Stem cell biologists are increasingly making use of computational models to decipher their data. However, there is sometimes uncertainty about what makes a “good” model. The purpose of this ...commentary is to argue for closer integration of experiment and theory in stem cell research and propose guidelines for good theory.
Stem cell biologists are increasingly making use of computational models to decipher their data. However, there is sometimes uncertainty about what makes a “good” model. The purpose of this commentary is to argue for closer integration of experiment and theory in stem cell research and propose guidelines for good theory.
The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we ...demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Complex biological processes, such as cellular differentiation, require intricate rewiring of intra-cellular signalling networks. Previous characterisations revealed a raised network entropy ...underlies less differentiated and malignant cell states. A connection between entropy and Ricci curvature led to applications of discrete curvatures to biological networks. However, predicting dynamic biological network rewiring remains an open problem. Here we apply Ricci curvature and Ricci flow to biological network rewiring. By investigating the relationship between network entropy and Forman-Ricci curvature, theoretically and empirically on single-cell RNA-sequencing data, we demonstrate that the two measures do not always positively correlate, as previously suggested, and provide complementary rather than interchangeable information. We next employ Ricci flow to derive network rewiring trajectories from stem cells to differentiated cells, accurately predicting true intermediate time points in gene expression time courses. In summary, we present a differential geometry toolkit for understanding dynamic network rewiring during cellular differentiation and cancer.
Single-cell sequencing (sc-Seq) experiments are producing increasingly large data sets. However, large data sets do not necessarily contain large amounts of information.
Here, we formally quantify ...the information obtained from a sc-Seq experiment and show that it corresponds to an intuitive notion of gene expression heterogeneity. We demonstrate a natural relation between our notion of heterogeneity and that of cell type, decomposing heterogeneity into that component attributable to differential expression between cell types (inter-cluster heterogeneity) and that remaining (intra-cluster heterogeneity). We test our definition of heterogeneity as the objective function of a clustering algorithm, and show that it is a useful descriptor for gene expression patterns associated with different cell types.
Thus, our definition of gene heterogeneity leads to a biologically meaningful notion of cell type, as groups of cells that are statistically equivalent with respect to their patterns of gene expression. Our measure of heterogeneity, and its decomposition into inter- and intra-cluster, is non-parametric, intrinsic, unbiased, and requires no additional assumptions about expression patterns. Based on this theory, we develop an efficient method for the automatic unsupervised clustering of cells from sc-Seq data, and provide an R package implementation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Baryawno et al. provide a comprehensive atlas of the mouse bone marrow stroma based on single-cell RNA-sequencing data. Their analysis reveals a taxonomy of 17 distinct cell types with diverse ...functions that highlights the complexity of the bone marrow stroma and paves the way for future in vivo assessment.
Baryawno et al. provide a comprehensive atlas of the mouse bone marrow stroma based on single-cell RNA-sequencing data. Their analysis reveals a taxonomy of 17 distinct cell types with diverse functions that highlights the complexity of the bone marrow stroma and paves the way for future in vivo assessment.
Adaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting ...cells (APCs), respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here, we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR aggregation. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell
that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis, we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.
During acute myelosuppression or thrombocytopenia, bone marrow (BM) hematopoietic cells respond rapidly to replenish peripheral blood platelets. While the cytokine thrombopoietin (Thpo) both ...regulates platelet production and maintains HSC potential, whether Thpo controls megakaryocyte (Mk)-lineage differentiation of HSCs is unclear. Here, we show that Thpo rapidly upregulates mitochondrial activity in HSCs, an activity accompanied by differentiation to an Mk lineage. Moreover, in unperturbed hematopoiesis, HSCs with high mitochondrial activity exhibit Mk-lineage differentiation in vitro and myeloid lineage-biased reconstitution in vivo. Furthermore, Thpo skewed HSCs to express the tetraspanin CD9, a pattern correlated with mitochondrial activity. Mitochondria-active HSCs are resistant to apoptosis and oxidative stress upon Thpo stimulation. Thpo-regulated mitochondrial activity associated with mitochondrial translocation of STAT3 phosphorylated at serine 727. Overall, we report an important role for Thpo in regulating rapid Mk-lineage commitment. Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage.
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•Thpo facilitates Mk-lineage differentiation through mitochondrial activation in HSCs•Mitochondria-rich HSCs exhibit Mk-lineage differentiation•Mitochondria-associated pSTAT3 is involved in mitochondria activation via Thpo signaling
Nakamura-Ishizu et al. show that Thpo rapidly upregulates HSC mitochondrial activity in HSCs, an activity accompanied by preferential differentiation to an Mk lineage. Thpo-induced mitochondrial activity correlates with the tetraspanin CD9 expression pattern on HSCs. The findings suggest that Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage.
Theory of cell fate Casey, Michael J.; Stumpf, Patrick S.; MacArthur, Ben D.
Wiley interdisciplinary reviews. Systems biology and medicine,
March/April 2020, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Cell fate decisions are controlled by complex intracellular molecular regulatory networks. Studies increasingly reveal the scale of this complexity: not only do cell fate regulatory networks contain ...numerous positive and negative feedback loops, they also involve a range of different kinds of nonlinear protein–protein and protein–DNA interactions. This inherent complexity and nonlinearity makes cell fate decisions hard to understand using experiment and intuition alone. In this primer, we will outline how tools from mathematics can be used to understand cell fate dynamics. We will briefly introduce some notions from dynamical systems theory, and discuss how they offer a framework within which to build a rigorous understanding of what we mean by a cell “fate”, and how cells change fate. We will also outline how modern experiments, particularly high‐throughput single‐cell experiments, are enabling us to test and explore the limits of these ideas, and build a better understanding of cellular identities.
This article is categorized under:
Models of Systems Properties and Processes > Mechanistic Models
Biological Mechanisms > Cell Fates
Models of Systems Properties and Processes > Cellular Models
The cell as a dynamical system: combining theory and experiment to understand cell fates.
Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component ...of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture. Moreover, treatment of HSCs with exogenous Pot1a inhibits the production of reactive oxygen species, suggesting a non-telomeric role for Pot1a in HSC maintenance. Consistent with these results, treatment with exogenous human POT1 protein maintains human HSC activity in culture. Collectively, these results show that Pot1a/POT1 sustains HSC activity and can be used to expand HSC numbers ex vivo.Repeated cell divisions induce DNA damage in haematopoietic stem cells (HSC) and telomeres are sensitive to this damage. Here, the authors show in murine HSCs that the telomere binding protein POT1a inhibited the production of reactive oxygen species, and rejuvenated aged HSCs.
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