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Vascular sprouts induce local attraction of proangiogenic neutrophils
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0003-3117-5367
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2017 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, p. 741-751Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2017. Vol. 102, p. 741-751
National Category
Physiology Bioinformatics (Computational Biology)
Identifiers
URN: urn:nbn:se:uu:diva-196483DOI: 10.1189/jlb.1MA0117-018RISI: 000413395700019OAI: oai:DiVA.org:uu-196483DiVA, id: diva2:610253
Projects
eSSENCEAvailable from: 2017-06-05 Created: 2013-03-10 Last updated: 2018-11-12Bibliographically approved
In thesis
1. Leukocytes in Angiogenesis: Learning from Transplanted Pancreatic Islets
Open this publication in new window or tab >>Leukocytes in Angiogenesis: Learning from Transplanted Pancreatic Islets
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis, the growth of new blood vessels, is a complex process involving several cell types and molecular signals. Excessive vascular growth is a problem in tumors, and insufficient vascularization hampers the function of transplanted insulin-producing pancreatic islets. Understanding the mechanisms behind blood vessel growth generates increased means to control angiogenesis. In this thesis a model of pancreatic islet transplantation to muscle has been used to study the involvement of leukocytes in the development of new vasculature.

Transplantation of isolated islets of Langerhans into mouse muscle promoted revascularization of the grafts to a level comparable to native islets in the pancreas. The complete and functional vascular restoration resulted in improved blood glucose control compared to the clinical standard implantation site, the liver. This proved muscle as a transplantation site to be a clinically relevant option for the treatment of type 1 diabetes.

The rapid islet revascularization process was found to be dependent on a distinct subset of neutrophils characterized by high expression of the chemokine receptor CXCR4 and the enzyme matrix metalloproteinase 9 (MMP-9). These cells were recruited to recently transplanted and hypoxic grafts by islet-secreted vascular endothelial growth factor A (VEGF-A). Leukocyte migration and interactions in the engraftment area were monitored using a high-speed confocal microscope followed by software tracking. New software was developed to visualize migration statistics. This tool revealed areas around the islet graft where neutrophil gathering coincided with sites of angiogenesis. Macrophages in the engraftment area positioned themselves close to the newly formed vasculature and were shown to have a stabilizing effect on the vessels. When macrophages were removed, no pericytes were recruited to the forming vasculature. The perivascular macrophages also began to express a pericyte marker when in the graft, suggesting a close relationship between these cell types or macrophage plasticity.

In conclusion, this thesis presents muscle as a proangiogenic transplantation site for pancreatic islets for the treatment of type 1 diabetes, where the revascularization of the grafts was dependent on the recruitment and actions of specialized immune cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 875
Keywords
angiogenesis, pancreatic islet transplantation, islets of Langerhans, diabetes mellitus, leukocytes, neutrophils, macrophages, pericytes, MMP-9, VEGF-A
National Category
Physiology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-196486 (URN)978-91-554-8616-7 (ISBN)
Public defence
2013-04-26, A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-04-05 Created: 2013-03-10 Last updated: 2018-01-11Bibliographically approved
2. Functional characterization of pro-angiogenic neutrophils
Open this publication in new window or tab >>Functional characterization of pro-angiogenic neutrophils
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The vascular system stretches throughout the body to provide oxygen, nutrition, and to remove waste products from cell metabolism. Angiogenesis, formation of new blood vessels by sprouting from pre-existing vessels, is one of the main mechanisms involved in blood vessel formation. A successful angiogenic process is dependent on the timely involvement of several parameters; from different cell types to anti- and pro-angiogenic soluble factors.

White blood cells are mostly famous for being involved in host defense against pathogens, through rapid reactions by innate immunity and delayed but specific responses through adaptive immunity. The neutrophils are innate immune cells, which are the most abundant white blood cells in the circulation. In addition to their classical roles in defense against invading microorganisms, it was recently revealed that neutrophils actively contribute to angiogenesis. Neutrophils that are involved in angiogenesis comprise a specific population, namely pro-angiogenic neutrophils (PANs), that are recruited to sites of hypoxia by using different adhesion molecules compared to when they chemotax towards infection.

The present investigations focus on characterization of PANs and comparing them to the classic neutrophil population in terms of their physical features and their functions. By modifying and applying new in vivo and in vitro models of angiogenesis, interactions between growing endothelial cells and neutrophils have been further revealed, as well as neutrophil recruitment and movement towards an active site of angiogenesis. We found that the main neutrophil contribution to angiogenesis at site of islet transplantation occurs at early stages of revascularization to establish new vessels, where after the neutrophils leave the site. Neutrophil recruitment to a site of infection relies to a large extent on macrophage signals, but this was not the case when they were recruited to sites of hypoxia. PANs are a specific sub-population of neutrophils that significantly differ from the rest of the neutrophil population not only in terms of their active contribution to angiogenesis, but also in terms of their physical features and their phagocytosis abilities. The role of vascular endothelial growth factor receptor (VEGFR1) and also chemokine CXCL12 (CXCR4/CXCL12 signaling) in neutrophil recruitment has been further revealed by our in vitro model; neutrophil migration to sprouting endothelium is directed by CXCL12 and VEGFR1. Furthermore we found that hypoxic condition boosted pro-angiogenic activities of PANs. Moreover, how vascular permeability affects neutrophil recruitment was studied; vascular permeability regulates inflammation by increasing chemokine transport into the blood vessels and thereby promotes neutrophil recruitment.

In conclusion, functional characterization of pro-angiogenic neutrophils performed in this thesis demonstrates differences beyond marker expression when compared to classic neutrophils. Moreover, intricate interactions necessary for the formation of new blood vessels between neutrophils and the growing vasculature were shown. Increased understanding of the contribution of neutrophils to blood vessel formation in hypoxic environment or/and tumors could be exploited further to develop potential therapies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1498
Keywords
angiogenesis, leukocytes, neutrophils, pro-angiogenic neutrophils, islets transplantation, intravital microscopy, aortic ring assay, phagocytosis, ROS production, hypoxia, vascular permeability, neutrophil recruitment
National Category
Immunology in the medical area
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-362217 (URN)978-91-513-0457-1 (ISBN)
Public defence
2018-11-20, A1:107A, BMC, Husargatan 3, Uppsala, 09:30 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
Available from: 2018-10-30 Created: 2018-10-03 Last updated: 2018-11-26

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Christoffersson, GustafLomei, JalalO'Callaghan, PaulKreuger, JohanEngblom, StefanPhillipson, Mia

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