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Cell Lineages and Growth Control by Feedback


The molecular mechanisms that regulate tissue growth are diverse, but the objectives of growth control are generic in many tissues: to reach and stably maintain an appropriate size, to regenerate rapidly following injury, to possess appropriate proportions of different cell types, and to form specific tissue structures during development. It is known that feedback mechanisms play a role in growth control, and that cells the give rise to a tissue are organized into lineages—successive stages in which cells at each stage have the option either to self-renew or differentiate to the next stage. Negative feedback on progenitor cell self-renewal has been previously shown to confer “perfect adaptation” for steady-state size control (maintenance of an exact tissue size independent of numbers of starting cells, rates of cell division, or rates of cell death), stability, and a low steady-state load of progenitor cells (Lander, Gokoffski et al. 2009). Negative feedback is also useful for fast regeneration, and it will be shown that negative feedback can be used to approximate a bang-bang controller and therefore be used to build a tissue in the shortest time possible. This control strategy, however, suffers from inherent performance tradeoffs. Namely, rapid regeneration and robustness to parameters/initial conditions tend to be competing objectives, and certain perturbations can result in undesirable oscillations. Stem cells in lineages, such as in the olfactory epithelium (OE), are also known to undergo branching decisions (i.e. to be bipotent) (Gokoffski, Wu et al. 2011) and to receive feedback that promotes self-renewal divisions, such as by FGFs (DeHamer, Guevara et al. 1994). This study seeks to understand the role of the latter phenomenon, which amounts to a type of positive feedback. We find that mixing negative and positive feedback on progenitor self-renewal enables two distinct types of stable growth: either high or low, which we refer to as bi-modality. A critical feedback ratio sets the threshold between the two states, and spatial simulations reveal that this threshold can be used by tissues to self-organize into distinct shapes. A transient, local exogenous positive signal can boost progenitor self-renewal within a discrete zone of planar tissue, which induces bud formation and self-sustaining growth. Furthermore, these zones can self-organize in ways that control tissue shape with spatial precision – i.e. a bud elongates and maintains a constant width as growth self-sustains at its tip, neighboring elongating branches maintain even spacing, and branch numbers change according to changes in the feedback ratio. Disturbances to growth factors that regulate progenitor self-renewal have been previously shown to have morphological consequences during early branching of the olfactory epithelium (OE) (Kawauchi, Kim et al. 2009). Finally, results will be presented from counting progenitor cells in BrdU/EdU pulse-chase/fix experiments in the embryonic OE to measure regional differences in progenitor self-renewal. Preliminary data reveals high progenitor self-renewal in regions undergoing branching morphogenesis, while low self-renewal maintains cell populations in equilibrium at the anterior end of the OE.

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