Abstract
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.
Highlights
In recent decades, biologists have come to view cell lineages as fundamental units of tissue and organ development, maintenance, and regeneration
As scientists and clinicians have become increasingly interested in harnessing these features of stem cells to repair injury and cure disease, there has been a resurgence of interest in the mechanisms underlying the execution and regulation of cell lineages (e.g., [9,10,11,12])
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
Summary
Biologists have come to view cell lineages as fundamental units of tissue and organ development, maintenance, and regeneration. The highly differentiated, often nondividing cells that characterize the mature functions of tissues are seen as end products of orderly, tissuespecific sequences of cell divisions, during which progenitor cells pass through distinct stages, marked by expression of stage-specific genes (e.g., [1,2,3,4]). As scientists and clinicians have become increasingly interested in harnessing these features of stem cells to repair injury and cure disease, there has been a resurgence of interest in the mechanisms underlying the execution and regulation of cell lineages (e.g., [9,10,11,12]). The functions of lineages are often presented in terms of progressive allocation of developmental potential: pluripotent stem cells often give rise to oligopotent progenitors, which in turn give rise to unipotent (committed) progenitors. The sequential expression of marker genes at different lineage stages may be related to transcriptional ‘‘priming’’ events needed to lock cells into specific patterns of gene expression [13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
