Abstract
The generation of induced pluripotent stem cells from adult somatic cells by ectopic expression of key transcription factors holds significant medical promise. However, current techniques for inducing pluripotency rely on viral infection and are therefore not, at present, viable within a clinical setting. Thus, there is now a need to better understand the molecular basis of stem cell pluripotency and lineage specification in order to investigate alternative methods to induce pluripotency for clinical application. However, the complexity of the underlying molecular circuitry makes this a conceptually difficult task. In order to address these issues, we considered a computational model of transcriptional control of cell fate specification. The model comprises two mutually interacting sub-circuits: a central pluripotency circuit consisting of interactions between stem-cell specific transcription factors OCT4, SOX2 and NANOG coupled to a differentiation circuit consisting of interactions between lineage-specifying master genes.The molecular switches which arise from feedback loops within these circuits give rise to a well-defined sequence of successive gene restrictions corresponding to a controlled differentiation cascade in response to environmental stimuli. Furthermore, we found that this differentiation cascade is strongly unidirectional: once silenced, core transcription factors cannot easily be reactivated. In the context of induced pluripotency, this indicates that differentiated cells are robustly resistant to reprogramming to a more primitive state. However, our model suggests that under certain circumstances, amplification of low-level fluctuations in transcriptional status (transcriptional “noise”) may be sufficient to trigger reactivation of the core pluripotency switch and reprogramming to a pluripotent state. This interpretation offers an explanation of a number of experimental observations concerning the molecular mechanisms of cellular reprogramming by defined factors and suggests a role for stochasticity in reprogramming of somatic cells to pluripotency.
Highlights
Stem cells are present during all phases of development, from the embryo to the adult, and are characterized by their ability to self-renew indefinitely and differentiate along a variety of distinct lineages
(cell types) to coexist in the same environment. This multistability derives from the positive feedback loops in the transcriptional circuitry [55] and results in a sequence of genetic ‘‘switches’’, which correspond to a sequence of successive gene restrictions
For some parameter values we found that the cell differentiates directly from a pluripotent state to a terminal osteoblastic state in which RUNX2 alone is active; while for other parameter values we found that differentiation proceeds through a sequence of intermediary states in which competing lineage-specifying master genes (LSMGs) are co-expressed before the terminal state is obtained
Summary
Stem cells are present during all phases of development, from the embryo to the adult, and are characterized by their ability to self-renew indefinitely and differentiate along a variety of distinct lineages. The traditional conceptual model of cellular differentiation is discrete and hierarchical in nature [4] In this view, cells can be one of a number of qualitatively different types (stem, progenitor or terminal cell for instance) and differentiation proceeds through a well-defined hierarchy of increasingly committed progenitor cells which act as transit populations between the most pluripotent stem cells and terminally differentiated cells, and serve to facilitate rapid clonal expansion. Cells can be one of a number of qualitatively different types (stem, progenitor or terminal cell for instance) and differentiation proceeds through a well-defined hierarchy of increasingly committed progenitor cells which act as transit populations between the most pluripotent stem cells and terminally differentiated cells, and serve to facilitate rapid clonal expansion This process was traditionally thought to progress through a series of irreversible gene restrictions which limited dedifferentiation to more primitive states. Recent experimental evidence suggests that under certain circumstances ‘‘terminally’’ differentiated cells may retain the capacity to dedifferentiate to more primitive states and possibly transdifferentiate to alternative terminal states [3,5,6,7,8], the molecular mechanisms by which this reprogramming occurs remain contentious [9]
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