Feedback between proliferation, intercalation, and growth mechanics in multicellular aggregates

Abstract Continuum mechanical models of growth in solid biological tissues and multicellular aggregates (such as spheroids and organoids) have traditionally treated growth as a simple increase in the natural (stress-free) volume of the body. At the cellular level, this corresponds to stress-free expansion of individual cells driven by mass accumulation. In reality, however, multicellular growth is primarily governed by proliferation, which involves not only active cell enlargement but also changes in cell number. The latter arises from topological transition events such as division and apoptosis, both of which play central roles in maintaining cell size homeostasis in growing populations. Furthermore, cells can reorganize spatially through simple neighbor exchange via intercalation, a topological transition that provides a mechanism for stress relaxation. Despite their biological significance, the mechanical implications and the active versus passive nature of these cellular processes during growth remain poorly explored. In this study, we address this gap by examining the interplay between growth mechanics, the underlying cellular processes, and cellular activity. To this end, we employ morpho-viscoelasticity, a continuum theory for growth in viscoplastic confluent cell aggregates, and implement it within a finite element framework. Through numerical simulations, we investigate the mechano-biochemical feedback in spheroid growth. The results highlight the nontrivial roles of cell size homeostasis and cellular reorganization in regulating cell stresses and morphologies within growing aggregates, offering mechanistic insights relevant for spheroid and organoid engineering applications.