How do lymphatic vessels form?

Early lymphatic development

In our lab we take advantage of the transparency and genetic amenability of the zebrafish embryo to uncover the mechanisms controlling specification of lymphatic endothelial cells and assembly of lymphatic vessels (Yaniv, 2006). Recently, we have revealed the existence of a novel niche of specialized progenitors, which gives rise to the lymphatic system, and have identified the first “lymphatic-inducing” signal. Moreover, using this factor we have been able to induce lymphatic differentiation of human embryonic stem cells, allowing for the first time the generation of human lymphatic endothelial cells in culture (Nicenboim, 2015).

Current projects in the lab involve further understanding of lymphatic formation in the zebrafish embryo, as well as characterization of organ-specific lymphatic vessels. In particular, we are interested in understanding how do lymphatic vessels in the heart form, what are their origins, and what is their putative role during cardiac pathologies. Finally, since the lymphatic system represents the main route for dissemination of metastatic cells, we aim to understand the mechanisms underlying tumor-induced lymphangiogenesis (the formation of new lymphatic vessels), and whether or not they relate to the circuits controlling lymphatic formation during embryonic development.

Specialized angioblasts in the floor of the Cardinal Vein give rise to the lymphatic system


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“Tubing” the vertebrate’s body- Mechanisms of blood...

Mechanisms of blood vessel formation

In our lab we look at several aspects of blood vessel formation:

The link between lipids and angiogenesis: The interaction between endothelial cells (ECs) and lipoproteins (the particles carrying cholesterol and triglycerides through the blood) has direct relevance to atherosclerosis, thrombosis and cardiovascular disease. In order to study the effects of lipoproteins on blood vessel development and function, we use novel zebrafish models of hypo-, and hyper-lipidemia.

Taking advantage of these models, in combination with hyperlipidemic mice and cultured human endothelial cells we have been able to show that lipoproteins directly regulate developmental angiogenesis (Avraham-Davidi, 2012). Furthermore, we showed that the ApoB protein carried within LDL, and not the lipid components, plays a major role in triggering the vascular response, opening up a new set of questions regarding the effects of hyperlipidemia on the vasculature.

live imaging of LDL uptake by endothelial cells

The formation of organ-specific vessels: At present it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions. For instance ECs in the brain, which generate the blood-brain barrier, are structurally different from ECs in the fenestrated capillaries of the kidney or liver. We use transgenic zebrafish expressing fluorescent reporters in different organs, in combination with long-term live imaging to study the mechanisms underlying the formation of organ-specific vessels. In addition, we have developed protocols for UV-mediated photoconversion of restricted populations of ECs, followed by FACS isolation and RNA-Seq analyses. Altogether these studies are expected to shed light on novel players specifically expressed in ECs of certain organs, and responsible for their distinct function.

zebrafish, heart, liver, pancreatic and  intestinal vasculature

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Angiogenesis related diseases

Tumor Angiogenesis and Lipid Metabolism

Based on our previous findings demonstrating that high lipid levels inhibit angiogenesis, we are currently extending the scope of our studies to tumor biology. We are especially interested in understanding how lipoprotein metabolism regulates the angiogenic process in tumors and how it affects metastasis formation. For that purpose we make use of zebrafish-, and mouse- models of hyperlipidemia in combination with flow cytometry and microscopy, which enable focusing on molecular events that occur specifically in the vessels located within the tumor bulk. The combination of multiple approaches and novel “viewpoints” will hopefully allow us to achieve a deep understanding of tumor angiogenesis and reveal new "weakpoints" in the ability of tumor to grow vessels.

Visualization of blood vessels in tumors via micro-CT. Perfusion of radiopaque cast allows 3D imaging and quantification of functional vasculature in cancer.

Vessel integrity and permeability

We use zebrafish to study vascularization of the CNS in normal and pathological conditions. Using transgenic and mutant zebrafish lines we characterize the mechanisms involved in pathological conditions manifested by impaired vessel integrity and permeability, such as cranial hemorrhage.

Zebrafish mutant with cranial hemorrhage


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Zebrafish skeleton development: High resolution micro-CT and FIB-SEM block surface serial imaging for phenotype identification PLoS One Jeremie Silvent; Anat Akiva; Vlad Brumfeld; Natalie Reznikov; Katya Rechav; Karina Yaniv; Lia Addadi; Steve Weiner
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A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2 BMC Biology Yuval Peretz; Noa Eren; Ayelet Kohl; Gideon Hen; Karina Yaniv; Karen Weisinger; Yuval Cinnamon
The mid-developmental transition and the evolution of animal body plans Nature Maxim Levin; L Anavy; AG Cole; Esther Winter; N Mostov; S Khair; N Senderovich; Ekaterina Kovalev; DH Silver; M Feder; SL Fernandez-Valverde; N Nakanishi; D Simmons; O Simakov; T Larsson; SY Liu; A Jerafi-Vider; Karina Yaniv; JF Ryan; MQ Martindale; JC Rink; D Arendt; SM Degnan; BM Degnan; T Hashimshony; I Yanai
Development of the lymphatic system: new questions and paradigms Development Jonathan Semo; Julian Nicenboim; Karina Yaniv
A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2 BMC Biol Peretz Y, Eren N, Kohl A, Hen G, Yaniv K, Weisinger K, Cinnamon Y, Sela-Donenfeld D.
Mineral Formation in the Larval Zebrafish Tail Bone Occurs via an Acidic Disordered Calcium Phosphate Phase Journal of the American Chemical Society Anat Akiva; Michael Kerschnitzki; Iddo Pinkas; Wolfgang Wagermaier; Karina Yaniv; Peter Fratzl; Lia Addadi; Steve Weiner
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Venous-derived angioblasts generate organ-specific vessels during zebrafish embryonic development. Development Karina Yaniv
Lymphatic vessels arise from specialized angioblasts within a venous niche Nature Julian Nicenboim; Guy Malkinson; Tal Lupo; Lihee Asaf; Yogev Sela; Oded Mayseless; Liron Gibbs-Bar; N. Senderovich; T. Hashimshony; Myoung Sook Shin; A. Jerafi-Vider; Inbal Avraham-Davidi; Vladislav Krupalnik; Roy Hofi; Gabriella Almog; J. W. Astin; Ofra Golani; Shifra Ben-Dor; P. S. Crosier; W. Herzog; N. D. Lawson; J. H. Hanna; I. Yanai; Karina Yaniv
On the pathway of mineral deposition in larval zebrafish caudal fin bone Bone Anat Akiva; Guy Malkinson; Admir Masic; Michael Kerschnitzki; Mathieu Bennet; Peter Fratzl; Lia Addadi; Steve Weiner; Karina Yaniv
Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake Disease Models & Mechanisms Jessica P. Otis; Erin M. Zeituni; James H. Thierer; Jennifer L. Anderson; Alexandria C. Brown; Erica D. Boehm; Derek M. Cerchione; Alexis M. Ceasrine; Inbal Avraham-Davidi; Hanoch Tempelhof; Karina Yaniv; Steven A. Farber
Development and origins of Zebrafish ocular vasculature BMC Developmental Biology Rivka Kaufman; Omri Weiss; Meyrav Sebbagh; Revital Ravid; Liron Gibbs-Bar; Karina Yaniv; Adi Inbal
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Simultaneous Raman Microspectroscopy and Fluorescence Imaging of Bone Mineralization in Living Zebrafish Larvae Biophysical Journal M. Bennet; Anat Akiva; D. Faivre; Guy Malkinson; Karina Yaniv; S. Abdelilah-Seyfried; P. Fratzl; A. Masic
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Lipid signaling in the endothelium Experimental Cell Research Inbal Avraham-Davidi; Moshe Grunspan; Karina Yaniv
Zebrafish as a Model for Monocarboxyl Transporter 8-Deficiency Journal of Biological Chemistry Gad David Vatine; David Zada; Tali Lerer-Goldshtein; Adi Tovin; Guy Malkinson; Karina Yaniv; Lior Appelbaum
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S1P(1) inhibits sprouting angiogenesis during vascular development Development Shoham, Adi Ben Shoham; Guy Malkinson; Sharon Krief; Yulia Shwartz; Yona Ely; Napoleone Ferrara; Karina Yaniv; Elazar Zelzer
ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1 Nature Medicine Karina Yaniv; Inbal Avraham-Davidi; Yona Ely; Van N. Pham; Daniel Castranova; Moshe Grunspan; Guy Malkinson; Liron Gibbs-Bar; Oded Mayseless; Gabriella Allmog; Brigid Lo; Carmen M. Warren; Tom T. Chen; Josette Ungos; Kameha Kidd; Kenna Shaw; Ilana Rogachev; Wuzhou Wan; Philip M. Murphy; Steven A. Farber
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Motoneurons are essential for vascular pathfinding Development Amy H. Lim; Arminda Suli; Karina Yaniv; Brant Weinstein; Dean Y. Li; Chi-Bin Chien
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Zebrafish as a new animal model to study lymphangiogenesis Anatomical Science International Sumio Isogai; Jiro Hitomi; Karina Yaniv; Brant M. Weinstein
Endothelial cells promote migration and proliferation of enteric neural crest cells via beta 1 integrin signaling Developmental Biology Nandor Nagy; Olive Mwizerwa; Karina Yaniv; Liran Carmel; Rafael Pieretti-Vanmarcke; Brant M. Weinstein; Allan M. Goldstein
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Live imaging of lymphatic development in the zebralish embryo FASEB Journal Karina Yaniv; Sumio Isogai; Daniel Castranova; Brant M. Weinstein
Imaging the developing lymphatic system using the zebrafish. Novartis Foundation Symposium Karina Yaniv; Sumio Isogai; Daniel Castranova; Louis Dye; Jiro Hitomi; Brant M Weinstein
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Live imaging of lymphatic development in the zebrafish Nature Medicine Karina Yaniv; S Isogai; D Castranova; L Dye; J Hitomi; BM Weinstein