“…Cells in the interior of aggregates are subject to a different microenvironment compared with free floating cells or cells on the surface of aggregates (Street, 1973), including differences in oxygen (Hulst et al , 1989) and nutrient availability (Patil and Roberts, 2013). Other factors that may contribute to the difference in S-phase duration include genetic and epigenetic instability, such as chromosome rearrangements, DNA methylation, and somatic mutation (reviewed by Lee and Phillips, 1988; Phillips et al , 1994; Tanurdzic et al , 2008).…”