SBI – Department of Systems Biology and Bioinformatics
Faculty of Computer Science and Electrical Engineering
University of Rostock
Ulmenstrasse 69 | 18057 Rostock
Germany
+49 381 498-7571
olaf.wolkenhauer@uni-rostock.de
Quantitative Modelling of Stem Cell Dynamics
The adult tissue of an organism includes stem cells, which through cell division cycles maintain and regenerate the functional tissue through differentiation and maturation. With regard to stem cell dynamics our research focus is on multilevel systems. Multilevelness is a defining characteristic of complex systems. The behavior of the system "as a whole" is considered to emerge from the functioning and interactions of its parts. What we are seeking is a conceptual (mathematical) framework to analyse how the "fate" of the tissue is an emergent property that inherently arises from the complex yet robust underlying biology of stem cells. Without specifying how the emergence takes place, the concept has almost a mystical character, it is an observation rather than a contribution to understanding the phenomenon. For understanding it is necessary to identify how the behavior of the whole changes when the parts and/or interactions between them change. Understanding cross-level relations in complex systems is key to "demystifying" the concept of emergence.
With regard to stem cell dynamics we are currently pursuing four modelling strategies that address different levels of abstraction: (i) simulation models, inspired by molecular dynamics techniques, to simulate the consequences of spatio-temporal changes in the stem cell environment on cell-cell communication and cell decisions, (ii) rate equation models, for noise-free compartmental models describing stem cell dynamics, (iii) logical models, using rank-order relations to explore cross-level principles that link stem cell lineages with the fate of the tissue and (iv) stochastic models, using the Langevin approach to distinguish internal noise (arising from the underlying gene expression) from the external noise (arising from cell-cell interactions and cell-environmental-driven fluctuations in the system).
With our models we are investigating the capability of stem cells to respond to environmental cues in order to produce differentiated cells and to maintain/regenerate tissue homeostasis. Although the tissue may appear stable with respect to total cell numbers and types, the underlying parts or cell lineages may in fact be quite dynamic or unstable in order to maintain macroscopic homeostasis. What we are focusing on is the relation between the stem cells lineages (their stemness) and the future development (fate) of the tissue. In particular, we study the balance of cell divisions that maintain, reduce, or expand the pool of those cells that can generate lineages (referred to as "stem cells"), transient cells and cells committed to differentiation and maturation to maintain the normal functioning of the tissue.
We recently established a novel conceptual framework in which to formalize cross-level principles in the context of tissue organization. To this end we provided a definition for stemness, which is the propensity of a cell lineage to contribute to a tissue fate. We do not consider stemness a property of a cell but link it to the process in which a cell lineage contributes towards tissue (mal)function. We then postulate a theorem to prove that the only logically feasible relationship between the stemness of cell lineages and the emergent fate of their tissue, which satisfies the given criteria, is one of dominance from a particular lineage.