Active Perception during Angiogenesis: Filopodia speed up Notch selection of tip cellsin silicoandin vivo

Abstract

How 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.

PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions

“…Consistent with this idea, preventing phosphorylation of Y820 via either mutation of Y820, R817, or via pharmacological inhibitors both inhibited c-Src activation and the ability of VEGFR-2 to stimulate filopodia formation in HEK-293 cells and PAE cells. Formation of filopodia protrusions is a key step for many angiogenic responses of endothelial cells such as sprouting and cell migration (Fischer et al, 2019;Zakirov et al, 2021). In agreement with observation, a recent study demonstrated that mice selectively deficient for c-Src in endothelial displayed significantly reduced blood vessel sprouting and loss in actin-rich filopodial protrusions (Schimmel et al, 2020).…”

Mechanical regulation of the early stages of angiogenesis

“…While some candidate mechanosensors such as the glycocalyx or mechanosensitive ion channels are essentially associated with individual cells, others such as cell–cell junctions are more suggestive of collective behaviour [ 36 , 347 ]. Recent evidence on the role of filopodia under VEGF stimulation [ 348 ] has set the course for a promising line of research. ECs sense and react to a VEGF stimulus individually, developing filopodia within seconds.…”

“…Filopodia, in turn, increase EC sensitivity to VEGF, amplifying differences in the input signal. This mechanism determines cell fate, supported by Notch signalling in a subsequent stage [ 348 ]. Based on this study, we suggest that the effects of IF around a microvessel could be explained by a similar process, with filopodia acting as flow sensors.…”

Systems biology of angiogenesis signaling: Computational models and omics

“…The agent‐based memAgent‐spring model developed by Bentley et al (2008) has been incorporated in various computational models of sprouting angiogenesis to study different mechanisms affecting of VEGF/Notch and endothelial tip cell selection, including the regulation of VE‐Cadherin dynamics (Bentley et al, 2014), VEGF‐driven positive feedback through tetraspanin (Page et al, 2019), and active perception during angiogenesis through filopodia (Zakirov et al, 2021).…”