Abstract
How do individual epithelial cells (ECs) organize into multicellular structures? ECs are studied in vitro to help answer that question. Characteristic growth features include stable cyst formation in embedded culture, inverted cyst formation in suspension culture, and lumen formation in overlay culture. Formation of these characteristic structures is believed to be a consequence of an intrinsic program of differentiation and de-differentiation. To help discover how such a program may function, we developed an in silico analogue in which space, events, and time are discretized. Software agents and objects represent cells and components of the environment. “Cells” act independently. The “program” governing their behavior is embedded within each in the form of axioms and an inflexible decisional process. Relationships between the axioms and recognized cell functions are specified. Interactions between “cells” and environment components during simulation give rise to a complex in silico phenotype characterized by context-dependent structures that mimic counterparts observed in four different in vitro culture conditions: a targeted set of in vitro phenotypic attributes was matched by in silico attributes. However, for a particular growth condition, the analogue failed to exhibit behaviors characteristic of functionally polarized ECs. We solved this problem by following an iterative refinement method that improved the first analogue and led to a second: it exhibited characteristic differentiation and growth properties in all simulated growth conditions. It is the first model to simultaneously provide a representation of nonpolarized and structurally polarized cell types, and a mechanism for their interconversion. The second analogue also uses an inflexible axiomatic program. When specific axioms are relaxed, growths strikingly characteristic of cancerous and precancerous lesions are observed. In one case, the simulated cause is aberrant matrix production. Analogue design facilitates gaining deeper insight into such phenomena by making it easy to replace low-resolution components with increasingly detailed and realistic components.
Highlights
How do individual cells organize into multicellular tissues? O’Brien et al [1] have convincingly argued that the morphogenetic behavior of epithelial cells (ECs) is guided by two distinct elements: an intrinsic differentiation program that drives formation of lumen-enclosing monolayers, and transient de-differentiation that allows the monolayer to be remodeled
We did this by devising a set of simple axioms that could be used by independent CELLS to mimic EC behavior in a range of simulated environments
Axiom emphasizes that computer programs are mathematical, formal systems, and the initial mechanistic premises in our simulations are analogous to axioms in formal systems
Summary
How do individual cells organize into multicellular tissues? O’Brien et al [1] have convincingly argued that the morphogenetic behavior of epithelial cells (ECs) is guided by two distinct elements: an intrinsic differentiation program that drives formation of lumen-enclosing monolayers, and transient de-differentiation that allows the monolayer to be remodeled. The intrinsic differentiation program is argued to be a consequence of an innate drive for each cell to achieve three surface types: free (contact with a luminal space), lateral (contact with another cell), and basal (contact with and attachment to matrix) Such broad-ranging conceptual models have been validated by the absence of contradiction within the accumulated experimental wet-lab evidence. We have built, studied, and improved in silico devices that instantiate the above conceptual model They exhibit several of the key behaviors described by O’Brien et al Understanding the operating principles and mechanisms responsible for normal EC growth and morphogenesis, along with the conditions that can lead to abnormalities, is expected to accelerate the development of treatments for diseases such as autosomal dominant polycystic kidney disease and carcinomas, and enable improved designs of artificial devices that utilize ECs
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