CELL-CYCLE MODEL TO DESCRIBE ANIMAL-CELL SIZE VARIATION AND LAG BETWEEN CELL NUMBER AND BIOMASS DYNAMICS

The use of cell numbers rather than mass to quantify the size of the b iotic phase in animal cell cultures causes several problems. First, th e cell size varies with growth conditions, thus yields expressed in te rms of cell numbers cannot be used in the normal mass balance sense. S econd, experience from microbial systems shows that cell number dynami cs lag behind biomass dynamics. This work demonstrates that this lag p henomenon also occurs in animal cell culture. Both the lag phenomenon and the variation in cell size are explained using a simple model of t he cell cycle. The basis for the model is that onset of DNA synthesis requires accumulation of G1 cyclins to a prescribed level. This requir ement is translated into a requirement for a cell to reach a critical size before commencement of DNA synthesis. A slower gl-owing cell will spend more time in G1 before reaching the critical mass. In contrast, the period between onset of DNA synthesis and mitosis, tau(B), is fix ed. The two parameters in the model, the critical size and tau(B), wer e determined from eight steady-state measurements of mean cell size in a continuous hybridoma culture. Using these parameters, it was possib le to predict with reasonable accuracy the transient behavior in a sep arate shift-up culture, i.e., a culture where cells were transferred f rom a lean environment to a rich environment. The implications for ana lyzing experimental data for animal cell culture are discussed. (C) 19 97 John Wiley & Sons, Inc.