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

Abstract

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’.

Reframing cognition: getting down to biological basics

“…There is so much we don't know, especially about the evolution of cognition. At the same time, interesting behaviour is being discovered in a wide variety of aneural organisms, simple neural organisms and even in aneural tissue, for example, the formation of blood vessels (see [34] in Part 2). New findings appear almost weekly in a wide variety of disparate journals that until now have had a limited impact beyond their individual fields of study, for example, microbiology, zoology, botany, biophysics, developmental biology, neurobiology, regenerative medicine, computational biology, immunology, artificial life, synthetic bioengineering, animal behaviour and cognitive science.…”

“…). ( o ) A blood vessel sprout grows in the zebrafish ( Danio rerio ) embryo, where long, thin projections (filopodia) speed up collective cell decisions based on ‘active perception’—sensorimotor feedback as they move [34]. (Image: Cellular Adaptive Behaviour Lab, Francis Crick Institute, London, UK.…”

Uncovering cognitive similarities and differences, conservation and innovation

“…class of cells (neurons) to a variety of important fundamental concepts that are proving their capacity to enlighten diverse fields, such as (but not limited to) regenerative biology (see Bentley group's article on angiogenesis, this issue [5]). A key philosophical idea, borrowed from computer science, is substrate independence: as long as the components of a living system can carry out appropriate, clearly specified cognitive functions, deep ideas can be readily ported from neuroscience and applied to diverse-including, as articles in this issue demonstrate, non-neural-implementations Figure 1.…”

Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting

“…Computational models simulating the crosstalk between VEGF and Notch signaling have contributed to our understanding of angiogenesis. Simulations from agent-based models have resulted in a wide range of experimentally validated predictions of sprouting angiogenesis, highlighting the strongly dynamic nature of the tip-stalk phenotypic competition ( Bentley et al., 2008 ; Bentley et al., 2009 , 2014 ; Jakobsson et al., 2010 ; Ubezio et al., 2016 ; Zakirov et al., 2021 ) and the importance of the temporal dynamics of Dll4-Notch1 signaling in defining vascular density ( Bentley and Chakravartula, 2017 ). The role of Jag1 in the VEGF-Notch crosstalk was computationally investigated by Boareto et al.…”