Principles of regulation of self-renewing cell lineages

Identifying the exact regulatory circuits that can stably maintain tissue homeostasis is critical for our basic understanding of multicellular organisms, and equally critical for identifying how tumors circumvent this regulation, thus providing targets for treatment. Despite great strides in the understanding of the molecular components of stem-cell regulation, the overall mechanisms orchestrating tissue homeostasis are still far from being understood. Typically, tissue contains the stem cells, transit amplifying cells, and terminally differentiated cells. Each of these cell types can potentially secrete regulatory factors and/or respond to factors secreted by other types. The feedback can be positive or negative in nature. This gives rise to a bewildering array of possible mechanisms that drive tissue regulation. In this paper, we propose a novel method of studying stem cell lineage regulation, and identify possible numbers, types, and directions of control loops that are compatible with stability, keep the variance low, and possess a certain degree of robustness. For example, there are exactly two minimal (two-loop) control networks that can regulate two-compartment (stem and differentiated cell) tissues, and 20 such networks in three-compartment tissues. If division and differentiation decisions are coupled, then there must be a negative control loop regulating divisions of stem cells (e.g. by means of contact inhibition). While this mechanism is associated with the highest robustness, there could be systems that maintain stability by means of positive divisions control, coupled with specific types of differentiation control. Some of the control mechanisms that we find have been proposed before, but most of them are new, and we describe evidence for their existence in data that have been previously published. By specifying the types of feedback interactions that can maintain homeostasis, our mathematical analysis can be used as a guide to experimentally zero in on the exact molecular mechanisms in specific tissues.