Stem Cell Fate Analysis Revisited: Interpretation of Individual Clone Dynamics in the Light of a New Paradigm of Stem Cell Organization

Abstract

Many experimental findings on heterogeneity, flexibility, and plasticity of tissue stem cells are currently challenging stem cell concepts that assume a cell intrinsically predefined, unidirectional differentiation program. In contrast to these classical concepts, nonhierarchical self-organizing systems provide an elegant and comprehensive alternative to explain the experimental data. Here we present the application of such a self-organizing concept to quantitatively describe the hematopoietic stem cell system. Focusing on the analysis of individual-stem-cell fates and clonal dynamics, we particularly discuss implications of the theoretical results on the interpretation of experimental findings. We demonstrate that it is possible to understand hematopoietic stem cell organization without assumptions on unidirectional developmental hierarchies, preprogrammed asymmetric division events or other assumptions implying the existence of a predetermined stem cell entity. The proposed perspective, therefore, changes the general paradigm of thinking about stem cells.

Bone marrow mesenchymal stem cells differentiate into urothelial cells and the implications for reconstructing urinary bladder mucosa

“…This approach has also been applied to BMSCs (Coleman et al 2007). Because stem cell behavior is not the result of a cell-autonomous program, but is instead the consequence of complex cell-cell and cell-environmental interactions, a suitable growth environment is essential for achieving the desired differentiated phenotype (Roeder et al 2007). Previous reports have revealed that BMSCs can undergo differentiation into urothelium-like cells.…”

Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: a model-based approach

“…Based on a simulation study, we previously estimated the magnitude of this effect in a homeostatic reference system, predicting a reduction to one-tenth of the initial clone numbers within the lifespan of a B6 mouse. 26 Although the process of clonal selection is predicted to be enhanced by differences in the growth characteristics of individual cells, 26 the estimated within-strain heterogeneity of clonal properties does not cause a significant acceleration of this process (data not shown). Nevertheless, our model predicts the exhaustion of clones with competitive disadvantages.…”

“…23,24 This model has previously been validated in different murine systems 22,25,26 and was valuable for the understanding of disease dynamics and treatment effects in human chronic myeloid leukemia. 27,28 The model features a stochastic single-cellbased approach to analyze stem-cell dynamics on the population as well as on the single-cell level.…”

Enabling stem cell therapies through synthetic stem cell–niche engineering

“…Applying such technologies to stem cell cultures will allow us to parse out intercellular communication networks established by the stem cells and their derivatives. Regarding characterization, systems biology approaches to studying interactions between stem cells and their niches, along with in silico modeling, have generated relevant network models capable of predicting whether a stem cell will self-renew or differentiate (29,87,88). These models can provide mechanistic insight into how stem cell-culture heterogeneity influences culture output, can be used to optimize culture output, and can predict how dysregulation may occur in malignancies (29,89).…”