Regulation of stem cell dynamics through volume exclusion

Abstract

Maintenance and regeneration of adult tissues rely on the self-renewal of stem cells. Regeneration without over-proliferation requires precise regulation of the stem cell proliferation and differentiation rates. The nature of such regulatory mechanisms in different tissues, and how to incorporate them in models of stem cell population dynamics, is incompletely understood. The critical birth-death (CBD) process is widely used to model stem cell populations, capturing key phenomena, such as scaling laws in clone size distributions. However, the CBD process neglects regulatory mechanisms. Here, we propose the birth-death process with volume exclusion (vBD), a variation of the birth-death process that considers crowding effects, such as may arise due to limited space in a stem cell niche. While the deterministic rate equations predict a single non-trivial attracting steady state, the master equation predicts extinction and transient distributions of stem cell numbers with three possible behaviours: long-lived quasi-steady state, and short-lived bimodal or unimodal distributions. In all cases, we approximate solutions to the vBD master equation using a renormalised system-size expansion, quasi-steady state approximation and the WKB method. Our study suggests that the size distribution of a stem cell population bears signatures that are useful to detect negative feedback mediated via volume exclusion.