Cell Lineages and the Logic of Proliferative Control

It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors (“chalones”) may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). 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 configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE—the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue—fit with expectations for the best possible control. 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 be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character. : Many tissues and organs grow to precise sizes and, when injured, regenerate accurately and rapidly. Here, we ask whether the organization of cells into lineages, and the feedback interactions that occur within lineages, are necessary elements of control strategies that make such behavior possible. Drawing on mathematical modeling and the results of experimental manipulation of the mouse olfactory epithelium, we show that performance objectives, such as robust size specification, fast regeneration from a variety of initial conditions, and maintenance of high ratios of differentiated to undifferentiated cells, can be simultaneously achieved through a combination of lineage structures, signaling mechanisms, and spatial distributions of cell types that correspond well with what is observed in many growing and regenerating tissues. Key to successful control is an integral-feedback mechanism that is implemented when terminally differentiated cells secrete molecules that lower the probability that progenitor cells replicate versus differentiate. Interestingly, this mechanism also explains how the distinctive proliferative behaviors of stem cell and “transit-amplifying” cell populations can emerge as a consequence of feedback effects, rather than intrinsic programming of cell types. Are common, generic strategies used in the quantitative control of tissue growth and regeneration? An investigation of feedback effects in multistage lineages suggests they are.