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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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The Yaniv Lab, focuses on understanding the mechanisms controlling blood and lymphatic vessel formation during embryonic development and pathological conditions. Above 20 million people die every year from CVDs, representing 30 percent of all global deaths. Today it is widely accepted that many of the genes activated during pathological angiogenesis and lymphangiogenesis are the same ones that play major roles in developmental vessel formation. Therefore, studies as those carried out in our laboratory have tremendous potential clinical relevance, and may unearth novel medically useful molecules.

Karina Yaniv
Karina Yaniv