Determining the control networks regulating stem cell lineages in colonic crypts.

The question of stem cell control is at the center of our understanding of tissue functioning, both in healthy and cancerous conditions. It is well accepted that cellular fate decisions (such as divisions, differentiation, apoptosis) are orchestrated by a network of regulatory signals emitted by different cell populations in the lineage and the surrounding tissue. The exact regulatory network that governs stem cell lineages in a given tissue is usually unknown. Here we propose an algorithm to identify a set of candidate control networks that are compatible with (a) measured means and variances of cell populations in different compartments, (b) qualitative information on cell population dynamics, such as the existence of local controls and oscillatory reaction of the system to population size perturbations, and (c) statistics of correlations between cell numbers in different compartments. Using the example of human colon crypts, where lineages are comprised of stem cells, transit amplifying cells, and differentiated cells, we start with a theoretically known set of 32 smallest control networks compatible with tissue stability. Utilizing near-equilibrium stochastic calculus of stem cells developed earlier, we apply a series of tests, where we compare the networks' expected behavior with the observations. This allows us to exclude most of the networks, until only three, very similar, candidate networks remain, which are most compatible with the measurements. This work demonstrates how theoretical analysis of control networks combined with only static biological data can shed light onto the inner workings of stem cell lineages, in the absence of direct experimental assessment of regulatory signaling mechanisms. The resulting candidate networks are dominated by negative control loops and possess the following properties: (1) stem cell division decisions are negatively controlled by the stem cell population, (2) stem cell differentiation decisions are negatively controlled by the transit amplifying cell population.