Stem cell homeostasis regulated by hierarchy and neutral competition.

Tissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. Two distinct models have been proposed as mechanisms of stem cell homeostasis. According to the classical model, there is hierarchy among stem cells, and master stem cells produce stem cells by asymmetric division; whereas, according to the recent model, stem cells are equipotent and neutrally compete. However, the mechanism remains controversial in several tissues and species. Here, we developed a mathematical model linking the two models, named the hierarchical neutral competition (hNC) model. Our theoretical analysis showed that the combination of the hierarchy and neutral competition exhibited bursts in clonal expansion, which was consistent with experimental data of rhesus macaque hematopoiesis. Furthermore, the scaling law in clone size distribution, considered a unique characteristic of the recent model, was satisfied even in the hNC model. Based on the findings above, we proposed the criterion for distinguishing the three models based on experiments.