Cell Lineages and the Logic ofProliferative ControlArthur D. Lander1,2,3[*, Kimberly K. Gokoffski1,4,5[, Frederic Y. M. Wan3,5, Qing Nie2,3,5, Anne L. Calof1,3,4*1 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, United States of America, 2 Biomedical Engineering, University ofCalifornia, Irvine, Irvine, California, United States of America, 3 Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States ofAmerica, 4 Anatomy and Neurobiology, University of California, Irvine, Irvine, California, United States of America, 5 Mathematics, University of California, Irvine, Irvine,California, United States of AmericaIt is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Althoughexperimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very littleknown 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 GDF11and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifyingperformance objectives—what, precisely, is being controlled, and to what degree—and go on to calculate how welldifferent 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 astem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator—may be theconsequences of control, and not a reflection of intrinsic differences in cellular or molecular character.Citation: Lander AD, Gokoffski KK, Wan FYM, Nie Q, Calof AL (2009) Cell lineages and the logic of proliferative control. PLoS Biol 7(1): e1000015. doi:10.1371/journal.pbio.1000015IntroductionIn recent decades, biologists have come to view cell lineagesas fundamental units of tissue and organ development,maintenance, and regeneration. The highly differentiated,often nondividing cells that characterize the mature func-tions of tissues are seen as end products of orderly, tissue-specific sequences of cell divisions, during which progenitorcells pass through distinct stages, marked by expression ofstage-specific genes (e.g., [1–4]). At the starting points oflineages—particularly those in self-renewing tissues such asblood, epidermis, and the intestinal lining—one finds stemcells, characterized both by multipotency (ability to producemany cell types) and their ability to maintain their ownnumbers through self-replication [5–8]. As scientists andclinicians have become increasingly interested in harnessingthese features of stem cells to repair injury and cure disease,there has been a resurgence of interest in the mechanismsunderlying the execution and regulation of cell lineages (e.g.,[9–12]).The functions of lineages are often presented in terms ofprogressive allocation of develop mental potential: Thus,pluripotent stem cells often give rise to oligopotent progen-itors, which in turn give rise to unipotent (committed)progenitors. The sequential expression of marker genes atdifferent lineage stages may be related to transcriptional‘‘ priming’’ events needed to lock cells into specific patterns ofgene expression [13,14].Not all lineage stages correlate with restriction of cell fate,however, raising the question of what else lineages do. Thefact that lineage intermediates often display ‘‘ transit-amplify-ing’’ behavior, i.e., are capable of at least some degree of self-replication, has led to the suggestion that lineage stages playessential roles in the control of tissue and organ growth (withgrowth referring in this case to increase in cell number).Here, we seek to discover what those roles are. We approachthis question from the perspective of lineages in general, andwithin the context of the mammalian olfactory epithelium(OE), the neural tissue that senses odo r and transmitsolfactory information to the brain. The OE is a continuallyself-renewing tissue, even in man, and is capable of rapidregeneration [15]. As discussed below, a wealth of exper-imental data on the OE lineage and the molecules thatregulate it makes the OE an attractive system in which toinvestigate the relationship between lineages and growthcontrol.Performance Objectives of Growing TissuesIn biology, ‘‘ control’’ is often used interchangeably with‘‘ regulation,’’ but in engineering , control has a precisemeaning: It refers to the strategies that enable a system toAcademic Editor: Charles F. Stevens, Salk Institute for Biological Studies, UnitedStates of AmericaReceived August 11, 2008; Accepted December 6, 2008; Published January 20,2009Copyright: ! 2009 Lander et al. This is an open-access article distributed under theterms of the Creative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the original authorand source are credited.Abbreviations: BrdU, bromodeoxyuridine; FST, follistatin; GDF8, growth anddifferentiation factor 8; GDF 11, growth and dif fere ntiation factor 11; INP,immediate neuronal precursor; Ngn1, Neurogenin1; OE, olfactory epithelium;ORN, olfactory receptor neuron; TGFb, transforming growth factor b* To whom correspondence should be addressed. E-mail: [email protected] (ADL);[email protected] (ALC)[ These authors contributed equally to this work.PLoS Biology | www.plosbiology.org January 2009 | Volume 7 | Issue 1 | e10000150084PLoSBIOLOGYachieve desired ends, usually in a robust manner. To begintalking about the control needs of growing tissues and organs,we must first ask what are the ‘‘ desired’’ ends, and to whatkinds of uncertainties and perturbations must growth anddifferentiation be robust?Perhaps the most obvious objective of a growth controlsystem is to reach and maintain a specified size. Sizes oforgans such as the brain, for exampl e, are geneticallyspecified within narrow tolerances (e.g., [16]). Moreover,self-renewing organs, such as