Stem cell decision making and critical-like exploratory networks

Abstract

A sound theoretical or conceptual model of gene regulatory processes that control stem cell fate is still lacking, compromising our ability to manipulate stem cells for therapeutic benefit. The complexity of the regulatory and signaling pathways limits development of useful, predictive models that employ solely reductionist methods using molecular components. However, there is clear evidence from other complex systems that coarse-grained or mesoscale models can yield useful insights and provide workable models for the prediction of some emergent properties such as cell phenotype. We present such a coarse-grained model of stem cell decision making, utilizing the concept of self-organized criticality, which is an order that propagates in some nonequilibrium systems. The model proposes that stochastic gene expression within a stem cell gene regulatory network self-organizes to a critical-like state, characterized by cascades of gene expression that prime various transcriptional programs associated with different cell fates. This diversity of cell fate options is reduced during the decision-making process, which involves a supercritical connectivity in the gene regulatory network as a stem cell leaves its niche microenvironment and an overall increase in transcription occurs. As modules of genes that correspond to specific cell fates approach their critical points, competitive interactions occur between them that are influenced by prevailing microenvironmental conditions. The conceptual model incorporates both intrinsic and extrinsic factors governing stem cell fate and provides a logical pathway to the development of a computational model. We further suggest that rapid self-organized criticality, rather than self-organized criticality, best describes the mesoscale organization of gene regulatory networks.

Self-Organizing Global Gene Expression Regulated through Criticality: Mechanism of the Cell-Fate Change

“…A basic principle for the cell-fate decision-making model (a coarse-grained model, the same as in our approach) is that gene regulatory networks adopt an exploratory process, where diverse cell-fate options are first generated by the priming of various transcriptional programs, and then a cell-fate gene module is selectively amplified as the network system approaches a critical state [75,76]; these review articles also present a useful survey of studies on self-organization in biological systems.…”

“…It has been pointed out that fine-tuning of a driving parameter for self-organization in classical SOC generates a controversy regarding the real meaning of self-organization (see more in [75]).…”

Nanog Dynamics in Mouse Embryonic Stem Cells: Results from Systems Biology Approaches

“…The hypothesis that pluripotency is an emergent property of a population of cells rather than a characteristic of a single cell [60], with noise and cellular heterogeneity conferring stem cell high entropy, and thus the potential to choose a number of specialized, differentiated fates [105, 106], still needs to be more extensively characterized not only for embryonic but also induced and adult stem cells. Also, the “exploratory hypothesis” for pluripotent cells, which conjectures stem cell decision-making as a two-step process in which firstly stochasticity induces a critical state that primes diverse transcriptional programs, and then one particular fate is chosen via interaction with external inputs [107, 108], represents, in our view, an interesting research avenue for further investigation.…”

Critical Behavior and Axis Defining Symmetry Breaking inHydraEmbryonic Development

“…Multicellular self-organization is a most intriguing phenomenon in the quest for understanding biological complexity and development [1]. One of the model organisms for the study of multicellular development is the freshwater polyp Hydra [2].…”