prognostic marker of patients with cancer.
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Affiliation(s)
- Jinguo Zhang
- Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Lingyun Zhang
- Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Qunbo Lin
- Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Weimin Ren
- Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Guoxiong Xu
- Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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28
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Nickel J, Ten Dijke P, Mueller TD. TGF-β family co-receptor function and signaling. Acta Biochim Biophys Sin (Shanghai) 2018; 50:12-36. [PMID: 29293886 DOI: 10.1093/abbs/gmx126] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 11/08/2017] [Indexed: 01/04/2023] Open
Abstract
Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.
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Affiliation(s)
- Joachim Nickel
- Universitätsklinikum Würzburg, Lehrstuhl für Tissue Engineering und Regenerative Medizin und Fraunhofer Institut für Silicatforschung (ISC), Translationszentrum "Regenerative Therapien", Röntgenring 11, D-97070 Würzburg, Germany
| | - Peter Ten Dijke
- Department of Molecular and Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands
| | - Thomas D Mueller
- Lehrstuhl für molekulare Pflanzenphysiologie und Biophysik, Julius-von-Sachs Institut für Biowissenschaften, Universität Würzburg, Julius-von-Sachs-Platz 2, D-97082 Würzburg, Germany
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29
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Decreased Endoglin expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia rat model. Pediatr Surg Int 2017; 33:263-268. [PMID: 27822781 DOI: 10.1007/s00383-016-4004-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/25/2016] [Indexed: 10/20/2022]
Abstract
AIM OF THE STUDY Pulmonary hypertension (PH) remains a therapeutical challenge in neonates born with congenital diaphragmatic hernia (CDH). Endoglin (Eng), an auxiliary receptor component of the transforming growth factor β (TGFβ) signalling pathway, is expressed mainly by endothelial cells and has been found to be involved in angiogenesis and vascular remodelling. Genetic studies have linked TGFβ and Eng mutations to human arterial PH and other cardiovascular syndromes. Eng interacts with the TGFβ receptors 1 and 2 (Tgfβr1, Tgfβr2). We designed this study to investigate the hypothesis that Eng is altered in the pulmonary vasculature of rats with nitrofen-induced CDH subjected to its interdependency with Tgfβr1 and Tgfβr2. METHODS After ethical approval (Rec 913b), time-pregnant Sprague-Dawley rats received either nitrofen or olive oil on gestational day (D9). The foetuses (n = 22) were sacrificed and divided into CDH and control group on D21. Gene and protein expressions of Eng, Tgfβr1 and Tgfβr2 were assessed via qRT-PCR and western blotting. Immunofluorescence staining for Eng was combined with CD34 to evaluate Eng expression in the pulmonary vasculature. MAIN RESULTS Relative mRNA levels of Eng, Tgfβr1 and Tgfβr2 were significantly downregulated in CDH lungs compared to controls (Eng CDH 0.341 ± 0.022, Eng Ctrl 0.471 ± 0.031, p = 0.0015; Tgfβr1 CDH 0.161 ± 0.008, Tgfβr1 Ctrl 0.194 ± 0.01, p = 0.0114; Tgfβr2 CDH 0.896 ± 0.099, Tgfβr2 Ctrl 1.379 ± 0.081, p = 0.0006) Western blotting confirmed the reduced pulmonary protein expression of these three proteins in the CDH lungs. A markedly diminished endothelial expression of Eng in the pulmonary vasculature of nitrofen-exposed foetuses compared to controls was seen in laser scanning confocal-microscopy. CONCLUSION This study demonstrates for the first time a reduced expression of Endoglin in the pulmonary vasculature of nitrofen-induced CDH. Abnormal Eng/Tgfβr1/Tgfβr2 signalling may contribute to impaired vascular remodelling and development of PH in this CDH animal model.
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30
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Tian X, Brookes O, Battaglia G. Pericytes from Mesenchymal Stem Cells as a model for the blood-brain barrier. Sci Rep 2017; 7:39676. [PMID: 28098158 PMCID: PMC5241806 DOI: 10.1038/srep39676] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 11/25/2016] [Indexed: 12/15/2022] Open
Abstract
Blood brain-barrier (BBB) in vitro models have been widely reported in studies of the BBB phenotype. However, established co-culture systems involve brain endothelial cells, astrocytes, neurons and pericytes, and therefore are often consuming and technically challenging. Here we use mesenchymal system cells (MSC) as a potential substitute for pericytes in a BBB model. Both MSC and pericyte markers in 2D culture environment were evaluated on different extracellular matrix compositions. Further experiments indicated that MSC contributed in a similar manner to pericytes in a co-cultured 3D model on increasing trans-endothelial electric resistance (TEER) and decreasing permeability against macromolecules.
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Affiliation(s)
- Xiaohe Tian
- School of Life Science, Anhui University, Hefei, China.,Department of Chemistry, University College London, London, UK
| | - Oliver Brookes
- School of Engineering and Materials Science, Queen Mary University of London, London, UK
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31
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Núñez-Gómez E, Pericacho M, Ollauri-Ibáñez C, Bernabéu C, López-Novoa JM. The role of endoglin in post-ischemic revascularization. Angiogenesis 2016; 20:1-24. [PMID: 27943030 DOI: 10.1007/s10456-016-9535-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by reorganizing preexisting capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling preexisting collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of endoglin in post-occlusion reperfusion is sustained by several observations: (1) endoglin expression is increased in vessels showing active angiogenesis/remodeling; (2) genetic endoglin haploinsufficiency in humans causes deficient angiogenesis; and (3) the reduction of endoglin expression by gene disruption or the administration of endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of endoglin in several phenomena (angiogenesis, arteriogenesis and collateral development) associated with post-ischemic revascularization.
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Affiliation(s)
- Elena Núñez-Gómez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Miguel Pericacho
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Claudia Ollauri-Ibáñez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Carmelo Bernabéu
- Centro de Investigaciones Biológicas, Spanish National Research Council (CIB, CSIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - José M López-Novoa
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain. .,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
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Monteiro R, Pinheiro P, Joseph N, Peterkin T, Koth J, Repapi E, Bonkhofer F, Kirmizitas A, Patient R. Transforming Growth Factor β Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells. Dev Cell 2016; 38:358-70. [PMID: 27499523 PMCID: PMC4998007 DOI: 10.1016/j.devcel.2016.06.024] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 05/19/2016] [Accepted: 06/21/2016] [Indexed: 01/15/2023]
Abstract
Hematopoietic stem cells (HSCs) are self-renewing multipotent stem cells that generate mature blood lineages throughout life. They, together with hematopoietic progenitor cells (collectively known as HSPCs), emerge from hemogenic endothelium in the floor of the embryonic dorsal aorta by an endothelial-to-hematopoietic transition (EHT). Here we demonstrate that transforming growth factor β (TGFβ) is required for HSPC specification and that it regulates the expression of the Notch ligand Jagged1a in endothelial cells prior to EHT, in a striking parallel with the epithelial-to-mesenchymal transition (EMT). The requirement for TGFβ is two fold and sequential: autocrine via Tgfβ1a and Tgfβ1b produced in the endothelial cells themselves, followed by a paracrine input of Tgfβ3 from the notochord, suggesting that the former programs the hemogenic endothelium and the latter drives EHT. Our findings have important implications for the generation of HSPCs from pluripotent cells in vitro.
TGFβ signaling is required for hematopoietic stem cell (HSC) emergence in embryos TGFβ regulates jag1a expression and programs endothelium to become hemogenic endothelium (HE) Tgfb1a/Tgfb1b and Tgfb3 act sequentially to program HE and give rise to HSCs
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Affiliation(s)
- Rui Monteiro
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; BHF Centre of Research Excellence, Oxford, UK.
| | - Philip Pinheiro
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Nicola Joseph
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Tessa Peterkin
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Jana Koth
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Emmanouela Repapi
- Computational Biology Research Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Florian Bonkhofer
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Arif Kirmizitas
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Roger Patient
- Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; BHF Centre of Research Excellence, Oxford, UK.
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33
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Rossi E, Smadja DM, Boscolo E, Langa C, Arevalo MA, Pericacho M, Gamella-Pozuelo L, Kauskot A, Botella LM, Gaussem P, Bischoff J, Lopez-Novoa JM, Bernabeu C. Endoglin regulates mural cell adhesion in the circulatory system. Cell Mol Life Sci 2016; 73:1715-39. [PMID: 26646071 PMCID: PMC4805714 DOI: 10.1007/s00018-015-2099-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 11/19/2015] [Accepted: 11/23/2015] [Indexed: 02/06/2023]
Abstract
The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or β1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng (+/-) mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Cell Adhesion/physiology
- Cell Line, Tumor
- Disease Models, Animal
- Endoglin
- Endothelium, Vascular/metabolism
- Female
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Integrin beta1/genetics
- Jurkat Cells
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Nude
- Mice, Transgenic
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/metabolism
- Neovascularization, Pathologic/metabolism
- Pericytes/metabolism
- Podocytes/metabolism
- Pre-Eclampsia/genetics
- Pre-Eclampsia/pathology
- Pregnancy
- Protein Binding
- RNA Interference
- RNA, Small Interfering
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Retina/metabolism
- Telangiectasia, Hereditary Hemorrhagic/genetics
- Telangiectasia, Hereditary Hemorrhagic/pathology
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Affiliation(s)
- Elisa Rossi
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), c/Ramiro de Maeztu 9, 28040, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
- Paris Descartes University, Sorbonne Paris Cite, Paris, France
- Hematology Department, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - David M Smadja
- Hematology Department, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
- Faculté de Pharmacie, Inserm UMR-S1140, Paris, France
| | - Elisa Boscolo
- Department of Surgery, Harvard Medical School, Children's Hospital, Boston, MA, 02115, USA
| | - Carmen Langa
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), c/Ramiro de Maeztu 9, 28040, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
| | - Miguel A Arevalo
- Departamento de Anatomía e Histología Humanas, Facultad de Medicina, Universidad de Salamanca, 37007, Salamanca, Spain
- Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007, Salamanca, Spain
| | - Miguel Pericacho
- Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007, Salamanca, Spain
- Departamento de Fisiología y Farmacología, Unidad de Fisiopatología Renal y Cardiovascular, Universidad de Salamanca, 37007, Salamanca, Spain
| | - Luis Gamella-Pozuelo
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), c/Ramiro de Maeztu 9, 28040, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
- Departamento de Fisiología y Farmacología, Unidad de Fisiopatología Renal y Cardiovascular, Universidad de Salamanca, 37007, Salamanca, Spain
| | - Alexandre Kauskot
- Inserm UMR-S1176, Le Kremlin Bicêtre, Paris, France
- Université Paris Sud, Le Kremlin Bicêtre, Paris, France
| | - Luisa M Botella
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), c/Ramiro de Maeztu 9, 28040, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
| | - Pascale Gaussem
- Hematology Department, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
- Faculté de Pharmacie, Inserm UMR-S1140, Paris, France
| | - Joyce Bischoff
- Department of Surgery, Harvard Medical School, Children's Hospital, Boston, MA, 02115, USA
| | - José M Lopez-Novoa
- Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007, Salamanca, Spain
- Departamento de Fisiología y Farmacología, Unidad de Fisiopatología Renal y Cardiovascular, Universidad de Salamanca, 37007, Salamanca, Spain
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), c/Ramiro de Maeztu 9, 28040, Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
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34
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Ferenbach DA, Bonventre JV. Acute kidney injury and chronic kidney disease: From the laboratory to the clinic. Nephrol Ther 2016; 12 Suppl 1:S41-8. [PMID: 26972097 DOI: 10.1016/j.nephro.2016.02.005] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Chronic kidney disease and acute kidney injury have traditionally been considered as separate entities with different etiologies. This view has changed in recent years, with chronic kidney disease recognized as a major risk factor for the development of new acute kidney injury, and acute kidney injury now accepted to lead to de novo or accelerated chronic and end stage kidney diseases. Patients with existing chronic kidney disease appear to be less able to mount a complete 'adaptive' repair after acute insults, and instead repair maladaptively, with accelerated fibrosis and rates of renal functional decline. This article reviews the epidemiological studies in man that have demonstrated the links between these two processes. We also examine clinical and experimental research in areas of importance to both acute and chronic disease: acute and chronic renal injury to the vasculature, the pericyte and leukocyte populations, the signaling pathways implicated in injury and repair, and the impact of cellular stress and increased levels of growth arrested and senescent cells. The importance and therapeutic potential raised by these processes for acute and chronic injury are discussed.
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Affiliation(s)
- David A Ferenbach
- Renal Division and Biomedical Engineering Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Joseph V Bonventre
- Renal Division and Biomedical Engineering Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
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35
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Jonker L. TGF-β & BMP receptors endoglin and ALK1: overview of their functional role and status as antiangiogenic targets. Microcirculation 2015; 21:93-103. [PMID: 25279424 DOI: 10.1111/micc.12099] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 10/05/2013] [Indexed: 12/18/2022]
Abstract
The formation of new blood vessels from existing vasculature, angiogenesis, is facilitated through a host of different signaling processes. Members of the TGF-β superfamily, TGF-β1, TGF-β3, and BMP9, are key propagators of both inhibition and initiation of angiogenesis. HHT, characterized by AVM and capillary bed defects, is caused by germline mutations in the ENG and ACVRL1/ALK1 genes, respectively. Clinical symptoms include epistaxis and GI hemorrhage. The membranous receptors endoglin and ALK1 activate proliferation and migration of endothelial cells during the angiogenic process via the downstream intracellular SMAD signaling pathway. Endothelial cell senescence or activation is dependent on the type of cytokine, ligand concentration, cell-cell interaction, and a multitude of other signaling molecules. Endoglin and ALK1 receptor levels in tumor vasculature correlate inversely with prognosis in humans, whereas in mice, endoglin deficiency decelerates tumor progression. Therefore, endoglin and ALK1 have been identified as potential therapeutic targets for antibody treatment in various cancers. Early phase clinical trials in humans are currently underway to evaluate the efficacy and safety of biological therapy targeting endoglin/ALK1-mediated cells signaling.
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Affiliation(s)
- Leon Jonker
- North Cumbria University Hospitals NHS Trust, Carlisle, UK
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36
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Neural tube opening and abnormal extraembryonic membrane development in SEC23A deficient mice. Sci Rep 2015; 5:15471. [PMID: 26494538 PMCID: PMC4616029 DOI: 10.1038/srep15471] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/23/2015] [Indexed: 01/14/2023] Open
Abstract
COPII (coat protein complex-II) vesicles transport proteins from the endoplasmic reticulum (ER) to the Golgi. Higher eukaryotes have two or more paralogs of most COPII components. Here we characterize mice deficient for SEC23A and studied interactions of Sec23a null allele with the previously reported Sec23b null allele. SEC23A deficiency leads to mid-embryonic lethality associated with defective development of extraembryonic membranes and neural tube opening in midbrain. Secretion defects of multiple collagen types are observed in different connective tissues, suggesting that collagens are primarily transported in SEC23A-containing vesicles in these cells. Other extracellular matrix proteins, such as fibronectin, are not affected by SEC23A deficiency. Intracellular accumulation of unsecreted proteins leads to strong induction of the unfolded protein response in collagen-producing cells. No collagen secretion defects are observed in SEC23B deficient embryos. We report that E-cadherin is a cargo that accumulates in acini of SEC23B deficient pancreas and salivary glands. Compensatory increase of one paralog is observed in the absence of the second paralog. Haploinsufficiency of the remaining Sec23 paralog on top of homozygous inactivation of the first paralog leads to earlier lethality of embryos. Our results suggest that mammalian SEC23A and SEC23B transport overlapping yet distinct spectra of cargo in vivo.
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37
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Anderson GA, Udan RS, Dickinson ME, Henkelman RM. Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics. PLoS One 2015; 10:e0137175. [PMID: 26340748 PMCID: PMC4560395 DOI: 10.1371/journal.pone.0137175] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 08/14/2015] [Indexed: 11/20/2022] Open
Abstract
Background Vascular patterning depends on coordinated timing of arteriovenous specification of endothelial cells and the concomitant hemodynamic forces supplied by the onset of cardiac function. Using a combination of 3D imaging by OPT and embryo registration techniques, we sought to identify structural differences between three different mouse models of cardiovascular perturbation. Results Endoglin mutant mice shared a high degree of similarity to Mlc2a mutant mice, which have been shown to have a primary developmental heart defect causing secondary vessel remodeling failures. Dll4 mutant mice, which have well-characterized arterial blood vessel specification defects, showed distinct differences in vascular patterning when compared to the disruptions seen in Mlc2a-/- and Eng-/- models. While Mlc2a-/- and Eng-/- embryos exhibited significantly larger atria than wild-type, Dll4-/- embryos had significantly smaller hearts than wild-type, but this quantitative volume decrease was not limited to the developing atrium. Dll4-/- embryos also had atretic dorsal aortae and smaller trunks, suggesting that the cardiac abnormalities were secondary to primary arterial blood vessel specification defects. Conclusions The similarities in Eng-/- and Mlc2a-/- embryos suggest that Eng-/- mice may suffer from a primary heart developmental defect and secondary defects in vessel patterning, while defects in Dll4-/- embryos are consistent with primary defects in vessel patterning.
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Affiliation(s)
- Gregory A. Anderson
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- The Hospital For Sick Children, Toronto, Ontario, Canada
- * E-mail:
| | - Ryan S. Udan
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Mary E. Dickinson
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America
| | - R. Mark Henkelman
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- The Hospital For Sick Children, Toronto, Ontario, Canada
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38
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VEGF, Notch and TGFβ/BMPs in regulation of sprouting angiogenesis and vascular patterning. Biochem Soc Trans 2015; 42:1576-83. [PMID: 25399573 DOI: 10.1042/bst20140231] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The blood vasculature is constantly adapting to meet the demand from tissue. In so doing, branches may form, reorganize or regress. These complex processes employ integration of multiple signalling cascades, some of them being restricted to endothelial and mural cells and, hence, suitable for targeting of the vasculature. Both genetic and drug targeting experiments have demonstrated the requirement for the vascular endothelial growth factor (VEGF) system, the Delta-like-Notch system and the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) cascades in vascular development. Although several of these signalling cascades in part converge into common downstream components, they differ in temporal and spatial regulation and expression. For example, the pro-angiogenic VEGFA is secreted by cells in need of oxygen, presented to the basal side of the endothelium, whereas BMP9 and BMP10 are supplied via the bloodstream in constant interaction with the apical side to suppress angiogenesis. Delta-like 4 (DLL4), on the other hand, is provided as an endothelial membrane bound ligand. In the present article, we discuss recent data on the integration of these pathways in the process of sprouting angiogenesis and vascular patterning and malformation.
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39
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Tual-Chalot S, Oh SP, Arthur HM. Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges. Front Genet 2015; 6:25. [PMID: 25741358 PMCID: PMC4332371 DOI: 10.3389/fgene.2015.00025] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 01/19/2015] [Indexed: 12/15/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by a multi-systemic vascular dysplasia and hemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). Both genes are associated with TGFβ/BMP signaling, and loss of function mutations in the co-receptor ENG are causal in HHT1, while HHT2 is associated with mutations in the signaling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis and heart development. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the future.
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Affiliation(s)
| | - S Paul Oh
- Department of Physiology and Functional Genomics, University of Florida , Gainesville, FL, USA
| | - Helen M Arthur
- Institute of Genetic Medicine, Newcastle University , Newcastle, UK
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40
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Thalgott J, Dos-Santos-Luis D, Lebrin F. Pericytes as targets in hereditary hemorrhagic telangiectasia. Front Genet 2015; 6:37. [PMID: 25763012 PMCID: PMC4327729 DOI: 10.3389/fgene.2015.00037] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 01/26/2015] [Indexed: 12/04/2022] Open
Abstract
Defective paracrine Transforming Growth Factor-β (TGF-β) signaling between endothelial cells and the neighboring mural cells have been thought to lead to the development of vascular lesions that are characteristic of Hereditary Hemorrhagic Telangiectasia (HHT). This review highlights recent progress in our understanding of TGF-β signaling in mural cell recruitment and vessel stabilization and how perturbed TGF-β signaling might contribute to defective endothelial-mural cell interaction affecting vessel functionalities. Our recent findings have provided exciting insights into the role of thalidomide, a drug that reduces both the frequency and the duration of epistaxis in individuals with HHT by targeting mural cells. These advances provide opportunities for the development of new therapies for vascular malformations.
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Affiliation(s)
- Jérémy Thalgott
- INSERM, Center for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM U1050, Group Pathological Angiogenesis and Vessel Normalization, Collège de France Paris, France
| | - Damien Dos-Santos-Luis
- INSERM, Center for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM U1050, Group Pathological Angiogenesis and Vessel Normalization, Collège de France Paris, France
| | - Franck Lebrin
- INSERM, Center for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM U1050, Group Pathological Angiogenesis and Vessel Normalization, Collège de France Paris, France
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41
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Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 2015; 11:264-76. [PMID: 25643664 DOI: 10.1038/nrneph.2015.3] [Citation(s) in RCA: 619] [Impact Index Per Article: 61.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults.
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42
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Arboleda-Velasquez JF, Valdez CN, Marko CK, D'Amore PA. From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy. Curr Diab Rep 2015; 15:573. [PMID: 25620405 PMCID: PMC5599150 DOI: 10.1007/s11892-014-0573-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pericytes, the mural cells that constitute the capillaries along with endothelial cells, have been associated with the pathobiology of diabetic retinopathy; however, therapeutic implications of this association remain largely unexplored. Pericytes appear to be highly susceptible to the metabolic challenges associated with a diabetic environment, and there is substantial evidence that their loss may contribute to microvascular instability leading to the formation of microaneurysms, microhemorrhages, acellular capillaries, and capillary nonperfusion. Since pericytes are strategically located at the interface between the vascular and neural components of the retina, they offer extraordinary opportunities for therapeutic interventions in diabetic retinopathy. Moreover, the availability of novel imaging methodologies now allows for the in vivo visualization of pericytes, enabling a new generation of clinical trials that use pericyte tracking as clinical endpoints. The recognition of multiple signaling mechanisms involved in pericyte development and survival should allow for a renewed interest in pericytes as a therapeutic target for diabetic retinopathy.
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Affiliation(s)
- Joseph F Arboleda-Velasquez
- Schepens Eye Research Institute/Massachusetts Eye and Ear and the Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA
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43
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Aki S, Yoshioka K, Okamoto Y, Takuwa N, Takuwa Y. Phosphatidylinositol 3-kinase class II α-isoform PI3K-C2α is required for transforming growth factor β-induced Smad signaling in endothelial cells. J Biol Chem 2015; 290:6086-105. [PMID: 25614622 DOI: 10.1074/jbc.m114.601484] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We have recently demonstrated that the PI3K class II-α isoform (PI3K-C2α), which generates phosphatidylinositol 3-phosphate and phosphatidylinositol 3,4-bisphosphates, plays crucial roles in angiogenesis, by analyzing PI3K-C2α knock-out mice. The PI3K-C2α actions are mediated at least in part through its participation in the internalization of VEGF receptor-2 and sphingosine-1-phosphate receptor S1P1 and thereby their signaling on endosomes. TGFβ, which is also an essential angiogenic factor, signals via the serine/threonine kinase receptor complex to induce phosphorylation of Smad2 and Smad3 (Smad2/3). SARA (Smad anchor for receptor activation) protein, which is localized in early endosomes through its FYVE domain, is required for Smad2/3 signaling. In the present study, we showed that PI3K-C2α knockdown nearly completely abolished TGFβ1-induced phosphorylation and nuclear translocation of Smad2/3 in vascular endothelial cells (ECs). PI3K-C2α was necessary for TGFβ-induced increase in phosphatidylinositol 3,4-bisphosphates in the plasma membrane and TGFβ receptor internalization into the SARA-containing early endosomes, but not for phosphatidylinositol 3-phosphate enrichment or localization of SARA in the early endosomes. PI3K-C2α was also required for TGFβ receptor-mediated formation of SARA-Smad2/3 complex. Inhibition of dynamin, which is required for the clathrin-dependent receptor endocytosis, suppressed both TGFβ receptor internalization and Smad2/3 phosphorylation. TGFβ1 stimulated Smad-dependent VEGF-A expression, VEGF receptor-mediated EC migration, and capillary-like tube formation, which were all abolished by either PI3K-C2α knockdown or a dynamin inhibitor. Finally, TGFβ1-induced microvessel formation in Matrigel plugs was greatly attenuated in EC-specific PI3K-C2α-deleted mice. These observations indicate that PI3K-C2α plays the pivotal role in TGFβ receptor endocytosis and thereby Smad2/3 signaling, participating in angiogenic actions of TGFβ.
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Affiliation(s)
- Sho Aki
- From the Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan and
| | - Kazuaki Yoshioka
- From the Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan and
| | - Yasuo Okamoto
- From the Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan and
| | - Noriko Takuwa
- From the Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan and the Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Kahoku, Ishikawa 929-1210, Japan
| | - Yoh Takuwa
- From the Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan and
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Proliferative ischemic retinopathy after arteriovenous malformation embolization in a child with hereditary hemorrhagic telangiectasia. Retin Cases Brief Rep 2014; 8:219-22. [PMID: 25372443 DOI: 10.1097/icb.0000000000000047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE To describe a case of hereditary hemorrhagic telangiectasia, presenting with multiple branch retinal artery occlusions, retinal ischemia, neovascularization, and vitreous hemorrhage after cerebral arteriovenous malformation embolization. METHODS The authors report a 7-year-old patient with decreased vision in his left eye after embolization of a pineal arteriovenous malformation secondary to hereditary hemorrhagic telangiectasia. Ophthalmic evaluation, fundus photography, fluorescein angiography, spectral domain optical coherence tomography, electroretinogram, examination under anesthesia, and pars plana vitrectomy (PPV) were performed. RESULTS Fundus examination of the left eye revealed extensive posterior segment ischemia, vascular tortuosity, and vitreous hemorrhage. Fluorescein angiography was remarkable for partial obstruction of retinal arteries, midperipheral nonperfusion, and associated leakage from multiple areas of neovascularization. Spectral domain optical coherence tomography was normal. Electroretinogram demonstrated decreased b-wave amplitude. The patient was subsequently treated with 25-gauge pars plana vitrectomy, panretinal endophotocoagulation, and intravitreal bevacizumab. Five weeks after surgery, best-corrected visual acuity had improved to 20/40, and examination showed resolution of vitreous hemorrhage and neovascularization. CONCLUSION Retinal vascular abnormalities, posterior segment ischemia, and vitreous hemorrhage suggested a combination of retinal involvement of hereditary hemorrhagic telangiectasia complicated by nontarget embolization.
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Meurer SK, Alsamman M, Scholten D, Weiskirchen R. Endoglin in liver fibrogenesis: Bridging basic science and clinical practice. World J Biol Chem 2014; 5:180-203. [PMID: 24921008 PMCID: PMC4050112 DOI: 10.4331/wjbc.v5.i2.180] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 12/29/2013] [Accepted: 01/17/2014] [Indexed: 02/05/2023] Open
Abstract
Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membrane-bound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β (TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type I and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin (i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e., sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and -independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.
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Molecular pathways governing development of vascular endothelial cells from ES/iPS cells. Stem Cell Rev Rep 2014; 9:586-98. [PMID: 23765563 DOI: 10.1007/s12015-013-9450-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Assembly of complex vascular networks occurs in numerous biological systems through morphogenetic processes such as vasculogenesis, angiogenesis and vascular remodeling. Pluripotent stem cells such as embryonic stem (ES) and induced pluripotent stem (iPS) cells can differentiate into any cell type, including endothelial cells (ECs), and have been extensively used as in vitro models to analyze molecular mechanisms underlying EC generation and differentiation. The emergence of these promising new approaches suggests that ECs could be used in clinical therapy. Much evidence suggests that ES/iPS cell differentiation into ECs in vitro mimics the in vivo vascular morphogenic process. Through sequential steps of maturation, ECs derived from ES/iPS cells can be further differentiated into arterial, venous, capillary and lymphatic ECs, as well as smooth muscle cells. Here, we review EC development from ES/iPS cells with special attention to molecular pathways functioning in EC specification.
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Bhatt RS, Atkins MB. Molecular pathways: can activin-like kinase pathway inhibition enhance the limited efficacy of VEGF inhibitors? Clin Cancer Res 2014; 20:2838-45. [PMID: 24714770 DOI: 10.1158/1078-0432.ccr-13-2788] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The vascular endothelial growth factor (VEGF) pathway is critical for tumor angiogenesis. However, VEGF pathway inhibition has been limited by intrinsic and acquired resistance. Simultaneously targeting multiple steps involved in tumor angiogenesis is a potential means of overcoming this resistance. Activin like kinase 1 (ALK1) and endoglin (ENG) have effects on angiogenesis that are distinct from those of VEGF. Whereas VEGF is important for vessel initiation, ALK1 and endoglin are involved in vessel network formation. Thus, ALK1 and endoglin pathway inhibitors are attractive partners for VEGF-based combination antiangiogenic therapy. Genetic evidence supports a role for this receptor family and its ligands, bone morphogenetic proteins (BMP) 9 and 10, in vascular development. Patients with genetic alterations in ALK1 or endoglin develop hereditary hemorrhagic telangiectasia, a disorder characterized by abnormal vessel development. There are several inhibitors of the ALK1 pathway advancing in clinical development for treatment of various tumor types, including renal cell and ovarian carcinomas. Targeting of alternate angiogenic pathways, particularly in combination with VEGF pathway blockade, holds the promise of optimally inhibiting angiogenically driven tumor progression. Clin Cancer Res; 20(11); 2838-45. ©2014 AACR.
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Affiliation(s)
- Rupal S Bhatt
- Authors' Affiliations: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and Departments of Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia
| | - Michael B Atkins
- Authors' Affiliations: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and Departments of Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia
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Feng Q, Tan HH, Ge ZZ, Gao YJ, Chen HM, Xiao SD. Thalidomide-induced angiopoietin 2, Notch1 and Dll4 downregulation under hypoxic condition in tissues with gastrointestinal vascular malformation and human umbilical vein endothelial cells. J Dig Dis 2014; 15:85-95. [PMID: 24219762 DOI: 10.1111/1751-2980.12114] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To determine the pathogenesis of gastrointestinal vascular malformation (GIVM) and the mechanism of thalidomide in treating GIVM by evaluating the expression of angiopoietin 2 (Ang2), Notch1, delta-like ligand 4 (Dll4) and hypoxia inducible factor 1α (Hif-1α). METHODS Data of 10 patients with histology-confirmed GIVM were reviewed. Immunohistochemistry of surgically resected GIVM tissues and the adjacent mucosa of the patients and normal tissues from those who had undergone colonoscopy for health examination was performed to examine the expressions of Ang2, Notch1, Dll4 and Hif-1α. In addition, in vitro effect of thalidomide on Ang2, Notch1 and Dll4 in human umbilical vein endothelial cells (HUVEC) and on HUVEC proliferation was also investigated during normoxic and hypoxic conditions. RESULTS GIVM lesions presented as tortuous, dilated arterioles, venules and capillaries. Ang2, Notch1 and Dll4 showed strong immunoreactivity in the cytoplasm and nuclei of GIVM lesions but negative or weak positivity in the intestinal mucosa of the adjacent tissues and normal mucosa. Under hypoxic condition the expressions of Hif-1α, Ang2, Notch1 and Dll4 were upregulated and the tube formation was more abundant with a greater diameter of tubes. Moreover, thalidomide downregulated their expression in HUVEC and HUVEC proliferation decreased in a concentration-dependent manner under both hypoxic and normoxic conditions. CONCLUSION Ang2, Notch1, Dll4 and Hif-1α may play an important role in the pathogenesis of GIVM and may be potential targets of thalidomide in the treatment of the disease.
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Affiliation(s)
- Qian Feng
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China
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Liu Z, Lebrin F, Maring JA, van den Driesche S, van der Brink S, van Dinther M, Thorikay M, Martin S, Kobayashi K, Hawinkels LJAC, van Meeteren LA, Pardali E, Korving J, Letarte M, Arthur HM, Theuer C, Goumans MJ, Mummery C, ten Dijke P. ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis. PLoS One 2014; 9:e86273. [PMID: 24489709 PMCID: PMC3904881 DOI: 10.1371/journal.pone.0086273] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 12/10/2013] [Indexed: 01/10/2023] Open
Abstract
ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis.
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Affiliation(s)
- Zhen Liu
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Franck Lebrin
- Hubrecht Institute, Utrecht, The Netherlands
- Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Collège de France, Paris, France
| | - Janita A. Maring
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | | | | | - Maarten van Dinther
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Midory Thorikay
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Sabrina Martin
- Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Collège de France, Paris, France
| | - Kazuki Kobayashi
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Lukas J. A. C. Hawinkels
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Laurens A. van Meeteren
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Evangelia Pardali
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Michelle Letarte
- Molecular Structure and Function Program, The Hospital of Sick Children, Department of Immunology and Heart and Stroke Richard Lewar Center of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - Helen M. Arthur
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom
| | - Charles Theuer
- Tracon Pharmaceuticals, San Diego, California, United States of America
| | - Marie-José Goumans
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
- * E-mail: (MJG); (CM); (PtD)
| | - Christine Mummery
- Hubrecht Institute, Utrecht, The Netherlands
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
- * E-mail: (MJG); (CM); (PtD)
| | - Peter ten Dijke
- Department of Molecular Cell Biology, Cancer Genomics Centre, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands
- * E-mail: (MJG); (CM); (PtD)
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50
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Stefanska M, Costa G, Lie-A-Ling M, Kouskoff V, Lacaud G. Smooth muscle cells largely develop independently of functional hemogenic endothelium. Stem Cell Res 2014; 12:222-32. [PMID: 24270161 DOI: 10.1016/j.scr.2013.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 10/24/2013] [Accepted: 10/26/2013] [Indexed: 10/26/2022] Open
Abstract
Vascular smooth muscle cells represent a major component of the cardiovascular system. In vitro studies have shown that FLK1(+) cells derived from embryonic stem (ES) cells can differentiate into both endothelial and smooth muscle cells. These FLK1(+) cells also contain a mesodermal precursor, the hemangioblast, able to produce endothelial, blood and smooth muscle cells. The generation of blood precursors from the hemangioblast was recently shown to occur through a transient cell population of specialised endothelium, a hemogenic endothelium. To date, the lineage relationship between this cell population and smooth muscle cell progenitors has not been investigated. In this study, we generated a reporter ES cell line in which expression of the fluorescent protein H2B-VENUS is driven by the α-smooth muscle actin (α-SMA) regulatory sequences. We demonstrated that this reporter cell line efficiently trace smooth muscle development during ES cell differentiation. Although some smooth muscle cells are associated with broad endothelial development, we established that smooth muscle cells are mostly generated independently from a specialised functional hemogenic endothelium. This study provides new and important insights into hematopoietic and vascular development, which may help in driving further progress towards the development of bioengineered vascular grafts for regenerative medicine.
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Affiliation(s)
- Monika Stefanska
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Guilherme Costa
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Michael Lie-A-Ling
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Valerie Kouskoff
- Cancer Research UK Stem Cell Hematopoiesis Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Georges Lacaud
- Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
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