Mechanisms of blood vessel formation

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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Mechanisms of blood vessel formation

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.

 

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Angiogenesis related diseases⠀⠀

Lymphatic transdifferentiation and specialized vasculature

The anal fin (AF), a bony locomotory organ that is established during metamorphosis. As it develops, it attracts rapid vascularization by secondary vessels—a specialized blood vessel type. Although extensive research has been devoted to understanding the physiology of this blood vessel type, its origins, molecular features and specialization mechanisms remained unclear.
Using recurrent imaging and lineage-tracing of ECs in the zebrafish anal fins, from early development to adulthood, we uncovered a new mechanism of specialized blood vessel formation through the transdifferentiation of lymphatic endothelial cells. We also used single-cell RNA-sequencing analysis to characterize the different cellular populations and transition states involved in the transdifferentiation process. Finally, we also showed that, similar to normal development, the vasculature is rederived from lymphatics during anal-fin regeneration, demonstrating that LECs in adult fish retain both potency and plasticity for generating blood ECs. Overall, our research highlights an innate mechanism of blood vessel formation through LEC transdifferentiation, and provides in vivo evidence for a link between cell ontogeny and functionality in ECs.
Currently, we are investigating the molecular mechanisms that underlie the transdifferentiation process. We are also using single-cell RNA-sequencing analysis to understand the differences between lymphatic-derived blood vessels and vessels that are derived from pre-existing blood vessels.

 

  

Neurovascular development

Neurovascular development is the parallel emergence and patterning of the central nervous system (CNS) and the vascular system during embryogenesis. During this process the association and interaction of the different cells from the brain microenvironment (endothelial cells, pericytes, glia, neurons and microglia) results in an organized and functional structure known as neurovascular unit (NVU). Several studies conducted have demonstrated that these same cells are evolutionarily conserved in zebrafish.
In this project we want to take advantage of zebrafish characteristics of external fertilization, optical clarity and genetic manipulation for studying in vivo the mechanisms that regulate the formation and functionality of the brain vasculature during embryonic development and pathological conditions.

 

  

Suppression of transcytosis activity across the blood brain barrier in zebrafish

In the project we are trying to find out what are the mechanisms for the suppressed transcytosis in the BBB using transgenic zebrafish lines which label specific cell types of the neurovascularunit such blood vessels, astrocytes, pericytes, neurons, glia and microglia

 

 

 

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Full description 

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.