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Abstract
The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles.
Highlights
Epithelial morphogenesis is fundamental to the development and functional specialization of tissues and organs
The details of many processes that occur within individual cells are well understood, we still lack a thorough understanding of how cells coordinate their behaviors to create complex tissues
In order to achieve deeper insight, we created a list of targeted attributes and plausible rules for the growth of multicellular cysts formed by Madin-Darby canine kidney (MDCK) cells grown in vitro
Summary
Epithelial morphogenesis is fundamental to the development and functional specialization of tissues and organs. Tight regulation of tissue size, shape and polarization is critical for normal organ development and function Disruption of these regulatory mechanisms leads to an array of diseases including autosomal dominant polycystic kidney disease, stenosis, and cancer. Epithelial cells, such as Madin-Darby canine kidney (MDCK) cells, cultured in a 3D matrix of natural basement membrane components, can recapitulate in vitro many of the in vivo growth characteristics of epithelial organs. They are valuable model systems for studying the cellular mechanisms of in vivo epithelial morphogenesis Their phenotypic simplicity coupled with accumulated knowledge of their molecular biology provide excellent case studies for gleaning needed insight into how molecular events and environmental feedback pathways at subcellular levels lead to cell- and cyst-level phenotype. These model systems lend themselves to computational analysis and modeling as the means to gain that insight and improve our understanding of organogenesis
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