Cell lineages and the logic of proliferative control

From Q-bio

It is widely accepted that the growth of tissues and organs is tightly controlled. Experimental studies are beginning to reveal the molecular mechanisms underlying such control, but little is known about the control strategies themselves. Here we consider how secreted negative feedback factors (“chalones”) control the output of multi-stage cell lineages, as exemplified by the actions of growth-and-differentiation-factor 11 (GDF11) and activin in the mammalian olfactory epithelium. We begin by specifying performance objectives—what, precisely, is being controlled, and to what degree—and go on to calculate how well different types of feedback configuration, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the olfactory epithelium—the number of lineage stages and feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue—correspond precisely to the features that good control requires. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules—such as whether a cell is a stem cell or transit amplifying cell, or whether a molecule is a growth inhibitor or stimulator—may very often be little more than the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character. This work underscores the central role of performance objectives in explaining and justifying the complexity of biological systems.