Cell Size Regulation in Mammalian Cells

Abstract

The regulation of cell growth and proliferation is fundamental for animal development and homeostasis but the mechanisms that coordinate cell growth with cell cycle progression are poorly understood. One possibility is that "cell-size checkpoints" act to delay division until cells have achieved a minimal size or mass however, the existence of such checkpoints in mammalian cells is controversial. In this study we provide further evidence against the operation of a size checkpoint in mammalian cells. We show that primary mammalian cells proliferate at a rate that is independent of cell size or cell mass and that cell size is "set" by the balance of extracellular growth factors and mitogens. Moreover, we show that commonly used culture conditions stimulate cell growth much more than cell cycle progression resulting in cells that proliferate at sizes 300-500% larger than their in vivo counterparts. This has profound effects on cell behaviour.

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

“…This division of labour allows a quiescent cell to grow without dividing and allows proliferating cells to divide at different sizes. The synergy of the pathways permits sustained, robust proliferation only in the presence of growth (Conlon and Raff, 2003;Conlon et al, 2001;Echave et al, 2007). In the present study, we show that IGF-stimulated growth is associated with sustained signalling through the PI3K pathway and is dependent on both Akt and TOR, whereas NRG-induced proliferation is associated with sustained signalling through the ERK pathway and is dependent on this pathway.…”

“…However, when the two factors are added together, they synergise to drive cell-cycle progression but not to drive cell growth. So, cells treated with NRG and IGF add volume at the same rate as cells treated with IGF alone, but only the cells treated with NRG proliferate (Conlon et al, 2001;Echave et al, 2007).…”

“…To assess the effects of NRG and IGF on mitochondrial biogenesis, we used similar conditions to those used previously to analyse cell size (Conlon et al, 2001;Echave et al, 2007). Proliferating Schwann cells were cell-cycle arrested in S phase, by the addition of aphidicolin, to ensure that all cells were at the same stage of the cell cycle and to remove the effects of different division rates on the number of mitochondria per cell.…”

Mechanisms and pathways of growth failure in primordial dwarfism

“…In yeast, it is well established that there is a ''restriction point'' where cells halt progress in G1 or G2 if they have not grown to a minimum size (Hartwell et al 1974;Nurse 1975;Jorgensen and Tyers 2004). In metazoans, the situation is less clear, with different experimental systems providing conflicting evidence on the existence of an equivalent ''cell size checkpoint'' (Echave et al 2007;Tzur et al 2009). At the tissue/organ level, further regulation is present, with organs growing to set sizes (the ''organ checkpoint'') (Leevers and McNeill 2005), and growth regulation of the whole organism is also controlled by the growth hormone/ insulin-like growth factor 1 (GH/IGF1) endocrine axis (Netchine et al 2011).…”

Spatial constraints control cell proliferation in tissues

“…The situation is even less clear in mammalian cells. Although early studies in cultured cells argued for a size checkpoint similar to that of yeast (6), more recent reports instead proposed the growth rate as a trigger for cell division (7)(8)(9)(10)(11). In this view, reaching a characteristic growth rate rather than a characteristic size triggers entry into S phase.…”