Configurational entropy is an intrinsic driver of tissue structural heterogeneity

Abstract

Tissues comprise ordered arrangements of cells that can be surprisingly disordered in their details. How the properties of single cells and their microenvironment contribute to the balance between order and disorder at the tissue-scale remains poorly understood. Here, we address this question using the self-organization of human mammary organoids as a model. We find that organoids behave like a dynamic structural ensemble at the steady state. We apply a maximum entropy formalism to derive the ensemble distribution from three measurable parameters - the degeneracy of structural states, interfacial energy, and tissue activity (the energy associated with positional fluctuations). We link these parameters with the molecular and microenvironmental factors that control them to precisely engineer the ensemble across multiple conditions. Our analysis reveals that the entropy associated with structural degeneracy sets a theoretical limit to tissue order and provides new insight for tissue engineering, development, and our understanding of disease progression.

Making sense of chaos: uncovering the mechanisms of conformational entropy

“…In single cell work, the diversity of cell types and behaviors masked by bulk methods is leading to new insights into the properties of systems 92 . Indeed, the configurational entropy of cell types may also play a role in tissue organization, connecting the importance of considering statistical mechanical concepts in decoding function across scales 93 . In the case of macromolecules, we look forward to future work that highlights how rare states contribute to specific functions and how conformational entropy can be leveraged as part of the toolkit to solve challenges in design, catalysis, and cellular signaling.…”

MAGIC matrices: freeform bioprinting materials to support complex and reproducible organoid morphogenesis

“…Consequently, they lack much of the complex morphology of real tissue and generally suffer from a high degree of structural heterogeneity [16][17][18][19][20][21] . Though some of this heterogeneity is intrinsic to the stochastic nature of cell and tissue growth and morphogenesis, there are significant external factors such as initial size, composition, and neighboring interfaces that contribute to morphological heterogeneity 22 . These manifest as differences in organoid mass, morphological features, and cell composition, all of which lead to 2 variability in the outcome of experimental perturbations.…”