scholarly journals AIBP-CAV1-VEGFR3 axis dictates lymphatic cell fate and controls lymphangiogenesis

2021 ◽  
Author(s):  
Xiaojie Yang ◽  
Jun-dae Kim ◽  
Kelvin Chan ◽  
Qilin Gu ◽  
Jonathan Astin ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Cell Fate ◽  
Cholesterol Efflux ◽  
Cell Function ◽  
Secreted Protein ◽  
Tissue Fluid ◽  
Fate Specification ◽  
Adult Mice ◽  
Dependent Inhibition ◽  
Lymphatic Cell

Abstract The lymphatics control tissue fluid homeostasis; its dysfunction contributes to lymphedema. VEGFR3 signaling dictates LEC fate specification and lymphangiogenesis. Cholesterol is essential for cell function and organ development, yet the molecular mechanism by which cholesterol controls lymphangiogenesis is unknown. Here, we show that APOA1 binding protein (AIBP), a secreted protein, enhances LEC specification and increases lymphangiogenesis. Mechanistically, AIBP-mediated cholesterol efflux disrupts LEC caveolae, which abolishes CAV-1-dependent inhibition of VEGFR3 signaling. Loss of Aibp2, the zebrafish paralog of human AIBP, reduces LEC progenitors and impairs lymphangiogenesis; the impairment can be rescued by caveolae disruption. CAV-1 mutant that is deficient in VEGFR3 binding, thereby abolishing its inhibition, enhances VEGFR3 signaling and accelerates lymphatic growth. Furthermore, AIBP expression is reduced in the epidermis of human lymphedema. Administrating recombinant AIBP augments VEGFC-induced lymphangiogenesis and increases secondary tail lymphedema resolution in adult mice. Our studies reveal AIBP and CAV-1 as critical regulators of VEGFR3 signaling and identify previously unidentified therapeutic targets for lymphedema treatment.  

scholarly journals Lymphatic Endothelial Cell Plasticity in Development and Disease

Physiology ◽  
2017 ◽  
Vol 32 (6) ◽  
pp. 444-452 ◽  
Author(s):  
Wanshu Ma ◽  
Guillermo Oliver
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Lymphatic Endothelial Cell ◽  
Lipid Absorption ◽  
Tissue Fluid ◽  
Mammalian Embryo ◽  
Fate Specification ◽  
Lymphatic Vasculature ◽  
Functional Features

The lymphatic vasculature is crucial for maintaining tissue-fluid homeostasis, providing immune surveillance and mediating lipid absorption. The lymphatic vasculature is tightly associated with the blood vasculature, although it exhibits distinct morphological and functional features. Endothelial cells (ECs) lineage fate specification is determined during embryonic development; however, accumulating evidence suggests that differentiated ECs exhibit remarkable heterogeneity and plasticity. In this review, we provide an overview of the molecular mechanisms promoting lymphatic cell fate specification in the mammalian embryo. We also summarize available data suggesting that lymphatic EC fate is reprogrammable in normal and pathological settings. We further discuss the possible advantages of cell fate manipulation to treat certain disorders associated with lymphatic dysfunction.

scholarly journals AIBP-CAV1-VEGFR3 axis dictates lymphatic cell fate and controls lymphangiogenesis

2020 ◽  
Author(s):  
Xiaojie Yang ◽  
Jun-dae Kim ◽  
Qilin Gu ◽  
Qing Yan ◽  
Jonathan Astin ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cholesterol Efflux ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Embryonic Stem ◽  
Lymphatic Endothelial Cell ◽  
Tissue Fluid ◽  
Cell Functions ◽  
Signaling Axis ◽  
And Migration

AbstractThe lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions.One Sentence SummaryOur studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.

scholarly journals Divergence of zebrafish and mouse lymphatic cell fate specification pathways

Development ◽  
2014 ◽  
Vol 141 (6) ◽  
pp. 1228-1238 ◽  
Author(s):  
A. van Impel ◽  
Z. Zhao ◽  
D. M. A. Hermkens ◽  
M. G. Roukens ◽  
J. C. Fischer ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
Lymphatic Cell

Sox proteins: regulators of cell fate specification and differentiation

Development ◽  
2013 ◽  
Vol 140 (20) ◽  
pp. 4129-4144 ◽  
Author(s):  
Y. Kamachi ◽  
H. Kondoh
Keyword(s):  
Cell Fate ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
Sox Proteins

scholarly journals NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lindsey Seldin ◽  
Andrew Muroyama ◽  
Terry Lechler
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Cell Types ◽  
Epidermal Differentiation ◽  
Spindle Orientation ◽  
Direct Function ◽  
Spindle Positioning ◽  
Adult Mice ◽  
Neonatal Lethality ◽  
The Matrix

Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA’s MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures.

scholarly journals Gene-free methodology for cell fate dynamics during development

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Francis Corson ◽  
Eric D Siggia
Keyword(s):  
Cell Fate ◽  
Cell Function ◽  
Geometric Model ◽  
Model Fit ◽  
Vulval Development ◽  
Epistatic Interactions ◽  
Compact Representations ◽  
Special Points ◽  
Unexpected Outcomes

Models of cell function that assign a variable to each gene frequently lead to systems of equations with many parameters whose behavior is obscure. Geometric models reduce dynamics to intuitive pictorial elements that provide compact representations for sparse in vivo data and transparent descriptions of developmental transitions. To illustrate, a geometric model fit to vulval development in Caenorhabditis elegans, implies a phase diagram where cell-fate choices are displayed in a plane defined by EGF and Notch signaling levels. This diagram defines allowable and forbidden cell-fate transitions as EGF or Notch levels change, and explains surprising observations previously attributed to context-dependent action of these signals. The diagram also reveals the existence of special points at which minor changes in signal levels lead to strong epistatic interactions between EGF and Notch. Our model correctly predicts experiments near these points and suggests specific timed perturbations in signals that can lead to additional unexpected outcomes.

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