Recent advances in cell culture studies provide invaluable insights on how the endothelial lineage is modulated by diverse signaling pathways. However, the cellular and molecular mechanisms that regulate the initial specification of endothelial lineage within developing embryos are largely unknown. To delineate the developmental origin of the endothelial lineage, we previously generated a laser assisted single-cell resolution fate map in the most ventral region of zebrafish gastrula that provided the first detailed distribution pattern of the hemangioblast, a hypothetical common precursor for both endothelial and hematopoietic lineages. Additionally, in our previous study, we found that hemangioblasts only produce a subset of the endothelial lineage, while the majority originates from endothelial specific progenitors, indicating the heterogeneous developmental origin of endothelial lineage. Our recent observation that avascular mutant embryos recover from their initial lack of endothelial cells later in development, further supports this idea, and suggests that the progenitors of the endothelial lineage consist of spatially and temporally distinct subpopulations. In this proposal, by using a multifaceted approach, we plan to delineate the heterogeneity of endothelial progenitors, and elucidate how distinct subpopulations of endothelial progenitors respond differently to Wnt signaling, which, based on our preliminary data, appears to be a key modulator of endothelial lineage specification.
Three specific aims are designed to achieve these goals. First, we will expand our single-cell resolution fate map analyses to test whether hemangioblasts exist in other areas of the gastrula. This approach will also determine the embryo-wide distribution patterns of progenitors with endothelial potential, and will allow us to identify subpopulations of endothelial progenitors with distinct developmental potentials. In the second aim, we plan to define the cellular origin of endothelial cells involved in the vascular recovery of avascular mutant embryos. The analyses on two of previously isolated avascular zebrafish mutants will identify subpopulations of progenitors that generate endothelial lineages in a temporally distinctive manner. Lastly, we will examine whether subpopulations of endothelial progenitors respond differently to Wnt signaling by using transgenic lines that are capable of manipulating the time and place of Wnt activity. Understanding the developmental heterogeneity of the endothelial lineage will provide invaluable insights on how endothelial lineage is established during development. In addition, the proposed research will enhance our knowledge on how distinct cell types emerge from pluripotent progenitors during development. Furthermore, the proposed research may provide essential groundwork for the therapeutic application of pluripotent progenitors with the ability to ameliorate clinical conditions affecting the circulatory system in humans.
. The proposed research aims to understand how endothelial cells emerge during development from progenitors. Information acquired from the proposed research will enhance our current knowledge on the mechanisms that regulate the differentiation of pluripotent progenitors (for example, stem cells) into specific cell types. Furthermore, it will also help us to understand the etiology of many vascular diseases and design a better way of using pluripotent progenitors for the therapeutic purposes.
|So, Ju-Hoon; Kim, Jun-Dae; Yoo, Kyeong-Won et al. (2014) FIH-1, a novel interactor of mindbomb, functions as an essential anti-angiogenic factor during zebrafish vascular development. PLoS One 9:e109517|
|Kim, Jun-Dae; Lee, Heon-Woo; Jin, Suk-Won (2014) Diversity is in my veins: role of bone morphogenetic protein signaling during venous morphogenesis in zebrafish illustrates the heterogeneity within endothelial cells. Arterioscler Thromb Vasc Biol 34:1838-45|
|Kim, Jun-Dae; Jin, Suk-Won (2014) A tale of two models: mouse and zebrafish as complementary models for lymphatic studies. Mol Cells 37:503-10|
|Dunworth, William P; Cardona-Costa, Jose; Bozkulak, Esra Cagavi et al. (2014) Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ Res 114:56-66|
|Kim, Jun-Dae; Kang, Yujung; Kim, Jongmin et al. (2014) Essential role of Apelin signaling during lymphatic development in zebrafish. Arterioscler Thromb Vasc Biol 34:338-45|
|Kang, Yujung; Kim, Jongmin; Anderson, Joshua P et al. (2013) Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development. Circ Res 113:22-31|
|Schmitt, Christopher E; Woolls, Melissa J; Jin, Suk-Won (2013) Mutant-specific gene expression profiling identifies SRY-related HMG box 11b (SOX11b) as a novel regulator of vascular development in zebrafish. Mol Cells 35:166-72|
|Kim, Se-Hee; Schmitt, Christopher E; Woolls, Melissa J et al. (2013) Vascular endothelial growth factor signaling regulates the segregation of artery and vein via ERK activity during vascular development. Biochem Biophys Res Commun 430:1212-6|
|Wiley, David M; Kim, Jun-Dae; Hao, Jijun et al. (2011) Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol 13:686-92|
|Lee, Christina Y; Vogeli, Kevin M; Kim, Se-Hee et al. (2009) Notch signaling functions as a cell-fate switch between the endothelial and hematopoietic lineages. Curr Biol 19:1616-22|