7 research outputs found
MDCK Cystogenesis Driven by Cell Stabilization within Computational Analogues
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