Abstract
Cell heterogeneity may be caused by stochastic or deterministic effects. The inheritance of regulators through cell division is a key deterministic force, but identifying inheritance effects in a systematic manner has been challenging. Here, we measure and analyze cell cycles in deep lineage trees of human cancer cells and mouse embryonic stem cells and develop a statistical framework to infer underlying rules of inheritance. The observed long-range intra-generational correlations in cell-cycle duration, up to second cousins, seem paradoxical because ancestral correlations decay rapidly. However, this correlation pattern is naturally explained by the inheritance of both cell size and cell-cycle speed over several generations, provided that cell growth and division are coupled through a minimum-size checkpoint. This model correctly predicts the effects of inhibiting cell growth or cycle progression. In sum, we show how fluctuations of cell cycles across lineage trees help in understanding the coordination of cell growth and division.
Highlights
Cells of the same type growing in homogeneous conditions often have highly heterogeneous cycle lengths (Smith and Martin, 1973)
Extensive live-cell imaging data of cell lineages have become available, characterizing, for example, lymphocyte activation (Mitchell et al, 2018; Duffy et al, 2012; Hawkins et al, 2009), stem cell dynamics (Filipczyk et al, 2015), cancer cell proliferation (Spencer et al, 2013; Barr et al, 2017; Ryl et al, 2017), or nematode development (Du et al, 2015). Such studies across many cell types have found that cycle lengths are similar in sister cells, which may be due to the inheritance of molecular regulators across mitosis (Spencer et al, 2013; Mitchell et al, 2018; Yang et al, 2017; Barr et al, 2017; Arora et al, 2017)
To study how far intra-generational cell-cycle correlations extend within cell pedigrees, we generated extensive lineage trees by imaging and tracking TET21N neuroblastoma cells for up to ten generations during exponential growth (Figure 1A, Figure 1—video 1, Figure 1—source data 1 and Figure 1—figure supplement 1A)
Summary
Cells of the same type growing in homogeneous conditions often have highly heterogeneous cycle lengths (Smith and Martin, 1973). Extensive live-cell imaging data of cell lineages have become available, characterizing, for example, lymphocyte activation (Mitchell et al, 2018; Duffy et al, 2012; Hawkins et al, 2009), stem cell dynamics (Filipczyk et al, 2015), cancer cell proliferation (Spencer et al, 2013; Barr et al, 2017; Ryl et al, 2017), or nematode development (Du et al, 2015) Such studies across many cell types have found that cycle lengths are similar in sister cells, which may be due to the inheritance of molecular regulators across mitosis (Spencer et al, 2013; Mitchell et al, 2018; Yang et al, 2017; Barr et al, 2017; Arora et al, 2017). Ancestral correlations in cycle length fade rapidly, often disappearing between grandmother and granddaughter cells, or already between mother and daughter cells
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