UC Irvine

Minimizing the number of mutations accumulated by differentiated cells is a widely accepted performance objective of stem cell systems.  One possible strategy to reduce mutation accumulation is to reduce pedigree depth (the number of cell divisions that separates a given cell from its ancestral founder) through cell cycle regulation.  Briefly, a tissue can modulate the shape of its stem cell lineage tree via spatial regulation of cell cycle length.  My thesis work focuses on (1) characterizing the theoretical cell cycle profile that minimizes mutation accumulation in the C. elegans germline (a model for stem cells and their niches) via computer simulations, (2) developing a computational approach to analyze spatial cell cycle data in microscopy images, and (3) using the aforementioned computational approach to characterize germline cell cycle properties.

We developed Simworm, a biologically realistic computational model of the germline. Using Simworm, we found that an approximate two-fold slowdown in stem cell cycle length optimizes pedigree depth, and this optimal profile is a result of balancing competing performance objectives of fast progeny production and growth with pedigree depth minimization.

In order to enable sensitive and high-throughput spatial studies of cell cycle kinetics, we developed Parismi which is a software package customized for image cytometry studies of the C. elegans germline. Parismi also has broader applications to other model systems such as HeLa cell culture, early mouse embryos, and the mouse olfactory epithelium.

To test our theoretical predictions about the existence of a two-fold cell cycle gradient minimizing pedigree depth, we used Parismi to characterize the substructure of the germline’s mitotic zone. We found the that the mitotic zone can be classified into three distinct sub-compartments with different cell cycle properties. We also identify a spatial gradient of Cyclin E as a possible mechanism for regulation of cell cycle length. Finally, we characterize an intermittent cycling phenotype in older worms, and show that intermittent cycling is a result of sperm depletion. Altogether, our study shows that germline cell cycle properties are consistent with design to minimize pedigree depth and provides insights into understanding a fundamental mechanism through which tissues reduce mutation rate.