scholarly journals Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues

2022 ◽  
Author(s):  
Calum Gabbutt ◽  
Ryan O. Schenck ◽  
Daniel J. Weisenberger ◽  
Christopher Kimberley ◽  
Alison Berner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Adult Stem Cell ◽  
Lineage Tracing ◽  
Rapid Expansion ◽  
High Temporal Resolution ◽  
Molecular Clocks ◽  
Cell Renewal ◽  
Cell Dynamics ◽  
Small Intestinal

AbstractMolecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated ‘flip–flops’ between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).

scholarly journals Reconstruction of Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks

2021 ◽  
Author(s):  
Calum Gabbutt ◽  
Ryan O Schenck ◽  
Daniel Weisenberger ◽  
Christopher Kimberley ◽  
Alison Berner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cell ◽  
Rapid Expansion ◽  
Molecular Clocks ◽  
Human Stem Cell ◽  
Cell Dynamics ◽  
Modelling Framework ◽  
Small Intestinal ◽  
Apc Mutation

Molecular clocks record cellular ancestry. However, currently used clocks 'tick too slowly' to measure the short-timescale dynamics of cellular renewal in adult tissues. Here we develop 'rapidly oscillating DNA methylation clocks' where ongoing (de)methylation causes the clock to 'tick-tock' back-and-forth between methylated and unmethylated states like a pendulum. We identify oscillators using standard methylation arrays and develop a mathematical modelling framework to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than colon (6.5 ± 1.0 vs 5.8 ± 1.7 stem cells/crypt) with slower stem cell replacement in small intestine (0.79 ± 0.5 vs 1.1 ± 0.8 replacements/stem cell/year). Germline APC mutation increased the number of replacements per crypt (13.0 ± 2.4 replacements/crypt/year vs 6.9 ± 4.6 for healthy colon). In blood, we measure rapid expansion of acute leukaemia and slower growth of chronic disease. Rapidly oscillating molecular clocks are a new methodology to quantitatively measure human somatic cell dynamics.

scholarly journals Stem cell dynamics in mouse hair follicles: A story from cell division counting and single cell lineage tracing

Cell Cycle ◽  
2010 ◽  
Vol 9 (8) ◽  
pp. 1504-1510 ◽  
Author(s):  
Ying V. Zhang ◽  
Brian S. White ◽  
David I. Shalloway ◽  
Tudorita Tumbar
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Single Cell ◽  
Cell Lineage ◽  
Hair Follicles ◽  
Lineage Tracing ◽  
Cell Dynamics

scholarly journals Adult stem cell lineage tracing and deep tissue imaging

BMB Reports ◽  
2015 ◽  
Vol 48 (12) ◽  
pp. 655-667 ◽  
Author(s):  
Juergen Fink ◽  
Amanda Andersson-Rolf ◽  
Bon-Kyoung Koo
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Adult Stem Cell ◽  
Lineage Tracing ◽  
Tissue Imaging ◽  
Deep Tissue ◽  
Stem Cell Lineage ◽  
Deep Tissue Imaging

scholarly journals Shavenbaby protein isoforms orchestrate the self-renewalversusdifferentiation ofDrosophilaintestinal stem cells

2019 ◽  
Author(s):  
Sandy Al Hayek ◽  
Ahmad Alsawadi ◽  
Zakaria Kambris ◽  
Jean-Philippe Boquete ◽  
Jérôme Bohère ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Adult Stem Cell ◽  
Regulatory Peptides ◽  
Protein Isoforms ◽  
Cell Renewal ◽  
Stem Cell Renewal ◽  
Polished Rice ◽  
Stem Cell Lineage ◽  
Underlying Mechanisms

SUMMARYSignaling pathways are key regulators of adult stem cell homeostasis and underlying mechanisms are often deregulated in cancers. Recent studies of epithelial tumors have involved OvoL/Svb transcription factors, which produce isoforms with antagonistic activities. Here we show that Svb, the unique OvoL factor inDrosophila, directly integrates multiple signaling inputs to coordinate the behavior of adult intestinal stem cell lineage. Under steady state, Svb mediates Wnt and EGFR signaling to ensure stem cell renewal and progenitor survival. This requires the post-translational processing of Svb into a transcriptional activator by Polished rice (Pri) regulatory peptides, under the regulation of ecdysone signaling. In response to PDM1, Svb expression is specifically maintained in enterocytes where it acts as a transcriptional repressor sufficient to override mitogenic signals and impose differentiation. Altogether, these results demonstrate that the OvoL/Svb transcriptional switch controls the balance between stem cell survival, self-renewal and differentiation.

scholarly journals Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

2018 ◽  
Vol 115 (4) ◽  
pp. E610-E619 ◽  
Author(s):  
Onur Basak ◽  
Teresa G. Krieger ◽  
Mauro J. Muraro ◽  
Kay Wiebrands ◽  
Daniel E. Stange ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Number ◽  
Lineage Tracing ◽  
Rapid Expansion ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Proliferating Cells ◽  
Self Renewal ◽  
Genetic Lineage Tracing

The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

Unravelling stem cell dynamics by lineage tracing

2013 ◽  
Vol 14 (8) ◽  
pp. 489-502 ◽  
Author(s):  
Cédric Blanpain ◽  
Benjamin D. Simons
Keyword(s):  
Stem Cell ◽  
Lineage Tracing ◽  
Cell Dynamics

scholarly journals Accumulation of a differentiation regulator specifies transit amplifying division number in an adult stem cell lineage

2009 ◽  
Vol 106 (52) ◽  
pp. 22311-22316 ◽  
Author(s):  
Megan L. Insco ◽  
Arlene Leon ◽  
Cheuk Ho Tam ◽  
Dennis M. McKearin ◽  
Margaret T. Fuller
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Adult Stem Cell ◽  
Stem Cell Lineage ◽  
Division Number

scholarly journals Universal principles of lineage architecture and stem cell identity in renewing tissues

2020 ◽  
Author(s):  
Philip Greulich ◽  
Ben D. MacArthur ◽  
Cristina Parigini ◽  
Rubén J. Sánchez-García
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Adult Stem Cell ◽  
Feedback Regulation ◽  
Cell Types ◽  
Universal Principles ◽  
Formal Framework ◽  
Cell Niche ◽  
Multicellular Organisms ◽  
The Relationship

Adult tissues in multicellular organisms typically contain a variety of stem, progenitor and differentiated cell types arranged in a lineage hierarchy that regulates healthy tissue turnover and repair. Lineage hierarchies in disparate tissues often exhibit common features, yet the general principles regulating their architecture are not known. Here, we provide a formal framework for understanding the relationship between cell molecular ‘states’ (patterns of gene, protein expression etc. in the cell) and cell ‘types’ that uses notions from network science to decompose the structure of cell state trajectories into functional units. Using this framework we show that many widely experimentally observed features of cell lineage architectures – including the fact that a single adult stem cell type always resides at the apex of a lineage hierarchy – arise as a natural consequence of homeostasis, and indeed are the only possible way that lineage architectures can be constructed to support homeostasis in renewing tissues. Furthermore, under suitable feedback regulation, for example from the stem cell niche, we show that the property of ‘stemness’ is entirely determined by the cell environment. Thus, we argue that stem cell identities are contextual and not determined by hard-wired, cell-intrinsic, characteristics.

scholarly journals Role of an active reserve stem cell subset of enteroendocrine cells in intestinal stem cell dynamics and the genesis of small intestinal neuroendocrine tumors

2020 ◽  
Vol 319 (4) ◽  
pp. G494-G501 ◽  
Author(s):  
Yoshitatsu Sei ◽  
Jianying Feng ◽  
Xilin Zhao ◽  
Stephen A. Wank
Keyword(s):  
Stem Cell ◽  
Neuroendocrine Tumors ◽  
Cell Subset ◽  
Tumor Formation ◽  
Intestinal Stem Cell ◽  
Cell Of Origin ◽  
Cell Dynamics ◽  
Constant Rate ◽  
Ec Cells ◽  
Small Intestinal

Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent studies recognize a subset of EC cells that is label-retaining at the +4 position in the crypt and functions as a reserve intestinal stem cell. Importantly, this +4 reserve EC cell subset not only contributes to regeneration of the intestinal epithelium during injury and inflammation but also to basal crypt homeostasis at a constant rate. The latter function suggests that the +4 EC cell subset serves as an active reserve stem cell via a constant rate of dedifferentiation. Characterization of early tumor formation of SI-NET, observed as crypt-based EC cell clusters in many cases of familial SI-NETs, suggests that the +4 active reserve EC cell subset is the cell of origin. This newly discovered active reserve stem cell property of EC cells can account for unique biological mechanisms and processes associated with the genesis and development of SI-NETs. The recognition of this property of the +4 active reserve EC cell subset may provide novel opportunities to explore NETs in the gastrointestinal tract and other organs.

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