Are cell jamming and unjamming essential in tissue development?

Abstract

The last decade has seen a surge of evidence supporting the existence of the transition of the multicellular tissue from a collective material phase that is regarded as being jammed to a collective material phase that is regarded as being unjammed. The jammed phase is solid-like and effectively 'frozen', and therefore is associated with tissue homeostasis, rigidity, and mechanical stability. The unjammed phase, by contrast, is fluid-like and effectively 'melted', and therefore is associated with mechanical fluidity, plasticity and malleability that are required in dynamic multicellular processes that sculpt organ microstructure. Such multicellular sculpturing, for example, occurs during embryogenesis, growth and remodeling. Although unjamming and jamming events in the multicellular collective are reminiscent of those that occur in the inert granular collective, such as grain in a hopper that can flow or clog, the analogy is instructive but limited, and the implications for cell biology remain unclear. Here we ask, are the cellular jamming transition and its inverse --the unjamming transition-- mere epiphenomena? That is, are they dispensable downstream events that accompany but neither cause nor quench these core multicellular processes? Drawing from selected examples in developmental biology, here we suggest the hypothesis that, to the contrary, the graded departure from a jammed phase enables controlled degrees of malleability as might be required in developmental dynamics. We further suggest that the coordinated approach to a jammed phase progressively slows those dynamics and ultimately enables long-term mechanical stability as might be required in the mature homeostatic multicellular tissue.

Keywords: Fluidity; Jamming; Migration; Phase transition; Plasticity percolation; Remodeling; Rigidity; Unjamming.

Fig. 1.

Primary human bronchial epithelial cells in air-liquid interface culture showing maximum intensity of immuno-fluorescent projections of the tight junction protein ZO-1. Left: The jammed epithelial cell layer is non-migratory and shows variable cobblestone cell shapes characteristic of mature epithelial layers (Gibson et al., 2006). Right: The unjammed layer is migratory, with cell shapes that become systematically more elongated, more variable, and spatially more correlated (Atia et al., 2018; Mitchel et al., 2020; Park et al., 2015). Images courtesy of Jennifer Mitchel.

Fig. 2.

Different types of percolation transitions can occur in model cellular networks. In a confluent cell layer with heterogeneous cell stiffness, it is possible to observe networks of rigid cells (top row, rigid cells in red) and networks of cells exerting forces on their neighbors (bottom row, boundaries under tension in bold). The fraction of rigid cells at which contact percolation occurs versus the fraction at which system-spanning networks of tension emerge are different, with contact percolation (top right) occurring at a much higher fraction of rigid cells than tension percolation (bottom middle). Adapted from Li et al. (2019).

Fig. 3.

As the number of cell-cell-contacts on the microscale varies smoothly tissue viscosity on the macroscale changes rather sharply. In subconfluent systems, the critical number of contacts sets the criterion for rigidity percolation and the jamming/unjamming transition. Adapted from Petridou and Heisenberg (2019).

Fig. 4.

Jamming is about more than cellular packing: in non-confluent tissues, as in the systems described by Petridou et al. (2021) or Mongera et al. (2018), jamming is driven in large part by increases in the fraction of space that is packed by cells (Fig. 3). In confluent tissues, by contrast, the packing density of space by cells is complete and the packing fraction is therefore fixed at unity. Nevertheless, in such systems there exist multiple density-independent alternative pathways to jamming and unjamming. For example, the so-called self-propelled Voronoi model of confluent tissues show that unjamming and fluidization increase with increasing magnitude of fluctuating propulsive forces, increasing persistence of those propulsive force, and increasing cell-cell-adhesion. Adapted from Bi et al. (2016).

Fig. 5.

Airway branching in the embryonic avian lung. (A) In the lung, buds branch out to form epithelial tubes within the surrounding pulmonary mesenchyme (A, left). Micrographs showing non-branching and branching regions were analyzed (A, right), and the projected shapes of cells at these different regions were quantified by the ratio between the perimeter of a cell and the square root of its area, a parameter also known as the shape index. (B) The distribution of cell shapes demonstrates striking differences that are indicative of jamming in non-branching regions (i.e. low shape index) and unjamming in branching regions (i.e. high shape index) (Atia et al., 2018; Bi et al., 2014, 2015; Park et al., 2015; Schotz et al., 2013). Adapted from Spurlin et al. (2019).

Fig. 6.

Sagittal and frontal sketches (a) and A-P cross-sectional images (b) of vertebrate body axis elongation in the zebrafish embryo. Computational model shows cells entering the mesodermal progenitor zone (MPZ) alongside fluid-like unjammed and solid-like unjammed regions (c). Unidirectional body axis elongation arises in the presence of a fluid-to-solid jamming transition (d) but not in its absence (e). Inset shows the cellular velocity field. Adapted from Mongera et al. (2018).