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The rates of stem cell division determine the cell cycle lengths of its lineage

ABSTRACT: Summary Adult stem cells and their transit-amplifying progeny alter their proliferation rates to maintain tissue homeostasis. To test how the division rates of stem cells and transit-amplifying progeny affect tissue growth and differentiation, we developed a computation strategy that estimates the average cell-cycle lengths (lifespans) of germline stem cells and their progeny from fixed-tissue demography in the Drosophila testis. Analysis of the wild-type data using this method indicated that during the germline transit-amplification, the cellular lifespans extend by nearly 1.3-fold after the first division and shrink by about 2-folds after the second division. Cell-autonomous perturbations of the stem cell lifespan accordingly altered the lifespans of successive transit-amplifying stages. Remarkably, almost 2-fold alterations in the lifespans of stem cells and their immediate daughters did not affect the subsequent differentiation. The results indicate that the early germline division rates can adjust the following division rates and the onset of differentiation. Graphical abstract Highlights • Prediction of cellular lifespan from the demography of transit-amplifying cells• Lifespans of spermatogonial cells change anomalously during transit-amplification• Anomalous lifespan extension during transit-amplification precedes the onset of Bam• Lifespan changes of early TA stages readjust that of the subsequent stages Cell biology; Stem cells research; Bioinformatics

SUBMITTER: Gadre P

PROVIDER: S-EPMC8555441 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Correction: Spatial regulation of Drosophila ovarian Follicle Stem Cell division rates and cell cycle transitions.

Project description:[This corrects the article DOI: 10.1371/journal.pgen.1010965.].

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Two different cell-cycle processes determine the timing of cell division in Escherichia coli.

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Project description: Not available

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An in vitro platform for quantifying cell cycle phase lengths in primary human intestinal stem cells.

Project description:Background and aimsThe intestinal epithelium exhibits dynamic control of cell cycle phase lengths, yet no experimental platform exists for directly analyzing cell cycle phases in living human intestinal stem cells (ISCs). Here, we develop primary human ISC lines with two different reporter constructs to provide fluorescent readouts to analyze cell cycle phases in cycling ISCs.Methods3D printing was used to construct a collagen press for making chamber slides that support primary human ISC growth and maintenance within the working distance of a confocal microscope objective. The PIP-FUCCI fluorescent cell cycle reporter and a variant with H2A-mScarlet that allows for automated tracking of cell cycle phases (PIP-H2A) were used in human ISCs along with live imaging and EdU pulsing. An analysis pipeline combining free-to-use programs and publicly available code was compiled to analyze live imaging results.ResultsChamber slides with soft collagen pressed to a thickness of 0.3 mm concurrently support ISC cycling and confocal imaging. PIP-FUCCI ISCs were found to be optimal for snapshot analysis wherein all nuclei are assigned to a cell cycle phase from a single image. PIP-H2A ISCs were better suited for live imaging since constant nuclear signal allowed for more automated analysis. CellPose2 and TrackMate were used together to track cycling cells.ConclusionsWe present two complete platforms for analyzing cell cycle phases in living primary human ISCs. The PIP-FUCCI construct allows for cell cycle phase assignment from one image of living cells, the PIP-H2A construct allows for semi-automated direct quantification of cell cycle phase lengths in human ISCs using our computational pipeline. These platforms hold great promise for future studies on how pharmaceutical agents affect the intestinal epithelium, how cell cycle is regulated in human ISCs, and more.

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Stem cell dynamics in mouse hair follicles: a story from cell division counting and single cell lineage tracing.

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

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Blood cell telomere lengths and shortening rates of chimpanzee and human females.

Project description:Slower rates of aging distinguish humans from our nearest living cousins. Chimpanzees rarely survive their forties while large fractions of women are postmenopausal even in high-mortality hunter-gatherer populations. Cellular and molecular mechanisms for these somatic aging differences remain to be identified, though telomeres might play a role. To find out, we compared telomere lengths across age-matched samples of female chimpanzees and women.We used a monochrome multiplex quantitative polymerase chain reaction to assay canonical telomere repeats in blood cells from captive female chimpanzees (65 individuals; age: 6.2-56.7 years) and compared them to the same measure in human females (43 individuals; age: 7.4-57.3 years).Our samples showed little difference in attrition rates between the species (~0.022 T/S per year for chimpanzees and ~0.012 T/S per year for humans with overlapping 95% confidence intervals), but telomeres were twice as long in chimpanzees as in humans (T/S ratios = 2.70 and 1.26, respectively).Based on the longevity differences, we initially hypothesized that telomere shortening rates would be faster in chimpanzees than in humans. Instead, it is shorter telomere length that appears to be the derived state in humans. This comparison indicates that better characterization of physiological aging in our closest living relatives will be indispensable for understanding the evolution of distinctive human longevity.

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A multiscale model of early cell lineage specification including cell division.

Project description:Embryonic development is a self-organised process during which cells divide, interact, change fate according to a complex gene regulatory network and organise themselves in a three-dimensional space. Here, we model this complex dynamic phenomenon in the context of the acquisition of epiblast and primitive endoderm identities within the inner cell mass of the preimplantation embryo in the mouse. The multiscale model describes cell division and interactions between cells, as well as biochemical reactions inside each individual cell and in the extracellular matrix. The computational results first confirm that the previously proposed mechanism by which extra-cellular signalling allows cells to select the appropriate fate in a tristable regulatory network is robust when considering a realistic framework involving cell division and three-dimensional interactions. The simulations recapitulate a variety of in vivo observations on wild-type and mutant embryos and suggest that the gene regulatory network confers differential plasticity to the different cell fates. A detailed analysis of the specification process emphasizes that developmental transitions and the salt-and-pepper patterning of epiblast and primitive endoderm cells from a homogenous population of inner cell mass cells arise from the interplay between the internal gene regulatory network and extracellular signalling by Fgf4. Importantly, noise is necessary to create some initial heterogeneity in the specification process. The simulations suggest that initial cell-to-cell differences originating from slight inhomogeneities in extracellular Fgf4 signalling, in possible combination with slightly different concentrations of the key transcription factors between daughter cells, are able to break the original symmetry and are amplified in a flexible and self-regulated manner until the blastocyst stage.

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Lineage-Specific Early Differentiation of Human Embryonic Stem Cells Requires a G2 Cell Cycle Pause.

Project description:Human embryonic stem cells (hESCs) have an abbreviated G1 phase of the cell cycle that allows rapid proliferation and maintenance of pluripotency. Lengthening of G1 corresponds to loss of pluripotency during differentiation. However, precise mechanisms that link alterations in the cell cycle and early differentiation remain to be defined. We investigated initial stages of mesendodermal lineage commitment in hESCs, and observed a cell cycle pause. Transcriptome profiling identified several genes with known roles in regulation of the G2/M transition that were differentially expressed early during lineage commitment. WEE1 kinase, which blocks entry into mitosis by phosphorylating CDK1 at Y15, was the most highly expressed of these genes. Inhibition of CDK1 phosphorylation by a specific inhibitor of WEE1 restored cell cycle progression by preventing the G2 pause. Directed differentiation of hESCs revealed that cells paused during commitment to the endo- and mesodermal, but not ectodermal, lineages. Functionally, WEE1 inhibition during meso- and endodermal differentiation selectively decreased expression of definitive endodermal markers SOX17 and FOXA2. Our findings identify a novel G2 cell cycle pause that is required for endodermal differentiation and provide important new mechanistic insights into early events of lineage commitment. Stem Cells 2016;34:1765-1775.

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Single-cell transcriptomic reconstruction reveals cell cycle and multi-lineage differentiation defects in Bcl11a-deficient hematopoietic stem cells.

Project description:BackgroundHematopoietic stem cells (HSCs) are a rare cell type with the ability of long-term self-renewal and multipotency to reconstitute all blood lineages. HSCs are typically purified from the bone marrow using cell surface markers. Recent studies have identified significant cellular heterogeneities in the HSC compartment with subsets of HSCs displaying lineage bias. We previously discovered that the transcription factor Bcl11a has critical functions in the lymphoid development of the HSC compartment.ResultsIn this report, we employ single-cell transcriptomic analysis to dissect the molecular heterogeneities in HSCs. We profile the transcriptomes of 180 highly purified HSCs (Bcl11a (+/+) and Bcl11a (-/-)). Detailed analysis of the RNA-seq data identifies cell cycle activity as the major source of transcriptomic variation in the HSC compartment, which allows reconstruction of HSC cell cycle progression in silico. Single-cell RNA-seq profiling of Bcl11a (-/-) HSCs reveals abnormal proliferative phenotypes. Analysis of lineage gene expression suggests that the Bcl11a (-/-) HSCs are constituted of two distinct myeloerythroid-restricted subpopulations. Remarkably, similar myeloid-restricted cells could also be detected in the wild-type HSC compartment, suggesting selective elimination of lymphoid-competent HSCs after Bcl11a deletion. These defects are experimentally validated in serial transplantation experiments where Bcl11a (-/-) HSCs are myeloerythroid-restricted and defective in self-renewal.ConclusionsOur study demonstrates the power of single-cell transcriptomics in dissecting cellular process and lineage heterogeneities in stem cell compartments, and further reveals the molecular and cellular defects in the Bcl11a-deficient HSC compartment.

| S-EPMC4576406 | biostudies-literature

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