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Author Notes:

Corresponding author: * E-mail: melissa.kemp@bme.gatech.edu

Conceived and designed the experiments: DEW MAK TCM MLK. Performed the experiments: DEW MAK.

Analyzed the data: DEW MAK. Contributed reagents/materials/analysis tools: DEW MAK TCM MLK.

Wrote the paper: DEW TCM MLK. Designed the software used for model: DEW.

We would like to thank Bethany Clement and Bryant Menn for assistance in classification of the Oct4 spatial pattern data.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

DEW is supported by the NSF Stem Cell IGERT program (DGE 0965945).

MAK was supported by an NSF Graduate Research Fellowship.

This work was also sponsored by the NSF Emergent Behaviors of Integrated Cellular Systems Science and Technology Center (CBET 0939511; MLK and TCM) and NIH R01 EB010061 (TCM).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemical Research Methods
  • Mathematical & Computational Biology
  • Biochemistry & Molecular Biology
  • BIOCHEMICAL RESEARCH METHODS
  • MATHEMATICAL & COMPUTATIONAL BIOLOGY
  • LEUKEMIA INHIBITORY FACTOR
  • TRANSCRIPTION FACTOR OCT4
  • SELF-RENEWAL
  • NEURAL DIFFERENTIATION
  • EMBRYOID BODIES
  • IN-VITRO
  • OSTEOGENIC DIFFERENTIATION
  • PROLIFERATION
  • ORGANIZATION
  • MULTISCALE

Spatial Pattern Dynamics of 3D Stem Cell Loss of Pluripotency via Rules-Based Computational Modeling

Journal Title:

PLoS Computational Biology

Volume:

Volume 9, Number 3

Publisher:

, Pages e1002952-e1002952

Type of Work:

Article | Final Publisher PDF

Abstract:

Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into cells from all germ lineages, making them a potentially robust cell source for regenerative medicine therapies, but difficulties in predicting and controlling ESC differentiation currently limit the development of therapies and applications from such cells. A common approach to induce the differentiation of ESCs in vitro is via the formation of multicellular aggregates known as embryoid bodies (EBs), yet cell fate specification within EBs is generally considered an ill-defined and poorly controlled process. Thus, the objective of this study was to use rules-based cellular modeling to provide insight into which processes influence initial cell fate transitions in 3-dimensional microenvironments. Mouse embryonic stem cells (D3 cell line) were differentiated to examine the temporal and spatial patterns associated with loss of pluripotency as measured through Oct4 expression. Global properties of the multicellular aggregates were accurately recapitulated by a physics-based aggregation simulation when compared to experimentally measured physical parameters of EBs. Oct4 expression patterns were analyzed by confocal microscopy over time and compared to simulated trajectories of EB patterns. The simulations demonstrated that loss of Oct4 can be modeled as a binary process, and that associated patterns can be explained by a set of simple rules that combine baseline stochasticity with intercellular communication. Competing influences between Oct4+ and Oct4- neighbors result in the observed patterns of pluripotency loss within EBs, establishing the utility of rules-based modeling for hypothesis generation of underlying ESC differentiation processes. Importantly, the results indicate that the rules dominate the emergence of patterns independent of EB structure, size, or cell division. In combination with strategies to engineer cellular microenvironments, this type of modeling approach is a powerful tool to predict stem cell behavior under a number of culture conditions that emulate characteristics of 3D stem cell niches.

Copyright information:

© 2013 White et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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