title: Elucidating functional heterogeneity in hematopoietic progenitor cells: a combined experimental and modeling approach.
abstract: A detailed understanding of the mechanisms maintaining the hierarchical balance of cell types in hematopoiesis will be important for the therapeutic manipulation of normal and leukemic cells. Mathematical modeling is expected to make an important contribution to this area, but the iterative development of increasingly accurate models will rely on repeated validation using experimental data of sufficient resolution to distinguish between alternative model scenarios. The multipotent hematopoietic progenitor FDCP-Mix cells maintain a hierarchy from self-renewal to post-mitotic differentiation in vitro and are accessible to detailed analysis. Here, we report the development of a combined mathematical modeling and experimental approach to study the principles underlying heterogeneity in FDCP-Mix cultures. We adapt a single-cell based model of hematopoiesis to the conditions of cell culture and describe an association between proliferative history and phenotype of FDCP-Mix cells. While data derived from population studies are incapable of distinguishing between three mechanistically different model scenarios, statistical analysis of single cell tracking data provides a resolution sufficient to select one of them. This scenario favors differences between granulocytic and monocytic lineage with respect to their proliferative behavior and death rates as a mechanistic explanation for the observed heterogeneity. Our results demonstrate the power of a combined experimental/modeling approach in which single cell fate analysis is the key to revealing regulatory principles at the cellular level.
authors.affiliation: Department of Hematology, Oncology and Hemostasiology, Universität Leipzig, Leipzig, Germany.
authors.forename: Enrica
authors.initials: E
authors.lastname: Bach
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry (IMB), Technische Universität Dresden, Dresden, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zerjatke
authors.affiliation: Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Dresden, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Herklotz
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry (IMB), Technische Universität Dresden, Dresden, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Scherf
authors.affiliation: Department of Hematology, Oncology and Hemostasiology, Universität Leipzig, Leipzig, Germany.
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry (IMB), Technische Universität Dresden, Dresden, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Roeder
authors.affiliation: Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Dresden, Germany; Institute of Biochemistry, Universität Leipzig, Leipzig, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Pompe
authors.affiliation: Department of Hematology, Oncology and Hemostasiology, Universität Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Cross
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry (IMB), Technische Universität Dresden, Dresden, Germany. Electronic address: ingmar.glauche@tu-dresden.de.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Glauche
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological