(53e) Stochastic Modeling of BMP Signaling Pathways Identifies Mechanisms of Noise Suppression In Cell Signaling

Abstract:  Bone Morphogenetic Proteins (BMPs) are growth factors that are often utilized during organismal development to direct cell differentiation. Their induction properties have also led to their widespread use to direct stem cell differentiation in vitro. BMP-mediated development is highly reproducible, with low cell-to-cell variability, but BMP-mediated control of stem cell differentiation is highly variable and exquisitely sensitive to BMP dose and duration. During development BMP signaling is regulated by BMP binding proteins that modulate ligand-receptor interactions such as the secreted binding protein Crossveinless-2 (Cv-2). To determine whether are nor extracellular regulation by Cv-2 like molecules could attenuate signaling noise, we developed a large-scale parameter screen of mathematical models for Cv-2 action. In the absence of Cv-2, low molecule numbers and slow reactions rates, consistent with measured in vitro  kinetic data yields high-amplitude, long-duration departures from the deterministic mean levels of BMP signaling. We find that if BMP signaling is regulated by Cv-2 like molecules, intrinsic noise can be greatly reduced depending on the specific choice of model parameters. To fully characterize the behavior of Cv-2 on signaling, we used a truncated state space approximation to the Chemical Master Equation (CME) that approximates the full probability distribution of each species over time. Efficient solution of the CME via the truncated state space method allowed us to carry-out an exhaustive parameter screen with nested continuation in 4 parameters and fully characterize the biological process. Cv-2 like molecules reduce the amplitude of stochastic noise for a subset of the parameters and significantly increased the frequency of fluctuations for a high percentage of parameter space. High frequency fluctuations are rapidly suppressed by the intracellular network providing a simple, yet reliable mechanism to reduce noise in cellular differentiation.