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cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0002-3436-3278
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2015 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 10, p. 1708-1721Article in journal (Refereed) Published
Abstract [en]

Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110 alpha PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.

Place, publisher, year, edition, pages
2015. Vol. 10, no 10, p. 1708-1721
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-251417DOI: 10.1016/j.celrep.2015.02.026ISI: 000351316700008OAI: oai:DiVA.org:uu-251417DiVA, id: diva2:807436
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-08-15Bibliographically approved
In thesis
1. Organ-specific mechanisms of vascular development in the mesentery
Open this publication in new window or tab >>Organ-specific mechanisms of vascular development in the mesentery
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Understanding how the vascular systems are formed has significant clinical importance. General mechanisms underlying vascular development have been extensively studied during the past decades. However, the mechanisms regulating the development and function of the blood and lymphatic vessels in specific organs are poorly understood.

The aim of this thesis was to investigate lymphatic vascular development in the mesentery, which is a fold of peritoneum that attaches the intestine to the abdominal wall, and contains arteries, veins, lymphatic vessels, nerves and lymph nodes. We found that mesenteric lymphatic vessels were formed through lymphvasculogenesis - coalescence of isolated lymphatic endothelial cell (LEC) clusters, rather than by lymphangiogenesis - sprouting from the veins or pre-existing lymphatic vessels. The lymphvasculogenic process was selectively sensitive to inhibition of the vascular endothelial growth factor receptor 3 (VEGFR3)/ phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling pathway. Using genetic lineage tracing, we uncovered that part of the mesenteric lymphatic vasculature was derived from cKit lineage cells likely originating from the blood-forming hemogenic endothelium of major arteries (Paper I). This is in contrast to the previously accepted dogma that all mammalian lymphatic vessels are of venous endothelial origin. By characterizing a mouse mutant lacking the non-venous-derived LEC progenitors we found that an alternative venous source of LECs could however compensate to build a functional mesenteric lymphatic vasculature (Paper IV). We further described in the developing mesentery that a transient loss of venous integrity, characterized by the formation of inter-endothelial cell gaps, was accompanied by extravasation of red blood cells, which were cleared by the developing lymphatic vessels. By studying mice with defective platelet function, we revealed a previously unappreciated role of platelets in maintaining the integrity of the remodeling embryonic blood vasculature and thus preventing excessive blood-filling of lymphatic vessels (Paper III). We also studied the mechanism of vessel maturation into functional lymphatic vessels, which involves smooth muscle cell recruitment. Analysis of mice with LEC-specific deletion of Pdgfb, encoding the platelet derived growth factor B (PDGFB), showed that LEC-autonomous PDGFB was required for the recruitment of smooth muscles cells that in turn control lymphatic vessel size and function (Paper II).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1485
Keywords
Lymphatic vasculature, mesentery, hemogenic endothelium, lymphvasculogenesis, endothelial integrity, platelet, blood-filled lymphatic vessel, morphogenesis and maturation, compensation
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-356488 (URN)978-91-513-0406-9 (ISBN)
Public defence
2018-10-05, Rudbeck Hall, Dag Hammarskjölds v 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-09-10 Created: 2018-08-15 Last updated: 2018-10-02

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