Joint regulation of growth and division timing drives size homeostasis in proliferating animal cells

Abstract

How organisms maintain cell size homeostasis is a long-standing problem that remains unresolved, especially in multicellular organisms. Recent experiments in diverse animal cell types demonstrate that within a cell population the extent of growth and cellular proliferation (i.e., fitness) is low for small and large cells, but high at intermediate sizes.Here we use mathematical models to explore size-control strategies that drive such a non-monotonic fitness profile resulting in an optimal cell size. Our analysis reveals that if cell size grows exponentially or linearly over time, then fitness always varies monotonically with size irrespective of how timing of division is regulated. Furthermore, if the cell divides upon attaining a critical size (as in the Sizer or size-checkpoint model), then fitness always increases with size irrespective of how growth rate is regulated. These results show that while several size control models can maintain cell size homeostasis, they fail to predict the optimal cell size, and hence unable to explain why cells prefer a certain size. Interestingly, fitness maximization at an optimal size requires two key ingredients: 1) The growth rate decreases with increasing size for large enough cells; and 2) The cell size at the time of division is a function of the newborn size. The latter condition is consistent with the Adder paradigm for division control (division is triggered upon adding a fixed size from birth), or a Sizer-Adder combination. Consistent with theory, Jurkat T cell growth rates, as measured via oxygen consumption or mitochondrial activity, increase with size for small cells, but decrease with size for large cells. In summary, regulation of both growth and cell division timing is critical for size control in animal cells, and this joint-regulation leads to an optimal size where cellular fitness is maximized.Size control is a fundamental aspect of biology that is seen at every level of organization, but in most cases remains poorly understood [1-5]. One simple solution for size control is the Sizer or size-checkpoint model that couples cellcycle transitions to attainment of a minimum cell mass or size. An alternative solution is the Adder model, where cells add a fixed amount of size in each division cycle independent of daughter size. While strong evidence for an Adder has been reported in diverse prokaryotes [6][7][8][9][10][11][12][13][14][15][16], and budding yeast [17], it remains to be seen if similar size homeostasis mechanisms are at play in higher eukaryotes.Recent experiments in proliferating animal cells reveal an intriguing observation about cellular fitness that ties deeply into size control as this suggested why cells aim to maintain certain size. In [18], fitness was assayed by first sorting a cell population into several subpopulations based on size, and then measuring the net proliferation

Cell size control and gene expression homeostasis in single-cells

“…Notably, a similar optimality also exists for mitochondrial activity (metabolism) of cells [33]. Since the metabolism is linked to the growth, it is not too surprising that existence of an optimal size can be theoretically shown to arise from joint regulation of timing and growth [34].…”

Optimal feedback mechanisms for regulating cell numbers

“…For example, tissue size may be regulated by either controlling the sizes of individual cells, or the number of constituent cells [2][3][4][5][6]. How individual cells maintain size homeostasis has been extensively studied across organisms ranging from bacteria, animal and plant cells [7][8][9][10][11][12][13][14][15][16]. Interestingly, data reveals cell-autonomous control strategies that regulate cellular growth or timing of cell-cycle events to suppress aberrant deviations in cell size around an optimal size specific to that cell type [17][18][19][20].…”