Abstract
BackgroundSystems 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.ResultsWe 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.ConclusionOur 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.
Highlights
Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems
Case study I Impact of different stimulants on human mesenchymal stem cells (hMSC) osteogenic differentiation In Bennett et al [48], we examined the protein expression profiles of four populations of hMSC stimulated to undergo osteogenic differentiation via either contact with pro-osteogenic extracellular matrix (ECM) proteins or addition of osteogenic media supplements (OS media)
The methods illustrated here provide a means for translating large data sets that capture global gene and protein expression changes during hMSC differentiation into simplified models
Summary
Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems. 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. Many of these models are bimodal i.e., they only consider row-column relationships. The reductionist approach to biological research has reigned supreme for generations, and as a result we understand how the linear arrangement of nucleotides encodes the linear arrangement of amino acids, how proteins interact to form functional groups such as signal transduction and metabolic pathways, etc. We encounter a gap in the structure/function relationship: having accumulated an extraordinary amount of detailed information about biological structures, we can't assemble it in a way that explains the correspondingly complex biological functions these structures perform
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