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A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity

Cerchiari, Alec E. and Garbe, James C. and Jee, Noel Y. and Todhunter, Michael E. and Broaders, Kyle E. and Peehl, Donna M. and Desai, Tejal A. and LaBarge, Mark A. and Thomson, Matthew and Gartner, Zev J. (2015) A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity. Proceedings of the National Academy of Sciences of the United States of America, 112 (7). pp. 2287-2292. ISSN 0027-8424. PMCID PMC4343104. https://resolver.caltech.edu/CaltechAUTHORS:20170206-125245656

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1410776112DOIArticle
http://www.pnas.org/content/112/7/2287.abstractPublisherArticle
http://www.pnas.org/content/suppl/2015/01/29/1410776112.DCSupplemental/pnas.201410776SI.pdfPublisherSupporting Information
http://www.pnas.org/content/suppl/2015/01/29/1410776112.DCSupplemental/pnas.1410776112.sapp.pdfPublisherAppendix
http://static-movie-usa.glencoesoftware.com/source/10.1073/696/aa2d548d39c3c430cc798f068fa6ccd949a9472d/pnas.1410776112.sm01.aviPublisherSupporting Information
http://static-movie-usa.glencoesoftware.com/source/10.1073/696/aa2d548d39c3c430cc798f068fa6ccd949a9472d/pnas.1410776112.sm02.aviPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343104/PubMed CentralArticle
ORCID:
AuthorORCID
Desai, Tejal A.0000-0003-3409-9208
Additional Information:© 2015 The Authors. Edited by Ken A. Dill, Stony Brook University, Stony Brook, NY, and approved December 30, 2014 (received for review June 9, 2014) The authors thank Dr. Maija Valta for help in preparing primary prostate organoids, Dr. Jennifer Liu and Dr. Alba de Moniz for technical assistance and comments, Dr. Justin Farlow for help with data analysis, and an anonymous reviewer for helpful comments on the manuscript. This work was supported by a seed grant from the National Institutes of Health (NIH) Bay Area Physical Sciences and Oncology Center (to Z.J.G. and M.A.L.); Department of Defense Breast Cancer Research Program Grants W81XWH-10-1-1023 and W81XWH-13-1-0221 (to Z.J.G.); NIH common funds Grants DP5 OD012194-03 (to M.T.) and DP2 HD080351-01 (to Z.J.G.); the Sidney Kimmel Foundation; and the University of California, San Francisco (UCSF) Program in Breakthrough Biomedical Research. Z.J.G. and M.T. are supported by the UCSF Center for Systems and Synthetic Biology (National Institute of General Medical Sciences Systems Biology Center Grant P50 GM081879). A.E.C. was supported by the US Department of Defense through a National Defense Science and Engineering Graduate Fellowship.
Funders:
Funding AgencyGrant Number
Department of DefenseW81XWH-10-1-1023
Department of DefenseW81XWH-13-1-0221
NIHDP5 OD012194-03
NIHDP2 HD080351-01
Sidney Kimmel FoundationUNSPECIFIED
University of California, San Francisco (UCSF)UNSPECIFIED
NIHP50 GM081879
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC4343104
Record Number:CaltechAUTHORS:20170206-125245656
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170206-125245656
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74083
Collection:CaltechAUTHORS
Deposited By: Donna Wrublewski
Deposited On:06 Feb 2017 23:32
Last Modified:09 Mar 2020 13:18

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