The Evolutionary Trade-off between Stem Cell Niche Size, Aging, and Tumorigenesis
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.
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