Abstract
Many epithelial tissues within large multicellular organisms are continually replenished by small independent populations of stem cells. These stem cells divide within their niches and differentiate into the constituent cell types of the tissue, and are largely responsible for maintaining tissue homeostasis. Mutations can accumulate in stem cell niches and change the rate of stem cell division and differentiation, contributing to both aging and tumorigenesis. Here, we create a mathematical model of the intestinal stem cell niche, crypt system, and epithelium. We calculate the expected effect of fixed mutations in stem cell niches and their expected effect on tissue homeostasis throughout the intestinal epithelium over the lifetime of an organism. We find that, due to the small population size of stem cell niches, fixed mutations are expected to accumulate via genetic drift and decrease stem cell fitness, leading to niche and tissue attrition, and contributing to organismal aging. We also explore mutation accumulation at various stem cell niche sizes, and demonstrate that an evolutionary trade-off exists between niche size, tissue aging, and the risk of tumorigenesis; where niches exist at a size that minimizes the probability of tumorigenesis, at the expense of accumulating deleterious mutations due to genetic drift. Finally, we show that the probability of tumorigenesis and the extent of aging trade-off differently depending on whether mutational effects confer a selective advantage, or not, in the stem cell niche.
