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Pancreatic Epithelial Cells Form Islet-Like Clusters in the Absence of Directed Migration

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Abstract

The endocrine differentiation of pancreatic ductal epithelial cells is dependent upon their transition from a two-dimensional monolayer to three-dimensional islet-like clusters. Although clustering of these cells is commonly observed in vitro, it is not yet known whether clustering results from long-range signaling (e.g., chemotaxis) or short-range interactions (e.g., differential adhesion). To determine the mechanism behind clustering, we used experimental and computational modeling to determine the individual contributions of long-range and short-range interactions. Experimentally, the migration of PANC-1 cells on tissue culture treated plastic was tracked by time-lapse microscopy with or without a central cluster of cells that could act as a concentrated source of some long-range signal. Cell migration data was analyzed in terms of distance, number of steps, and migration rate in each direction, as well as migration rate as a function of distance from the cluster. Results did not indicate directed migration toward a central cluster (p > 0.05). Computationally, an agent-based model was used to demonstrate the plausibility of clustering by short-range interactions only. In the presence of random cell migration, this model showed that a high, but not maximal, cell–cell adhesion probability and minimal cell–substrate adhesion probability supported the greatest islet-like cluster formation.

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Acknowledgments

This work was supported by National Science Foundation Grants NSF-CMMI (0928739 and 1334757).

Conflict of interest

Mr. Holfinger and Drs. Reinhardt, Reen, Schultz, Passino, Ackerman, Kniss, Sander, Gallego-Perez, and Gooch have no conflicts of interest.

Ethical Standards

No human or animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, 43210, USA

    Steven J. Holfinger, James W. Reinhardt, Rashmeet Reen, Douglas A. Kniss, Daniel Gallego-Perez & Keith J. Gooch

  2. Department of Electrical and Computer Engineering, The Ohio State University, Columbus, OH, 43210, USA

    Kevin M. Schultz & Kevin M. Passino

  3. Department of Obstetrics and Gynecology, College of Medicine, and Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA

    William E. Ackerman & Douglas A. Kniss

  4. Department of Physics, University of Michigan, Ann Arbor, MI, 48109, USA

    Leonard M. Sander

  5. The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 270 Bevis Hall 1080 Carmack Rd., Columbus, OH, 43210, USA

    Keith J. Gooch

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  1. Steven J. Holfinger
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  2. James W. Reinhardt
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  10. Keith J. Gooch
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Correspondence to Keith J. Gooch.

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Associate Editor Michael R. King oversaw the review of this article.

Steven J. Holfinger and James W. Reinhardt are co-first authors.

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Holfinger, S.J., Reinhardt, J.W., Reen, R. et al. Pancreatic Epithelial Cells Form Islet-Like Clusters in the Absence of Directed Migration. Cel. Mol. Bioeng. 8, 496–506 (2015). https://doi.org/10.1007/s12195-015-0396-5

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  • DOI: https://doi.org/10.1007/s12195-015-0396-5

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