Dynamic stem cell heterogeneity

Krieger, Teresa G; Simons, Benjamin D.

doi:10.1242/dev.101063

Cited by 115 publications

(105 citation statements)

References 105 publications

(116 reference statements)

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“…Moreover, many adult stem cells balance their fate via neutral competition (Krieger and Simons, 2015). Our model proposes a mechanism whereby Notch/Delta signalling could result in neutral competition of stem cells by lateral inhibition between sibling cells.…”

Section: Discussionmentioning

confidence: 96%

Diversity of fate outcomes in cell pairs under lateral inhibition

et al. 2017

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Cell fate determination by lateral inhibition via Notch/Delta signalling has been extensively studied. Most formalised models consider Notch/Delta interactions in fields of cells, with parameters that typically lead to symmetry breaking of signalling states between neighbouring cells, commonly resulting in salt-and-pepper fate patterns. Here, we consider the case of signalling between isolated cell pairs, and find that the bifurcation properties of a standard mathematical model of lateral inhibition can lead to stable symmetric signalling states. We apply this model to the adult intestinal stem cell (ISC) of Drosophila, the fate of which is stochastic but dependent on the Notch/Delta pathway. We observe a correlation between signalling state in cell pairs and their contact area. We interpret this behaviour in terms of the properties of our model in the presence of population variability in contact areas, which affects the effective signalling threshold of individual cells. Our results suggest that the dynamics of Notch/Delta signalling can contribute to explain stochasticity in stem cell fate decisions, and that the standard model for lateral inhibition can account for a wider range of developmental outcomes than previously considered.

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Section: Discussionmentioning

confidence: 96%

Diversity of fate outcomes in cell pairs under lateral inhibition

et al. 2017

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“…Similar effects may compromise the dN/dS ratio, a measure of the relative abundance of nonsynonymous to synonymous mutations (21). However, by analyzing the full probability distribution of mutant clone sizes, and drawing upon knowledge of adult stem cell self-renewal strategies (1,22), we show that quantitative insights can be gained into the dynamics and fate behavior of mutant clones, providing access to both the normal state properties of tissue-maintaining cells and their dynamics following premalignant transformation. In doing so, we offer a different perspective on the deep sequencing study of Martincorena et al (16).…”

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confidence: 95%

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

Simons

2015

Proc. Natl. Acad. Sci. U.S.A.

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Using deep sequencing technology, methods based on the sporadic acquisition of somatic DNA mutations in human tissues have been used to trace the clonal evolution of progenitor cells in diseased states. However, the potential of these approaches to explore cell fate behavior of normal tissues and the initiation of preneoplasia remain underexploited. Focusing on the results of a recent deep sequencing study of eyelid epidermis, we show that the quantitative analysis of mutant clone size provides a general method to resolve the pattern of normal stem cell fate and to detect and characterize the mutational signature of rare field transformations in human tissues, with implications for the early detection of preneoplasia.stem cells | DNA sequencing | epidermis | cancer A dvances in genetic lineage tracing in transgenic animal models have provided important insights into the proliferative potential and fate behavior of stem and progenitor cell populations in normal tissues (1, 2). As well as providing constraints on the mechanisms that regulate stem cell self-renewal, these approaches have established a quantitative framework to address tumor initiation and progression (3-6). However, studies based on the clonal activation of oncogenes in animal models can fail to recapitulate the natural processes that lead to neoplasia in human tissues. In recent years, there has been increasing emphasis on the characterization of cancer genomes in human tissues and their potential to elucidate the pathways involved in tumor progression (7)(8)(9)(10)(11)(12)(13)(14). Although these studies have revealed a range of cancer genes (15), the heterogeneity and evolutionary diversity of the tumor environment make the separation of driver and passenger mutations challenging.Against the trend to focus on human tumor samples, a recent study has used ultradeep exome sequencing to determine the mutational profile of normal human eyelid epidermis (16). In the course of DNA replication, all dividing cells are subject to random SNPs. If the mutation rate is sufficiently low that their acquisition at a given locus in a cell subpopulation is typically associated with a single event, they confer a potentially unique hereditary label on cells, allowing the fate of their progeny to be traced over time. By resolving the mutant allele fraction in a biopsy using deep sequencing, the relative size of mutant clones can be inferred. A similar approach based on the spontaneous acquisition of mitochondrial DNA mutation has been used to address progenitor cell fate in human airways and intestinal epithelia (17,18). To assess the selective growth advantage of different mutations in normal epidermis, Martincorena et al. (16) compared the dN/dS ratio and average size of clones derived from mutations in genes associated with cancer drivers with those associated with synonymous mutations in nondriver genes. Their analysis showed a significant increase in the abundance and average size of clones that bear mutations in NOTCH1 and tumor protein p53 (TP53) compared wit...

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“…In cellular contexts, it is also important to re-interpret our results in the presence of stochastic fluctuations, which can play a role in cell fate determination [56][57][58][59][60][61][62][63]. Noise induced transitions between different cell types can play an important role in gaining a comprehensive understanding of the differentiation process.…”

Section: Discussionmentioning

confidence: 93%

Reprogramming, oscillations and transdifferentiation in epigenetic landscapes

Kaity

Sarkar

Chakrabarti

et al. 2017

Preprint

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Waddington's epigenetic landscape provides a phenomenological understanding of the cell differentiation pathways from the pluripotent to mature lineage-committed cell lines. In light of recent successes in the reverse programming process there has been significant interest in quantifying the underlying landscape picture through the mathematics of gene regulatory networks. We investigate the role of time delays arising from multistep chemical reactions and epigenetic rearrangement on the cell differentiation landscape for a realistic two-gene regulatory network, consisting of selfpromoting and mutually inhibiting genes. Our work provides the first theoretical basis of the transdifferentiation process in the presence of delays, where one differentiated cell type can transition to another directly without passing through the undifferentiated state. Additionally, the interplay of time-delayed feedback and a time dependent chemical drive leads to long-lived oscillatory states in appropriate parameter regimes. This work emphasizes the important role played by time-delayed feedback loops in gene regulatory circuits and provides a framework for the characterization of epigenetic landscapes.

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Dynamic stem cell heterogeneity

Cited by 115 publications

References 105 publications

Diversity of fate outcomes in cell pairs under lateral inhibition

Diversity of fate outcomes in cell pairs under lateral inhibition

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

Reprogramming, oscillations and transdifferentiation in epigenetic landscapes

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