Methodology article

Multiway modeling and analysis in stem cell systems biology

Bülent Yener¹ , Evrim Acar¹ , Pheadra Aguis³ , Kristin Bennett⁴ , Scott L Vandenberg⁵ and George E Plopper²

¹Department of Computer Science, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA

²Department of Biology Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA

³Institute of Computer Science, University of Tartu, Liivi 2, Tartu, Estonia

⁴Department of Mathematics Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA

⁵Department of Computer Science, Siena College, 515 Loudon Road, Loudonville, NY 12211, USA

author email corresponding author email

BMC Systems Biology 2008, 2:63doi:10.1186/1752-0509-2-63

Published:	14 July 2008

Abstract

Background

Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems. Stem cells are an attractive target for this analysis, due to their broad therapeutic potential. A central theme of systems biology is the use of computational modeling to reconstruct complex systems from a wealth of reductionist, molecular data (e.g., gene/protein expression, signal transduction activity, metabolic activity, etc.). A number of deterministic, probabilistic, and statistical learning models are used to understand sophisticated cellular behaviors such as protein expression during cellular differentiation and the activity of signaling networks. However, many of these models are bimodal i.e., they only consider row-column relationships. In contrast, multiway modeling techniques (also known as tensor models) can analyze multimodal data, which capture much more information about complex behaviors such as cell differentiation. In particular, tensors can be very powerful tools for modeling the dynamic activity of biological networks over time. Here, we review the application of systems biology to stem cells and illustrate application of tensor analysis to model collagen-induced osteogenic differentiation of human mesenchymal stem cells.

Results

We applied Tucker1, Tucker3, and Parallel Factor Analysis (PARAFAC) models to identify protein/gene expression patterns during extracellular matrix-induced osteogenic differentiation of human mesenchymal stem cells. In one case, we organized our data into a tensor of type protein/gene locus link × gene ontology category × osteogenic stimulant, and found that our cells expressed two distinct, stimulus-dependent sets of functionally related genes as they underwent osteogenic differentiation. In a second case, we organized DNA microarray data in a three-way tensor of gene IDs × osteogenic stimulus × replicates, and found that application of tensile strain to a collagen I substrate accelerated the osteogenic differentiation induced by a static collagen I substrate.

Conclusion

Our results suggest gene- and protein-level models whereby stem cells undergo transdifferentiation to osteoblasts, and lay the foundation for mechanistic, hypothesis-driven studies. Our analysis methods are applicable to a wide range of stem cell differentiation models.