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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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.
No human or animal studies were carried out by the authors for this article.
Steven J. Holfinger and James W. Reinhardt are co-first authors.
Associate Editor Michael R. King oversaw the review of this article.
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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) doi:10.1007/s12195-015-0396-5
- Islet cells
- Differential adhesion
- Agent-based modeling
- Time-lapse microscopy