title: Distinct cellular states determine calcium signaling response.
abstract: The heterogeneity in mammalian cells signaling response is largely a result of pre-existing cell-to-cell variability. It is unknown whether cell-to-cell variability rises from biochemical stochastic fluctuations or distinct cellular states. Here, we utilize calcium response to adenosine trisphosphate as a model for investigating the structure of heterogeneity within a population of cells and analyze whether distinct cellular response states coexist. We use a functional definition of cellular state that is based on a mechanistic dynamical systems model of calcium signaling. Using Bayesian parameter inference, we obtain high confidence parameter value distributions for several hundred cells, each fitted individually. Clustering the inferred parameter distributions revealed three major distinct cellular states within the population. The existence of distinct cellular states raises the possibility that the observed variability in response is a result of structured heterogeneity between cells. The inferred parameter distribution predicts, and experiments confirm that variability in IP3R response explains the majority of calcium heterogeneity. Our work shows how mechanistic models and single-cell parameter fitting can uncover hidden population structure and demonstrate the need for parameter inference at the single-cell level.
authors.affiliation: Departments of Chemistry and Biochemistry, Integrative Biology and Physiology, and Institute for Quantitative and Computational Biosciences (QCB), UCLA, Los Angeles, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Yao
authors.affiliation: Departments of Chemistry and Biochemistry, Integrative Biology and Physiology, and Institute for Quantitative and Computational Biosciences (QCB), UCLA, Los Angeles, CA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pilko
authors.affiliation: Departments of Chemistry and Biochemistry, Integrative Biology and Physiology, and Institute for Quantitative and Computational Biosciences (QCB), UCLA, Los Angeles, CA, USA rwollman@ucsd.edu.
authors.forename: Roy
authors.identifier: http://orcid.org/0000-0003-3865-2605
authors.initials: R
authors.lastname: Wollman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001499:Bayes Theorem; D020013:Calcium Signaling; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D042361:Mammary Glands, Human / Q000378:metabolism; D008954:Models, Biological; D059010:Single-Cell Analysis / Q000379:methods*; D049490:Systems Biology / Q000379:methods
chemical_list: D000255:Adenosine Triphosphate
keywords: calcium signaling; cell states; cellular heterogeneity; single‐cell biology