Hyaluronic acid over-expression drives tissue architecture in both healthy and diseased states

Tissue architecture is shaped by a variety of biomechanical and biochemical mechanisms, including morphogen patterning, differential growth, and spatial variations in cellular contractility. These mechanisms typically emphasize forces generated within cells. Here, we explore a complementary mechanism in which intercellular space itself exerts forces that shape tissue architecture. More specifically, we focus on hyaluronic acid (HA), a glycosaminoglycan of the extracellular matrix, that draws fluid into the spaces between cells through osmotic pressure, allowing these spaces to expand and mechanically deform the surrounding tissue. We propose that spatial patterning of HA-mediated extracellular forces, acting together with tissue geometry and junctional mechanics, provides a common physical framework capable of generating distinct tissue architectures. We test this hypothesis using a computational framework coupling a cell-based extended vertex model for biological tissues to a flow network representing HA and extracellular fluid in the extracellular space. This coupled model demonstrates a range of architectural responses spanning changes in tissue topology and morphology: global HA overexpression drives fluid accumulation and cell-cell junction rupture to produce multiple lumens in nontrivial patterns; a localized HA-rich region generates pressure gradients that drive budding; {\it multiple localized HA-rich regions generate branching;} and {\it extended HA-rich patterns can drive tubular structures.} Our results have direct experimental implications and establish the spatial patterning of HA-mediated intercellular forces as a mechanical morphogen helping shape tissue architecture.