Ben D. MacArthur

TL;DR: It is demonstrated that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

TL;DR: These reports suggest that the control of cell fate has both deterministic and stochastic elements: complex underlying regulatory networks define stable molecular 'attractor' states towards which individual cells are drawn over time, whereas stochastically fluctuations in gene and protein expression levels drive transitions between coexisting attractors, ensuring robustness at the population level.

Abstract: Molecular regulation of embryonic stem cell (ESC) fate involves a coordinated interaction between epigenetic, transcriptional and translational mechanisms. It is unclear how these different molecular regulatory mechanisms interact to regulate changes in stem cell fate. Here we present a dynamic systems-level study of cell fate change in murine ESCs following a well-defined perturbation. Global changes in histone acetylation, chromatin-bound RNA polymerase II, messenger RNA (mRNA), and nuclear protein levels were measured over 5 days after downregulation of Nanog, a key pluripotency regulator. Our data demonstrate how a single genetic perturbation leads to progressive widespread changes in several molecular regulatory layers, and provide a dynamic view of information flow in the epigenome, transcriptome and proteome. We observe that a large proportion of changes in nuclear protein levels are not accompanied by concordant changes in the expression of corresponding mRNAs, indicating important roles for translational and post-translational regulation of ESC fate. Gene-ontology analysis across different molecular layers indicates that although chromatin reconfiguration is important for altering cell fate, it is preceded by transcription-factor-mediated regulatory events. The temporal order of gene expression alterations shows the order of the regulatory network reconfiguration and offers further insight into the gene regulatory network. Our studies extend the conventional systems biology approach to include many molecular species, regulatory layers and temporal series, and underscore the complexity of the multilayer regulatory mechanisms responsible for changes in protein expression that determine stem cell fate.

TL;DR: The results show that cell-scaffold constructs that rely solely on diffusion for their supply of nutrients will inevitably produce proliferation-dominated regions near the outer edge of the scaffold in situations when the cell number density and oxygen consumption rate exceed a critical level.

TL;DR: It is argued that the pluripotent state is not well defined at the single-cell level but rather is a statistical property of stem cell populations, amenable to analysis using the tools of statistical mechanics and information theory.