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Ligand Accumulation in Autocrine Cell Cultures

Michael I. Monine ^*, Alexander M. Berezhkovskii , Elizabeth J. Joslin , H. Steven Wiley , Douglas A. Lauffenburger  and Stanislav Y. Shvartsman ^*

^* Department of Chemical Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey; Mathematical and Statistical Computing Laboratory, Division of Computational Biology, Center for Information Technology, National Institutes of Health, Bethesda, Maryland; Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts; and Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington

Correspondence: Address reprint requests to Stanislav Y. Shvartsman, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Carl Icahn Laboratory, Washington Rd., Princeton, NJ 08544. Tel.: 609-258-4694; Fax: 609-258-0211; E-mail: stas{at}princeton.edu.

Cell-culture assays are routinely used to analyze autocrine signaling systems, but quantitative experiments are rarely possible. To enable the quantitative design and analysis of experiments with autocrine cells, we develop a biophysical theory of ligand accumulation in cell-culture assays. Our theory predicts the ligand concentration as a function of time and measurable parameters of autocrine cells and cell-culture experiments. The key step of our analysis is the derivation of the survival probability of a single ligand released from the surface of an autocrine cell. An expression for this probability is derived using the boundary homogenization approach and tested by stochastic simulations. We use this expression in the integral balance equations, from which we find the Laplace transform of the ligand concentration. We demonstrate how the theory works by analyzing the autocrine epidermal growth factor receptor system and discuss the extension of our methods to other experiments with cultured autocrine cells.

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