VIPAR, a quantitative approach to 3D histopathology applied to lymphatic malformations

Hägerling, René; Drees, Dominik; Scherzinger, Aaron; Dierkes, Cathrin; Martin-Almedina, Silvia; Butz, Stefan; Gordon, Kristiana; Schäfers, Michael; Hinrichs, Klaus; Østergaard, Pia; Vestweber, Dietmar; Goerge, Tobias; Mansour, Sahar; Jiang, Xiaoyi; Mortimer, Peter; Kiefer, Friedemann

doi:10.1172/jci.insight.93424

Cited by 38 publications

(42 citation statements)

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“…In wholemount preparations of the intestinal wall, triple staining for ESAM1, aSMA, and LYVE1 allowed simultaneous visualization of the centrally located lymphatic lacteal as well as the surrounding blood capillary network and smooth muscle cells ( Fig 5A-E). Like PECAM1, the junctional molecule ESAM1 is expressed more strongly on blood endothelium compared to LECs and therefore readily identifies blood vessels (Hagerling et al, 2017). In wild-type mice, the central lacteal spans 70-90% of the villus length (Figs 5A and B, and EV3A), while aSMA-positive fibers extend along the entire length of the villus (Fig 5A and Given the massive deterioration of the mesenteric lymphatic vessels, we wondered if the lacteal lymphatics deteriorated as a consequence of the demise of mesenteric collecting vessels.…”

Section: Ve-cadherin Deletion In Lecs Results In Fragmentation or Dismentioning

confidence: 99%

Distinct roles of VE ‐cadherin for development and maintenance of specific lymph vessel beds

et al. 2018

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Endothelial cells line blood and lymphatic vessels and form intercellular junctions, which preserve vessel structure and integrity. The vascular endothelial cadherin, VE‐cadherin, mediates endothelial adhesion and is indispensible for blood vessel development and permeability regulation. However, its requirement for lymphatic vessels has not been addressed. During development, VE‐cadherin deletion in lymphatic endothelial cells resulted in abortive lymphangiogenesis, edema, and prenatal death. Unexpectedly, inducible postnatal or adult deletion elicited vessel bed‐specific responses. Mature dermal lymph vessels resisted VE‐cadherin loss and maintained button junctions, which was associated with an upregulation of junctional molecules. Very different, mesenteric lymphatic collectors deteriorated and formed a strongly hyperplastic layer of lymphatic endothelial cells on the mesothelium. This massive hyperproliferation may have been favored by high mesenteric VEGF‐C expression and was associated with VEGFR‐3 phosphorylation and upregulation of the transcriptional activator TAZ. Finally, intestinal lacteals fragmented into cysts or became highly distended possibly as a consequence of the mesenteric defects. Taken together, we demonstrate here the importance of VE‐cadherin for lymphatic vessel development and maintenance, which is however remarkably vessel bed‐specific.

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Section: Ve-cadherin Deletion In Lecs Results In Fragmentation or Dismentioning

confidence: 99%

Distinct roles of VE ‐cadherin for development and maintenance of specific lymph vessel beds

et al. 2018

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“…Certainly, development of novel segmentation algorithms for quantification of imaged microvascular networks will be essential to organize such large datasets . One of such promising tools is VIPAR (volume information‐based histopathological analysis by 3D reconstruction and data extraction procedure), the efficacy of which was recently presented by Kiefer's group . Using VIPAR, the researchers could decipher various features of complex lymphatic vasculature within human skin biopsies cleared with Murray's Clear.…”

Section: Application Of Toc For Particular Peripheral Organsmentioning

confidence: 99%

Advances in Ex Situ Tissue Optical Clearing

Matryba

Kaczmarek

Gołąb

2019

Laser & Photonics Reviews

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Examination of whole organs with subcellular resolution in health, disease, and during development is necessary to decipher their biological complexity. However, until recently, this has been virtually impossible due to the natural opacity of organ tissue. Recent progress in tissue optical clearing (TOC) has overcome this limitation by turning organs into transparent, light-permitting specimens. At least 20 original TOC methods have been developed in less than a decade, which were followed by hundreds of attempts that were aimed at their optimization and practical application. The majority of proof-of-concept studies have focused on the brain. However, it is apparent that TOC might be equally valuable when applied to peripheral organs or even the whole body. The progress in TOC for peripheral organs is delineated in an organ-by-organ fashion and whole-body clearing approaches are discussed. Additionally, physical and optical approaches for TOC affecting the optical properties of the samples and image quality are discussed to explore their advantages, limitations, and future possibilities.

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“…Im Anschluss an die Immunfluoreszenzfärbung der gesamten Probe wurden die Gewebeproben optisch geklärt und mittels eines LaVision Ultramicroscope II (LaVision BioTec) bei verschiedenen Vergrößerungen mikroskopiert. Die 3D-Rekonstruktion und Analyse der Aufnahmen erfolgten mittels VIPAR [12].…”

Section: Lichtblattmikroskopieunclassified

“…Dieses fehlende Verständnis ist in den unzureichenden Bildgebungsmöglichkeiten begründet, die Gefäßarchitektur auf zellulärer Ebene und im 3-dimensionalen (3D) Kontext nicht ausreichend darstellen zu können [12].…”

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Light sheet microscopy-based 3-dimensional histopathology of the lymphatic vasculature in Emberger syndrome

Hägerling

2020

Phlebologie

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Introduction Lymphovascular diseases represent a heterogenous group of inherited and sporadic disorders and refer to a range of possible underlying pathologies and pathogenesis.Emberger Syndrome, an inherited form of lymphedema, is characterized by bilateral lower limb lymphedema, however, upper limbs do not show any signs of swelling.To identify disease-associated histopathological alterations in patients with Emberger Syndrome and to elucidate potential histological differences between the lymphatic vasculature of upper and lower limbs, a detailed knowledge on the 3-dimensional tissue and vessel architecture is essential. However, the current gold standard in 2-dimensional histology provides only very limited spatial information. Material and methods To elucidate the underlying vascular pathology in Emberger Syndrome on the cellular level, we applied the 3-dimensional visualization and analysis approach VIPAR (volume information-based histopathological analysis by 3D reconstruction and data extraction) to entire wholemount immunofluorescence-stained human tissue samples. VIPAR is a light sheet microscopy-based imaging technique, which allows 3-dimensional reconstruction of entire tissue biopsies followed by automated and semi-automated analysis of vascular parameters in 3-dimensional space. Results Using VIPAR we could show that in Emberger Syndrome the dermal lymphatic vasculature is intact and non-disrupted.However, lower limbs showed an hypoplastic lymphatic vasculature with absence of lymphatic valves in pre-collecting and collecting vessels. In contrast to the lower limbs, the lymphatic vasculature of the upper limbs showed no morphological alterations of lymphatic vessels and lymphatic valves compared to healthy controls. Discussion Based on the 3-dimensional histopathological analysis we were able to perform a detailed phenotyping of lymphatic vessels in the upper and lower limb in Emberger Syndrome and to identify the underlying vascular pathology. In addition, we could show vascular alteration between the upper and lower limbs indicating a vascular heterogeneity of dermal lymph vessels causing the lower limb lymphedema.

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VIPAR, a quantitative approach to 3D histopathology applied to lymphatic malformations

Cited by 38 publications

References 38 publications

Distinct roles of VE ‐cadherin for development and maintenance of specific lymph vessel beds

Distinct roles of VE ‐cadherin for development and maintenance of specific lymph vessel beds

Advances in Ex Situ Tissue Optical Clearing

Light sheet microscopy-based 3-dimensional histopathology of the lymphatic vasculature in Emberger syndrome

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