Can Active Perception Generate Bistability? Heterogeneous Collective Dynamics and Vascular Patterning

Abstract

During morphogenesis (the generation of form), biological cells, agents or robots must collectively coordinate where and when to move. How to solve such complex, spatial problems in a timely manner, is fundamental to survival in biological organisms, though temporal regulators are largely unexplored. We take the generation of new blood vessel networks (angiogenesis) as our case study system, where tissues low in oxygen stimulate endothelial cells “ECs” (the inner lining of blood vessels) to grow new network branches. This requires ECs to take on heterogeneous states by collectively competing with one another for migratory status via lateral inhibition. We propose here that the traditional “decide then move” perspective of cell behavior in angiogenesis may miss a key temporal regulator as it is too slow to account for the rapid, adaptive assignment of heterogeneous cell states. Here we show that a “move and decide” view may provide a better account. In a study focused on an individual EC in a simulated collective, we find that active perception (sensorimotor feedback) can generate bistability through migration-induced cell shape changes. We further exemplify that when parameters affecting active perception are modulated, bistability is lost in the single cell. As a consequence, active perception can directly modulate collective decision timing. Introduction Collective behavior during morphogenesis requires timely coordination of many autonomous agents, which becomes increasingly complex if the task requires agents have heterogeneous and adaptive phenotypes. Understanding collective coordination mechanisms holds great promise for morphogenetic engineering of well-adapted robot designs (Doursat et al 2012). To this end, the vasculature in living systems is a perfect case study. New vessels grow and remodel in a dynamic adaptive way to maintain a network with near-intimate contact to every cell in the body, required due to the diffusion limit of Oxygen (Aird 2005). When new vessel growth (angiogenesis) is needed, e.g., in development or wound healing, endothelial cells (ECs) lining blood vessel tubes adaptively respond to the release of diffusing growth factors from hypoxic (low in oxygen) tissue. The ECs then collectively coordinate such that some cells migrate and lead new tubular branches (“sprouts”), while others line the tube walls and ensure that the branches are well spaced (Geudens and Gerhardt 2011) (Fig. 1a). The selection of these two states “active” or “inhibited” cell movement is known to be coordinated by Notch-driven “lateral inhibition”, where cells battle to inhibit their neighbors (Hellstrom et al 2007, Jakobsson et al 2009). Lateral inhibition is known to generate stable alternating patterns of on and off cell states in many systems, hereafter referred to as a Salt and Pepper pattern “SP Jakobsson et al 2010; Bentley et al 2014a). This occurs when ECs 1) meet new neighbors during branch fusion (required to form Figure 1. a) Endothelial cells, initially all the same, collectively coordinate to become heterogeneous when stimulated to grow new blood vessel branches. Some cells move, leading new sprouts, others are inhibited, lining the branch and keeping them regularly spaced. The optimal spatial arrangement is a “salt and pepper” (SP Fig 1b) (Bentley et al 2009) and 2) rearrange their positions in the collective (Jakobsson et al 2010). Thus, the cellular collective must be capable of rapidly re-establishing the S&P pattern of behaviors in the face of local neighborhood changes, to keep the network branching structure optimized. Otherwise, cells would drift into a “half-way house” state of homogenous movement (Fig. 1c). Lack of differential movement has been shown to disrupt branching as cells hypersprout instead (Hellstrom et al 2008), and has been implicated in abnormal vessel thickening in disease (Bentley et al 2014a). Here we ask, is there an extra dimension of temporal regulation that keeps the system from li