The role of the bi-compartmental stem cell niche in delaying cancer

In recent years, by using modern imaging techniques, scientists have found evidence of collaboration between different types of stem cells (SCs), and proposed a bi-compartmental organization of the SC niche. Here we create a class of stochastic models to simulate the dynamics of such a heterogeneous SC niche. We consider two SC groups: the border compartment, S₁, is in direct contact with transit-amplifying (TA) cells, and the central compartment, S₂, is hierarchically upstream from S₁. The S₁ SCs differentiate or divide asymmetrically when the tissue needs TA cells. Both groups proliferate when the tissue requires SCs (thus maintaining homeostasis). There is an influx of S₂ cells into the border compartment, either by migration, or by proliferation. We examine this model in the context of double-hit mutant generation, which is a rate-limiting step in the development of many cancers. We discover that this type of a cooperative pattern in the stem niche with two compartments leads to a significantly smaller rate of double-hit mutant production compared with a homogeneous, one-compartmental SC niche. Furthermore, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs, consistent with the literature. Finally, the optimal architecture (which minimizes the rate of double-hit mutant production) requires a large proliferation rate of S₁ cells along with a small, but non-zero, proliferation rate of S₂ cells. This result is remarkably similar to the niche structure described recently by several authors, where one of the two SC compartments was found more actively engaged in tissue homeostasis and turnover, while the other was characterized by higher levels of quiescence (but contributed strongly to injury recovery). Both numerical and analytical results are presented.