Heterogeneity in the lymphatic vascular system and its origin

Ulvmar, Maria H.; Mäkinen, Taija

doi:10.1093/cvr/cvw175

Cited by 137 publications

(131 citation statements)

References 137 publications

(225 reference statements)

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“…Given the rapidly emerging data regarding the heterogeneity and the likelihood of organ-specific regulation of lymphangiogenesis in ontogeny (61), it becomes more important, and perhaps even more daunting, to understand the regulation of lymphangiogenesis in inflammation, particularly in chronic inflammation in TLOs. Do LVs in TLOs arise from veins?…”

Section: Lvs: Characteristics Functions and Regulation In Tlosmentioning

confidence: 99%

High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation

Ruddle

2016

Front. Immunol.

104

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High endothelial venules (HEVs) and lymphatic vessels (LVs) are essential for the function of the immune system, by providing communication between the body and lymph nodes (LNs), specialized sites of antigen presentation and recognition. HEVs bring in naïve and central memory cells and LVs transport antigen, antigen-presenting cells, and lymphocytes in and out of LNs. Tertiary lymphoid organs (TLOs) are accumulations of lymphoid and stromal cells that arise and organize at ectopic sites in response to chronic inflammation in autoimmunity, microbial infection, graft rejection, and cancer. TLOs are distinguished from primary lymphoid organs – the thymus and bone marrow, and secondary lymphoid organs (SLOs) – the LNs, spleen, and Peyer’s patches, in that they arise in response to inflammatory signals, rather than in ontogeny. TLOs usually do not have a capsule but are rather contained within the confines of another organ. Their structure, cellular composition, chemokine expression, and vascular and stromal support resemble SLOs and are the defining aspects of TLOs. T and B cells, antigen-presenting cells, fibroblast reticular cells, and other stromal cells and vascular elements including HEVs and LVs are all typical components of TLOs. A key question is whether the HEVs and LVs play comparable roles and are regulated similarly to those in LNs. Data are presented that support this concept, especially with regard to TLO HEVs. Emerging data suggest that the functions and regulation of TLO LVs are also similar to those in LNs. These observations support the concept that TLOs are not merely cellular accumulations but are functional entities that provide sites to generate effector cells, and that their HEVs and LVs are crucial elements in those activities.

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Section: Lvs: Characteristics Functions and Regulation In Tlosmentioning

confidence: 99%

High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation

Ruddle

2016

Front. Immunol.

104

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“…Lymphatic vascular development in the embryo first begins with the appearance of LEC progenitor cells in the cardinal and intersomitic veins at ~E9.5, identified by their upregulation of LEC markers Prox1 and LYVE-1, which subsequently dissociate from the veins, migrate away and coalesce to form the early lymphatic vascular plexuses and lymph sacs. These further grow via lymphangiogenesis in which new lymphatic vessels grow from the existing plexus (reviewed in (Ulvmar & Mäkinen, 2016). …”

Section: Retinoic Acid In Development Of the Embryonic Lymphatic Vascmentioning

confidence: 99%

Retinoic acid signaling in vascular development

Pawlikowski

Wragge

Siegenthaler

2019

Genesis

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Formation of the vasculature is an essential developmental process, delivering oxygen and nutrients to support cellular processes needed for tissue growth and maturation. Retinoic acid (RA) and its downstream signaling pathway is vital for normal pre- and post-natal development, playing key roles in the specification and formation of many organs and tissues. Here we review the role of RA in blood and lymph vascular development, beginning with embryonic yolk sac vasculogenesis and remodeling and discussing RA’s organ-specific roles in angiogenesis and vessel maturation. In particular, we highlight the multi-faceted role of RA signaling in CNS vascular development and acquisition of blood-brain barrier properties.

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“…As previously discussed, however, there are a few exceptions currently known to this general rule such as for the lymphatics associated with the heart[59], skin[60], mesentery[61], and perhaps other organ-associated lymphatics that arise from non-venous precursors. The heterogeneity of the lymphatic vascular network was recently reviewed[62]). The steps of vasculogenesis, angiogenesis (i.e., the sprouting of blood vessels from pre-existing ones), and lymphangiogenesis give rise to the circulatory system.…”

Section: Discovery Of Other Lymphatic Endothelial Markersmentioning

confidence: 99%

Fluorescent reporter transgenic mice for in vivo live imaging of angiogenesis and lymphangiogenesis

et al. 2018

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The study of lymphangiogenesis is an emerging science that has revealed the lymphatic system as a central player in many pathological conditions including cancer metastasis, lymphedema, and organ graft rejection. A thorough understanding of the mechanisms of lymphatic growth will play a key role in the development of therapeutic strategies against these conditions. Despite the known potential of this field, the study of lymphatics has historically lagged behind that of hemangiogenesis. Until recently, significant strides in lymphatic studies were impeded by a lack of lymphatic-specific markers and suitable experimental models compared to those of the more immediately visible blood vasculature. Lymphangiogenesis has also been shown to be a key phenomenon in developmental biological processes, such as cell proliferation, guided migration, differentiation, and cell-to-cell communication, making lymphatic-specific visualization techniques highly desirable and desperately needed. Imaging modalities including immunohistochemistry and in situ hybridization are limited by the need to sacrifice animal models for tissue harvesting at every experimental time point. Moreover, the processes of mounting and staining harvested tissues may introduce artifacts that can confound results. These traditional methods for investigating lymphatic and blood vasculature are associated with several problems including animal variability (e.g., between mice) when replicating lymphatic growth environments and the cost concerns of prolonged, labor-intensive studies, all of which complicate the study of dynamic lymphatic processes. With the discovery of lymphatic-specific markers, researchers have been able to develop several lymphatic and blood vessel-specific, promoter-driven, fluorescent-reporter transgenic mice for visualization of lymphatics in vivo and in vitro. For instance, GFP, mOrange, tdTomato, and other fluorescent proteins can be expressed under control of a lymphatic-specific marker like Prospero-related homeobox 1 (Prox1), which is a highly conserved transcription factor for determining embryonic organogenesis in vertebrates that is implicated in lymphangiogenesis as well as several human cancers. Importantly, Prox1-null mouse embryos develop without lymphatic vessels. In human adults, Prox1 maintains lymphatic endothelial cells and upregulates proteins associated with lymphangiogenesis (e.g., VEGFR-3) and downregulates angiogenesis-associated gene expression (e.g., STAT6). To visualize lymphatic development in the context of angiogenesis, dual fluorescent-transgenic reporters, like Prox1-GFP/Flt1-DsRed mice, have been bred to characterize lymphatic and blood vessels simultaneously in vivo. In this review, we discuss the trends in lymphatic visualization and the potential usage of transgenic breeds in hemangiogenesis and lymphangiogenesis research to understand spatial and temporal correlations between vascular development and pathological progression.

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Heterogeneity in the lymphatic vascular system and its origin

Cited by 137 publications

References 137 publications

High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation

High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation

Retinoic acid signaling in vascular development

Fluorescent reporter transgenic mice for in vivo live imaging of angiogenesis and lymphangiogenesis

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