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Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1.

ABSTRACT: During angiogenesis, single endothelial cells (EC) specialize into tip cells that guide vessel sprouting towards growth factor gradients and instruct the adjacent vessel stalk. The balance between tip and stalk cells is regulated by endothelial Notch signalling through the expression of Notch ligand Delta-like 4 (Dll4) in tip cells, which suppresses a tip cell fate in adjacent stalk cells. Here we show, using genetic reporter and conditional deletion strategies, that myeloid cells regulate tip cell numbers and Dll4 expression via the Notch ligand Dll1 during vascular development in the retina. Dll1 is selectively expressed by a subpopulation of retinal myeloid cells, which progressively localizes to the sprouting vascular network. Conditional, myeloid-specific deletion of Dll1 impairs endothelial Dll4 tip-stalk gradient resulting in an increase of endothelial tip cells and EC filopodia, accompanied by an increase in vascular density and branching. In vitro, co-culture of human EC with monocyte-derived macrophages induced Dll1 upregulation in macrophages and Dll4 upregulation and an endothelial tip cell signature in EC. Furthermore, culturing human EC on recombinant DLL1 induced endothelial Dll4 expression and a tip cell program, indicating that changes are Dll1-dependent. Thus, myeloid cells regulate tip cell fate and angiogenesis through expression of Notch ligand Dll1.

SUBMITTER: Haupt F

PROVIDER: S-EPMC6611798 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1.

Haupt Fabian F Krishnasamy Kashyap K Napp L Christian LC Augustynik Michael M Limbourg Anne A Gamrekelashvili Jaba J Bauersachs Johann J Haller Hermann H Limbourg Florian P FP

Scientific reports 20190705 1

During angiogenesis, single endothelial cells (EC) specialize into tip cells that guide vessel sprouting towards growth factor gradients and instruct the adjacent vessel stalk. The balance between tip and stalk cells is regulated by endothelial Notch signalling through the expression of Notch ligand Delta-like 4 (Dll4) in tip cells, which suppresses a tip cell fate in adjacent stalk cells. Here we show, using genetic reporter and conditional deletion strategies, that myeloid cells regulate tip c ...[more]

PMID: 31278348

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Project description:Recent experimental work in lung morphogenesis has described an elegant pattern of branching phenomena. Two primary forms of branching have been identified: side branching and tip splitting. In our previous study of lung branching morphogenesis, we used a 4 variable partial differential equation (PDE), due to Meinhardt, as our mathematical model to describe the reaction and diffusion of morphogens creating those branched patterns. By altering key parameters in the model, we were able to reproduce all the branching styles and the switch between branching modes. Here, we attempt to explain the branching phenomena described above, as growing out of two fundamental instabilities, one in the longitudinal (growth) direction and the other in the transverse direction. We begin by decoupling the original branching process into two semi-independent sub-processes, 1) a classic activator/inhibitor system along the growing stalk, and 2) the spatial growth of the stalk. We then reduced the full branching model into an activator/inhibitor model that embeds growth of the stalk as a controllable parameter, to explore the mechanisms that determine different branching patterns. We found that, in this model, 1) side branching results from a pattern-formation instability of the activator/inhibitor subsystem in the longitudinal direction. This instability is far from equilibrium, requiring a large inhomogeneity in the initial conditions. It successively creates periodic activator peaks along the growing stalk, each of which later on migrates out and forms a side branch; 2) tip splitting is due to a Turing-style instability along the transversal direction, that creates the spatial splitting of the activator peak into 2 simultaneously-formed peaks at the growing tip, the occurrence of which requires the widening of the growing stalk. Tip splitting is abolished when transversal stalk widening is prevented; 3) when both instabilities are satisfied, tip bifurcation occurs together with side branching.

Dataset Information

Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1.

Publications

Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1.

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