title: A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity.
abstract: Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its self-organization from aggregates of primary cells in vitro. We find that self-organization is dominated by the interfacial energy of the tissue-ECM boundary, rather than by differential homo- and heterotypic energies of cell-cell interaction. Surprisingly, interactions with the tissue-ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell-cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell-cell contact formation. We also find that this mechanism of self-organization is conserved in the human prostate. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity. Our model also predicts that mutations affecting binary cell-ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer.
authors: University of California at Berkeley-University of California at San Francisco Graduate Program in Bioengineering, University of California, Berkeley, CA 94720; Departments of Bioengineering and Therapeutic Sciences and Pharmaceutical Chemistry, and.
authors: Alec E
authors: AE
authors: Cerchiari
authors: Departments of Bioengineering and Therapeutic Sciences and Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; and.
authors: James C
authors: JC
authors: Garbe
authors: Pharmaceutical Chemistry, and.
authors: Noel Y
authors: NY
authors: Jee
authors: Pharmaceutical Chemistry, and.
authors: Michael E
authors: ME
authors: Todhunter
authors: Pharmaceutical Chemistry, and.
authors: Kyle E
authors: KE
authors: Broaders
authors: Stanford University School of Medicine, Stanford University, Palo Alto, CA 94305.
authors: Donna M
authors: DM
authors: Peehl
authors: University of California at Berkeley-University of California at San Francisco Graduate Program in Bioengineering, University of California, Berkeley, CA 94720; Departments of Bioengineering and Therapeutic Sciences and.
authors: Tejal A
authors: TA
authors: Desai
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; and.
authors: Mark A
authors: MA
authors: LaBarge
authors: Center for Systems and Synthetic Biology, University of California, San Francisco, CA 94143;
authors: Matthew
authors: M
authors: Thomson
authors: University of California at Berkeley-University of California at San Francisco Graduate Program in Bioengineering, University of California, Berkeley, CA 94720; Pharmaceutical Chemistry, and Center for Systems and Synthetic Biology, University of California, San Francisco, CA 94143; zev.gartner@ucsf.edu.
authors: Zev J
authors: ZJ
authors: Gartner
mesh_terms: D002450:Cell Communication; D004847:Epithelial Cells / Q000166:cytology; D005109:Extracellular Matrix; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*
keywords: cell sorting; differential adhesion; heterogeneity; mammary; prostate
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