Cerchiari Alec E, Garbe James C, Jee Noel Y, Todhunter Michael E, Broaders Kyle E, Peehl Donna M, Desai Tejal A, LaBarge Mark A, Thomson Matthew, Gartner Zev J
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.
Departments of Bioengineering and Therapeutic Sciences and Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; and.
Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2287-92. doi: 10.1073/pnas.1410776112. Epub 2015 Jan 29.
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.
发育中的组织包含可移动的细胞群体，这些细胞能够基于其界面表面能的差异自组织形成空间有序的组织。然而，尚不清楚当界面能在时间或空间上变得不均匀时，通过这种机制的自组织如何保持稳健。人类乳腺的导管和腺泡是典型的异质性和动态组织，由两种同心排列的细胞类型组成。为了研究细胞异质性和可塑性对乳腺中细胞定位的影响，我们在体外从原代细胞聚集体中重建了其自组织过程。我们发现，自组织主要由组织 - 细胞外基质（ECM）边界的界面能主导，而不是由细胞 - 细胞相互作用的差异同型和异型能量主导。令人惊讶的是，与组织 - ECM边界的相互作用是二元的，即只有一种细胞类型与边界有明显的相互作用。通过数学建模和对细胞 - 细胞黏附关键调节因子的细胞类型特异性敲低，我们表明这种自组织策略对于影响细胞 - 细胞接触形成的严重扰动具有稳健性。我们还发现这种自组织机制在人类前列腺中是保守的。因此，与组织边界的二元界面相互作用为形成和维持表现出丰富异质性和可塑性的双组分组织的结构提供了一种灵活且可推广的策略。我们的模型还预测，影响二元细胞 - ECM相互作用的突变是灾难性的，可能导致乳腺癌等疾病中组织结构的丧失。
