Near Equilibrium Calculus of Stem Cells in Application to the Airway Epithelium Lineage

Homeostatic maintenance of tissues is orchestrated by well tuned networks of cellular signaling. Such networks regulate, in a stochastic manner, fates of all cells within the respective lineages. Processes such as symmetric and asymmetric divisions, differentiation, de-differentiation, and death have to be controlled in a dynamic fashion, such that the cell population is maintained at a stable equilibrium, has a sufficiently low level of stochastic variation, and is capable of responding efficiently to external damage. Cellular lineages in real tissues may consist of a number of different cell types, connected by hierarchical relationships, albeit not necessarily linear, and engaged in a number of different processes. Here we develop a general mathematical methodology for near equilibrium studies of arbitrarily complex hierarchical cell populations, under regulation by a control network. This methodology allows us to (1) determine stability properties of the network, (2) calculate the stochastic variance, and (3) predict how different control mechanisms affect stability and robustness of the system. We demonstrate the versatility of this tool by using the example of the airway epithelium lineage. Recent research shows that airway epithelium stem cells divide mostly asymmetrically, while the so-called secretory cells divide predominantly symmetrically. It further provides quantitative data on the recovery dynamics of the airway epithelium, which can include secretory cell de-differentiation. Using our new methodology, we demonstrate that while a number of regulatory networks can be compatible with the observed recovery behavior, the observed division patterns of cells are the most optimal from the viewpoint of homeostatic lineage stability and minimizing the variation of the cell population size. This not only explains the observed yet poorly understood features of airway tissue architecture, but also helps to deduce the information on the still largely hypothetical regulatory mechanisms governing tissue turnover, and lends insight into how different control loops influence the stability and variance properties of cell populations.Author Summary: Tissue stability is the basic property of healthy organs, and yet the mechanisms governing the stable, long-term maintenance of cell numbers in tissues are poorly understood. While more and more signaling pathways are being discovered, for the most part it remains unknown how they are being put together by different cell types into complex, nonlinear, hierarchical control networks that, on the one hand, reliably maintain constant cell numbers, and on the other hand, quickly adjust to oversee the robust response to tissue damage. Theoretical approaches can fill the gap by being able to reconstruct the underlying control network, based on the observations about the aspects of cellular dynamics. We argue that while many hypothetical networks may be capable of basic cell lineage maintenance, some are much more efficient from the viewpoint of variance minimization. Thus, we developed a new methodology that can test various control networks for stability, variance, and robustness. In the example of the airway epithelium that we highlight, it turns out that the evolutionary selected, actual architecture coincides with the mathematically optimal solution that minimizes the fluctuations of cell numbers at homeostasis.