Karina Yaniv

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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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

Research

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

 

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.

 

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

 

 

 

Publications

2022
Title Journal Authors Download PDF
Generation of specialized blood vessels via lymphatic transdifferentiation Nature (London) Das R. N., Tevet Y., Safriel S., Han Y., Moshe N., Lambiase G., Bassi I., Nicenboim J., Brückner M., Hirsch D., Eilam-Altstadter R., Herzog W., Avraham R., Poss K. D. & Yaniv K.
How many fish make a mouse? Nature cardiovascluar research Tzahor E. & Yaniv K.
2021
Title Journal Authors Download PDF
Zebrafish mutants provide insights into Apolipoprotein B functions during embryonic development and pathological conditions JCI insight Templehof H., Moshe N., Avraham-Davidi I. & Yaniv K.
VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells Cell reports (Cambridge) Jerafi-Vider A., Bassi I., Moshe N., Tevet Y., Hen G., Splittstoesser D., Shin M., Lawson N. D. & Yaniv K.
Generation of specialized blood vessels through transdifferentiation of lymphatic endothelial cells BioRxiv Das R. N., Bassi I., Han Y., Lambiase G., Tevet Y., Moshe N., Safriel S. R., Nicenboim J., Brückner M., Hirsch D., Eilam-Altstadter R., Herzog W., Poss K. D. & Yaniv K.
Beyond cells: The extracellular circulating 20S proteasomes Biochimica et Biophysica Acta - Molecular Basis of Disease Dwivedi V., Yaniv K. & Sharon M.
2020
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Discovering New Progenitor Cell Populations through Lineage Tracing and In Vivo Imaging Cold Spring Harbor perspectives in biology Das R. N. & Yaniv K.
Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis: Implications for Cancer Lymphangiogenesis Frontiers in Physiology Gutierrez-Miranda L. & Yaniv K.
Formation and Growth of Cardiac Lymphatics during Embryonic Development, Heart Regeneration, and Disease Cold Spring Harbor perspectives in biology Gancz D., Perlmoter G. & Yaniv K.
BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression Life Science Alliance Cohen B., Tempelhof H., Raz T., Oren R., Nicenboim J., Bochner F., Even R., Jelinski A., Eilam R., Ben-Dor S., Adaddi Y., Golani O., Lazar S., Yaniv K. & Neeman M.
2019
Title Journal Authors Download PDF
Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration eLife Gancz D., Raftrey B. C., Perlmoter G., Marin-Juez R., Semo J., Matsuoka R. L., Karra R., Raviv H., Moshe N., Addadi Y., Golani O., Poss K. D., Red-Horse K., Stainier D. Y. R. & Yaniv K.
Transient p53-Mediated Regenerative Senescence in the Injured Heart Circulation Sarig R., Rimmer R., Bassat E., Zhang L., Umansky K. B., Lendengolts D., Perlmoter G., Yaniv K. & Tzahor E.
Intercellular pathways from the vasculature to the forming bone in the zebrafish larval caudal fin: Possible role in bone formation Journal of Structural Biology Akiva A., Nelkenbaum O., Schertel A., Yaniv K., Weiner S. & Addadi L.
2018
Title Journal Authors Download PDF
Somatic NRAS mutation in patient with generalized lymphatic anomaly Angiogenesis Manevitz-Mendelson E., Leichner G. S., Barel O., Davidi-Avrahami I., Ziv-Strasser L., Eyal E., Pessach I., Rimon U., Barzilai A., Hirshberg A., Chechekes K., Amariglio N., Rechavi G., Yaniv K. & Greenberger S.
2017
Title Journal Authors Download PDF
Zebrafish skeleton development: High resolution micro-CT and FIB-SEM block surface serial imaging for phenotype identification PLoS ONE Silvent J., Akiva A., Brumfeld V., Reznikov N., Rechav K., Yaniv K., Addadi L. & Weiner S.
2016
Title Journal Authors Download PDF
Mineral Formation in the Larval Zebrafish Tail Bone Occurs via an Acidic Disordered Calcium Phosphate Phase Journal of the American Chemical Society Akiva A., Kerschnitzki M., Pinkas I., Wagermaier W., Yaniv K., Fratzl P., Addadi L. & Weiner S.
A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2 BMC Biology Peretz Y., Eren N., Kohl A., Hen G., Yaniv K., Weisinger K., Cinnamon Y. & Sela-Donenfeld D.
The mid-developmental transition and the evolution of animal body plans Nature Levin M., Anavy L., Cole A., Winter E., Mostov N., Khair S., Senderovich N., Kovalev E., Silver D., Feder M., Fernandez-Valverde S., Nakanishi N., Simmons D., Simakov O., Larsson T., Liu S., Jerafi-Vider A., Yaniv K., Ryan J., Martindale M., Rink J., Arendt D., Degnan S., Degnan B., Hashimshony T. & Yanai I.
Development of the lymphatic system: new questions and paradigms Development Semo J., Nicenboim J. & Yaniv K.
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.
2015
Title Journal Authors Download PDF
Venous-derived angioblasts generate organ-specific vessels during zebrafish embryonic development Development Hen G., Nicenboim J., Mayseless O., Asaf L., Shin M., Busolin G., Hofi R., Almog G., Tiso N., Lawson N. D. & Yaniv K.
Lymphatic vessels arise from specialized angioblasts within a venous niche Nature Nicenboim J., Malkinson G., Lupo T., Asaf L., Sela Y., Mayseless O., Gibbs-Bar L., Senderovich N., Hashimshony T., Shin M. S., Jerafi-Vider A., Avraham-Davidi I., Krupalnik V., Hofi R., Almog G., Astin J. W., Golani O., Ben-Dor S., Crosier P. S., Herzog W., Lawson N. D., Hanna J. H., Yanai I. & Yaniv K.
On the pathway of mineral deposition in larval zebrafish caudal fin bone Bone Akiva A., Malkinson G., Masic A., Kerschnitzki M., Bennet M., Fratzl P., Addadi L., Weiner S. & Yaniv K.
Development and origins of zebrafish ocular vasculature BMC Developmental Biology Kaufman R., Weiss O., Sebbagh M., Ravid R., Gibbs-Bar L., Yaniv K. & Inbal A.
Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake Disease Models & Mechanisms Otis J. P., Zeituni E. M., Thierer J. H., Anderson J. L., Brown A. C., Boehm E. D., Cerchione D. M., Ceasrine A. M., Avraham-Davidi I., Tempelhof H., Yaniv K. & Farber S. A.
2014
Title Journal Authors Download PDF
Simultaneous Raman Microspectroscopy and Fluorescence Imaging of Bone Mineralization in Living Zebrafish Larvae Biophysical Journal Bennet M., Akiva A., Faivre D., Malkinson G., Yaniv K., Abdelilah-Seyfried S., Fratzl P. & Masic A.
2013
Title Journal Authors Download PDF
Lipid signaling in the endothelium Experimental Cell Research Avraham-Davidi I., Grunspan M. & Yaniv K.
Zebrafish as a Model for Monocarboxyl Transporter 8-Deficiency Journal of Biological Chemistry Vatine G. D., Zada D., Lerer-Goldshtein T., Tovin A., Malkinson G., Yaniv K. & Appelbaum L.
2012
Title Journal Authors Download PDF
S1P(1) inhibits sprouting angiogenesis during vascular development Development Ben Shoham S. A., Malkinson G., Krief S., Shwartz Y., Ely Y., Ferrara N., Yaniv K. & Zelzer E.
ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1 Nature Medicine Yaniv K., Avraham-Davidi I., Ely Y., Pham V. N., Castranova D., Grunspan M., Malkinson G., Gibbs-Bar L., Mayseless O., Allmog G., Lo B., Warren C. M., Chen T. T., Ungos J., Kidd K., Shaw K., Rogachev I., Wan W., Murphy P. M. & Farber S. A.
2011
Title Journal Authors Download PDF
Motoneurons are essential for vascular pathfinding Development Lim A. H., Suli A., Yaniv K., Weinstein B., Li D. Y. & Chien C.
2009
Title Journal Authors Download PDF
Zebrafish as a new animal model to study lymphangiogenesis Anatomical Science International Isogai S., Hitomi J., Yaniv K. & Weinstein B. M.
Endothelial cells promote migration and proliferation of enteric neural crest cells via beta 1 integrin signaling Developmental Biology Nagy N., Mwizerwa O., Yaniv K., Carmel L., Pieretti-Vanmarcke R., Weinstein B. M. & Goldstein A. M.
2007
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Live imaging of lymphatic development in the zebralish embryo FASEB Journal Yaniv K., Isogai S., Castranova D. & Weinstein B. M.
Imaging the developing lymphatic system using the zebrafish. Yaniv K., Isogai S., Castranova D., Dye L., Hitomi J. & Weinstein B. M.
2006
Title Journal Authors Download PDF
Live imaging of lymphatic development in the zebrafish Nature Medicine Yaniv K., Isogai S., Castranova D., Dye L., Hitomi J. & Weinstein B.

Group

Ayelet Vider

Years: 2011-2018
Degree studied in the lab: M.Sc, Ph.D. student

 

Yona Eli

Years: 2010-2018
Lab manager

Hanoch Tempelhof

Years: 2011-2018
Degree studied in the lab: M.Sc, Ph.D. student

Julian Nicenboim

Years: 2010-2017
Degree studied in the lab: M.Sc, Ph.D. student

Dr. Gideon Hen

Years: 2011-2014
Degree studied in the lab: Postdoctoral Fellow

Moshe Grunspan

Years: 2011-2016
Degree studied in the lab: Ph.D. student

Dr. Yogev Sela

Years: 2011-2016
Degree studied in the lab: Postdoctoral Fellow

Liron Gibbs Bar

Years: 2010-2015
Degree studied in the lab: Ph.D. student

Dr. Inbal Avraham-Davidi

Years: 2010-2015
Degree studied in the lab: Postdoctoral Fellow

Tal Lupo

Years: 2012-2015
Degree studied in the lab: M.Sc Student

Oded Mayseless

Years: 2010-2014
Degree studied in the lab: M.Sc Student

Dr. Guy Malkinson

Years: 2010-2014
Degree studied in the lab: Postdoctoral Fellow

Neta Strasser

Years: 2010-2013
Degree studied in the lab: M.Sc Student

 

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Join us

We are always seeking enthusiastic PhD students and postdoctoral fellows.

Excellent candidates are welcome to apply!

Contact Us

Dr. Karina Yaniv, Principal Investigator

 

Faculty Of Biology
Department of Immunology and Regenerative Biology
Max and Lillian Candiotty Building, Room 210
Weizmann Institute of Science
Rehovot 76100, ISRAEL
 

karina.yaniv@weizmann.ac.il

Phone: +972-(0)8-9342224