Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis

AbstractHow do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms utilize feedback between movement and sensing known as ‘sensorimotor coordination’ or ‘active perception’ to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept in silico/in vivo study demonstrating that filopodia (actin-rich, dynamic, finger like cell-membrane protrusions) play an unexpected role in speeding up collective endothelial decisions during the time-constrained process of ‘tip cell’ selection during blood vessel formation (angiogenesis).We first validate simulation predictions in vivo with live imaging of zebrafish intersegmental vessel growth. Further simulation studies then indicate the effect is due to the coupled positive feedback between movement and sensing on filopodia conferring a bistable switch-like property to Notch lateral inhibition, ensuring tip selection is a rapid and robust process. We then employ measures from computational neuroscience to assess whether filopodia function as a primitive (‘basal’) form of active perception and find evidence in support. By viewing cell behaviour in tissues through the ‘basal cognitive lens’ we acquire a fresh perspective on not only the well-studied tip cell selection process, revealing a hidden, yet vital, time-keeping role for filopodia, but on how to interpret and understand cell behaviour in general, opening up a myriad of new and exciting research directions.

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Agent-based simulation of notch-mediated tip cell selection in angiogenic sprout initialisation

Journal of Theoretical Biology ◽

10.1016/j.jtbi.2007.09.015 ◽

2008 ◽

Vol 250 (1) ◽

pp. 25-36 ◽

Cited By ~ 153

Author(s):

Katie Bentley ◽

Holger Gerhardt ◽

Paul A. Bates

Keyword(s):

Cell Selection ◽

Agent Based Simulation ◽

Agent Based ◽

Tip Cell

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Temporal modulation of collective cell behavior controls vascular network topology

eLife ◽

10.7554/elife.13212 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 13

Author(s):

Esther Kur ◽

Jiha Kim ◽

Aleksandra Tata ◽

Cesar H Comin ◽

Kyle I Harrington ◽

...

Keyword(s):

Feedback Loop ◽

Network Formation ◽

Vascular Network ◽

General Mechanism ◽

Network Density ◽

Vascular Density ◽

Cell Selection ◽

Temporal Regulation ◽

Tip Cell

Vascular network density determines the amount of oxygen and nutrients delivered to host tissues, but how the vast diversity of densities is generated is unknown. Reiterations of endothelial-tip-cell selection, sprout extension and anastomosis are the basis for vascular network generation, a process governed by the VEGF/Notch feedback loop. Here, we find that temporal regulation of this feedback loop, a previously unexplored dimension, is the key mechanism to determine vascular density. Iterating between computational modeling and in vivo live imaging, we demonstrate that the rate of tip-cell selection determines the length of linear sprout extension at the expense of branching, dictating network density. We provide the first example of a host tissue-derived signal (Semaphorin3E-Plexin-D1) that accelerates tip cell selection rate, yielding a dense network. We propose that temporal regulation of this critical, iterative aspect of network formation could be a general mechanism, and additional temporal regulators may exist to sculpt vascular topology.

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Extrinsic Notch Ligand Delta-Like 1 Regulates Tip Cell Selection and Vascular Branching Morphogenesis

Circulation Research ◽

10.1161/circresaha.111.263319 ◽

2012 ◽

Vol 110 (4) ◽

pp. 530-535 ◽

Cited By ~ 28

Author(s):

L.C. Napp ◽

M. Augustynik ◽

F. Paesler ◽

K. Krishnasamy ◽

J. Woiterski ◽

...

Keyword(s):

Branching Morphogenesis ◽

Cell Selection ◽

Notch Ligand ◽

Tip Cell ◽

Vascular Branching

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Active perception during angiogenesis: filopodia speed up Notch selection of tip cells in silico and in vivo

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0753 ◽

2021 ◽

Vol 376 (1821) ◽

pp. 20190753 ◽

Cited By ~ 2

Author(s):

Bahti Zakirov ◽

Georgios Charalambous ◽

Raphael Thuret ◽

Irene M. Aspalter ◽

Kelvin Van-Vuuren ◽

...

Keyword(s):

In Silico ◽

Selection Process ◽

Cellular Level ◽

Cell Selection ◽

Active Perception ◽

Conceptual Approach ◽

Bistable Switch ◽

Cell Behaviour ◽

Tip Cell

How do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms use feedback between movement and sensing known as ‘sensorimotor coordination’ or ‘active perception’ to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept in silico / in vivo study demonstrating that filopodia (actin-rich, dynamic, finger-like cell membrane protrusions) play an unexpected role in speeding up collective endothelial decisions during the time-constrained process of ‘tip cell’ selection during blood vessel formation (angiogenesis). We first validate simulation predictions in vivo with live imaging of zebrafish intersegmental vessel growth. Further simulation studies then indicate the effect is due to the coupled positive feedback between movement and sensing on filopodia conferring a bistable switch-like property to Notch lateral inhibition, ensuring tip selection is a rapid and robust process. We then employ measures from computational neuroscience to assess whether filopodia function as a primitive (basal) form of active perception and find evidence in support. By viewing cell behaviour through the ‘basal cognitive lens' we acquire a fresh perspective on the tip cell selection process, revealing a hidden, yet vital time-keeping role for filopodia. Finally, we discuss a myriad of new and exciting research directions stemming from our conceptual approach to interpreting cell behaviour. This article is part of the theme issue ‘Basal cognition: multicellularity, neurons and the cognitive lens’.

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A VEGF reaction-diffusion mechanism that selects variable densities of endothelial tip cells

10.1101/624999 ◽

2019 ◽

Author(s):

W. Bedell ◽

A. D. Stroock

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Production Rate ◽

Cell Selection ◽

Vascular Endothelial ◽

Tip Cell ◽

Hypothetical Mechanism ◽

Endothelial Growth Factor ◽

Tip Cells

AbstractThe patterned differentiation of endothelial cells into tip and stalk cells represents an important step in the process of angiogenic sprouting. Vascular biologists hypothesize that changes in the density and overall structure of the vasculature can be traced in part to changes in the number of tip cells selected in the endothelium prior to sprout formation. However, the dominant hypotheses for tip cell selection invoke lateral inhibition via Notch; this juxtacrine mechanism predicts that a fixed fraction of endothelial cells become tip cells through a pattern-forming instability. Here, we present and analyze a hypothetical mechanism for tip cell selection that is based on endothelial competition for diffusible vascular endothelial growth factor (VEGF); this mechanism predicts that variable densities of tip cells emerge depending on the local (paracrine) production rate of VEGF. First, we hypothesize a network of VEGF signaling and trafficking based on previous experimental findings that could allow internalization of VEGF to occur with positive feedback. We formalize the hypothesis into a set of nonlinear ordinary differential equations and perform linear stability analysis to elucidate a general criterion for tip cell pattern formation under the mechanism. We use numerical integration to explore the nonlinear dynamics and final steady-states of tip cell patterns under this mechanism; the observed density of tip cells can be tuned from 10% to 84%. We conclude with proposals of future experiments and computational studies to explore how competitive consumption of diffusible VEGF may play a role in determining vascular structure.Statement of SignificanceThe patterned differentiation of endothelial cells into tip and stalk cells represents an important step in the process of blood vessel growth. Vascular biologists hypothesize that changes in the density and overall structure of the vasculature can be traced in part to changes in the number of tip cells selected during angiogenesis. However, the dominant hypotheses for tip cell selection predict that a locally fixed fraction of endothelial cells become tip cells following stimulation by vascular endothelial growth factor (VEGF). Here, we present and analyze a hypothetical mechanism for tip cell selection based on endothelial competition for diffusible VEGF; this mechanism predicts that variable densities of tip cells emerge depending on the local production rate of VEGF.

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