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Leukocytes in Angiogenesis: Learning from Transplanted Pancreatic Islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
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. , 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 875
Keyword [en]
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: urn:nbn:se:uu:diva-196486ISBN: 978-91-554-8616-7 (print)OAI: oai:DiVA.org:uu-196486DiVA: diva2:610285
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: 2013-08-30Bibliographically approved
List of papers
1. Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets
Open this publication in new window or tab >>Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets
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2010 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 10, 2569-2578 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation. Research Design and Methods: The current study presents a new experimental model which is found applicable to clinical islet transplantation. Islets were implanted into striated muscle where after intra-islet vascular density and blood flow were visualized with intravital and confocal microscopy in mice, and by magnetic resonance imaging in three auto-transplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody and diabetes was induced by alloxan treatment. Results: Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable to islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in auto-transplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared to adjacent muscle tissue through high-resolution magnetic resonance imaging. Conclusions: This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intra-islet blood perfusion following transplantation to striated muscle under experimental and clinical situations.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-130874 (URN)10.2337/db10-0205 (DOI)000283205700030 ()20651296 (PubMedID)
Funder
Swedish Research Council, 57p-20680, 57x-20675
Available from: 2010-09-15 Created: 2010-09-15 Last updated: 2017-12-12Bibliographically approved
2. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
Open this publication in new window or tab >>VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
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2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 23, 4653-4662 p.Article in journal (Refereed) Published
Abstract [sv]

Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-188352 (URN)10.1182/blood-2012-04-421040 (DOI)000313113300031 ()
Available from: 2012-12-16 Created: 2012-12-16 Last updated: 2017-12-06Bibliographically approved
3. Vascular sprouts induce local attraction of proangiogenic neutrophils
Open this publication in new window or tab >>Vascular sprouts induce local attraction of proangiogenic neutrophils
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2017 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, 741-751 p.Article in journal (Refereed) Published
National Category
Physiology Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-196483 (URN)10.1189/jlb.1MA0117-018R (DOI)
Projects
eSSENCE
Available from: 2017-06-05 Created: 2013-03-10 Last updated: 2017-08-31Bibliographically approved
4. Pericyte repopulation of transplanted pancreatic islets is macrophage dependent
Open this publication in new window or tab >>Pericyte repopulation of transplanted pancreatic islets is macrophage dependent
(English)Manuscript (preprint) (Other academic)
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-196485 (URN)
Available from: 2013-03-10 Created: 2013-03-10 Last updated: 2013-08-30

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