scholarly journals Patterns of Cell Division and the Risk of Cancer

Genetics ◽  
2003 ◽  
Vol 163 (4) ◽  
pp. 1527-1532 ◽  
Author(s):  
Steven A Frank ◽  
Yoh Iwasa ◽  
Martin A Nowak
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Basal Layer ◽  
Mutation Rates ◽  
Tissue Architecture ◽  
Cell Lineages ◽  
Cell Mutation ◽  
Long Stem ◽  
Risk Of Cancer ◽  
Transit Cell

Abstract Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.

scholarly journals Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 655-665 ◽  
Author(s):  
Joseph Christopher ◽  
Ann-Sofie Thorsen ◽  
Sam Abujudeh ◽  
Filipe C. Lourenço ◽  
Richard Kemp ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fold Increase ◽  
Mutation Rates ◽  
Wild Type ◽  
Cell Dynamics ◽  
Tissue Samples ◽  
Age Related ◽  
Increased Risk ◽  
Microsatellite Mutation ◽  
Risk Of Cancer

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10−2) compared to wild-type epithelium (6.2 × 10−5).

scholarly journals The Epidermal Stem Cell Compartment: Variation in Expression Levels of E–Cadherin and Catenins Within the Basal Layer of Human Epidermis

1997 ◽  
Vol 45 (6) ◽  
pp. 867-874 ◽  
Author(s):  
Jean-Pierre Molès ◽  
Fiona M. Watt
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Basal Layer ◽  
Human Epidermis ◽  
Proliferative Potential ◽  
Stem Cell Markers ◽  
Cell Compartment ◽  
Stem Cell Compartment ◽  
E Cadherin ◽  
Cell Cell

The basal layer of the epidermis contains two types of proliferating keratinocyte: stem cells, with high proliferative potential, and transit amplifying cells, which are destined to undergo terminal differentiation after a few rounds of division. It has been shown previously that two- to three-fold differences in the average staining intensity of fluorescein-conjugated antibodies to β1 integrin subunits reflect profound differences in the proliferative potential of keratinocytes, with integrin-bright populations being enriched for stem cells. In the search for additional stem cell markers, we have stained sections of normal human epidermis with antibodies to proteins involved in intercellular adhesion and quantitated the fluorescence of individual cell-cell borders. In the basal layer, patches of brightly labeled cells were detected with antibodies to E-cadherin, β-catenin, and γ-catenin, but not with antibodies to P-cadherin, α-catenin, or with pan-desmocollin and pan-desmoglein antibodies. In the body sites examined, palm and foreskin, integrinbright regions were strongly labeled for γ-catenin and weakly labeled for E-cadherin and β-catenin. Our data suggest that there are gradients of both cell-cell and cell-extracellular matrix adhesiveness within the epidermal basal layer and that the levels of E-cadherin and of β-and γ-catenin may provide markers for the stem cell compartment, stem cells expressing relatively higher levels of γ-catenin and lower levels of E-cadherin and β-catenin than other basal keratinocytes.

scholarly journals Murine interfollicular epidermal differentiation is gradualistic with GRHL3 controlling progression from stem to transition cell states

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ziguang Lin ◽  
Suoqin Jin ◽  
Jefferson Chen ◽  
Zhuorui Li ◽  
Zhongqi Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Skin Diseases ◽  
Basal Layer ◽  
Terminal Differentiation ◽  
Skin Surface ◽  
Single Step ◽  
Epidermal Differentiation ◽  
Inflammatory Skin Diseases ◽  
Cell State

Abstract The interfollicular epidermis (IFE) forms a water-tight barrier that is often disrupted in inflammatory skin diseases. During homeostasis, the IFE is replenished by stem cells in the basal layer that differentiate as they migrate toward the skin surface. Conventionally, IFE differentiation is thought to be stepwise as reflected in sharp boundaries between its basal, spinous, granular and cornified layers. The transcription factor GRHL3 regulates IFE differentiation by transcriptionally activating terminal differentiation genes. Here we use single cell RNA-seq to show that murine IFE differentiation is best described as a single step gradualistic process with a large number of transition cells between the basal and spinous layer. RNA-velocity analysis identifies a commitment point that separates the plastic basal and transition cell state from unidirectionally differentiating cells. We also show that in addition to promoting IFE terminal differentiation, GRHL3 is essential for suppressing epidermal stem cell expansion and the emergence of an abnormal stem cell state by suppressing Wnt signaling in stem cells.

scholarly journals Epidermal stem cells: markers, patterning and the control of stem cell fate

1998 ◽  
Vol 353 (1370) ◽  
pp. 831-837 ◽  
Author(s):  
Fiona M. Watt
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Basal Layer ◽  
Constitutive Expression ◽  
Terminal Differentiation ◽  
Factor C ◽  
Extracellular Matrix Receptors ◽  
Integrin Family ◽  
Keratinocyte Stem Cells

Within the epidermis, proliferation takes place in the basal layer of keratinocytes that are attached to an underlying basement membrane. Cells that leave the basal layer undergo terminal differentiation as they move towards the tissue surface. The basal layer contains two types of proliferative keratinocyte: stem cells, which have unlimited self–renewal capacity, and transit amplifying cells, those daughters of stem cells that are destined to withdraw from the cell cycle and terminally differentiate after a few rounds of division. Stem cells express higher levels of the β 1 –integrin family of extracellular matrix receptors than transit amplifying cells and this can be used to isolate each subpopulation of keratinocyte and to determine its location within the epidermis. Variation in the levels of E–cadherin, β–catenin and plakoglobin within the basal layer suggests that stem cells may also differ from transit amplifying cells in intercellular adhesiveness. Stem cells have a patterned distribution within the epidermal basal layer and patterning is subject to autoregulation. Constitutive expression of the transcription factor c–Myc promotes terminal differentiation by driving keratinocytes from the stem cell compartment into the transit amplifying compartment.

scholarly journals The number of Follicle Stem Cells in a Drosophila ovariole.

2021 ◽  
Author(s):  
Daniel Kalderon ◽  
David Melamed ◽  
Amy Reilein
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Central Issue ◽  
Cell Lineages ◽  
General Relevance ◽  
Follicle Stem Cells ◽  
Drosophila Ovary ◽  
Lineage Analysis

A paper by Reilein et al (2017) presented several fundamental new insights into the behavior of adult Follicle Stem Cells (FSCs) in the Drosophila ovary, including evidence that each ovariole hosts a large number of FSCs (14-16) maintained by population asymmetry (Reilein et al., 2017), rather than just two FSCs, dividing with largely individually asymmetric outcomes, as originally proposed (Margolis and Spradling, 1995; Nystul and Spradling, 2007). Fadiga and Nystul (2019) contest some of these conclusions on the basis of their repetition of a multicolor lineage strategy used by Reilein et al (2017) and repetition of earlier single-color lineage analysis. Here we outline a number of shortcomings in the execution and interpretation of those experiments that, in our opinion, undermine their conclusions. The central issue of general relevance concerns the importance of comprehensively analyzing all stem cell lineages, independent of any pre-conceptions, in order to identify all constituents and capture heterogeneous behaviors.

scholarly journals A CTX Family Cell Adhesion Molecule, JAM4, Is Expressed in Stem Cell and Progenitor Cell Populations of both Male Germ Cell and Hematopoietic Cell Lineages

2006 ◽  
Vol 26 (22) ◽  
pp. 8498-8506 ◽  
Author(s):  
Go Nagamatsu ◽  
Masako Ohmura ◽  
Takuo Mizukami ◽  
Isao Hamaguchi ◽  
Susumu Hirabayashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Adhesion ◽  
Membrane Proteins ◽  
Germ Cell ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Male Germ Cell ◽  
Cell Lineages ◽  
Deficient Mice

ABSTRACT Stem cells are maintained in an undifferentiated state by interacting with a microenvironment known as the “niche,” which is comprised of various secreted and membrane proteins. Our goal was to identify niche molecules participating in stem cell-stem cell and/or stem cell-supporting cell interactions. Here, we isolated genes encoding secreted and membrane proteins from purified male germ stem cells using a signal sequence trap approach. Among the genes identified, we focused on the junctional adhesion molecule 4 (JAM4), an immunoglobulin type cell adhesion molecule. JAM4 protein was actually localized to the plasma membrane in male germ cells. JAM4 expression was downregulated as cells differentiated in both germ cell and hematopoietic cell lineages. To analyze function in vivo, we generated JAM4-deficient mice. Histological analysis of testes from homozygous nulls did not show obvious abnormalities, nor did liver and kidney tissues, both of which strongly express JAM4. The numbers of hematopoietic stem cells in bone marrow were indistinguishable between wild-type and mutant mice, as was male germ cell development. These results suggest that JAM4 is expressed in stem cells and progenitor cells but that other cell adhesion molecules may substitute for JAM4 function in JAM4-deficient mice both in male germ cell and hematopoietic lineages.

scholarly journals Aubergine and piRNAs repress the proto-oncogene Cbl for germline stem cell self-renewal

2017 ◽  
Author(s):  
Patricia Rojas-Ríos ◽  
Aymeric Chartier ◽  
Martine Simonelig
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mrna Translation ◽  
Translational Repression ◽  
Germline Stem Cell ◽  
Germline Stem Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Lineages

AbstractPIWI proteins have essential roles in germ cells and stem cell lineages. In Drosophila, Piwi is required in somatic niche cells and germline stem cells (GSCs) for GSC self-renewal and differentiation. Whether and how other PIWI proteins are involved in GSC biology remains unknown. Here, we show that Aubergine (Aub), another PIWI protein, is intrinsically required in GSCs for their self-renewal and differentiation. Aub loading with piRNAs is essential for these functions. The major role of Aub is in self-renewal and depends on mRNA regulation. We identify the Cbl proto-oncogene, a regulator of mammalian hematopoietic stem cells, as a novel GSC differentiation factor. Aub represses Cbl mRNA translation for GSC self-renewal, and does so through recruitment of the CCR4-NOT complex. This study reveals the role of piRNAs and PIWI proteins in translational repression for stem cell homeostasis and highlights piRNAs as major post-transcriptional regulators in key developmental decisions.

scholarly journals The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis

Development ◽  
1999 ◽  
Vol 126 (11) ◽  
pp. 2409-2418 ◽  
Author(s):  
U.B. Jensen ◽  
S. Lowell ◽  
F.M. Watt
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
High Surface ◽  
Basal Layer ◽  
Spatial Relationship ◽  
Human Epidermis ◽  
Stem Cell Marker ◽  
Integrin Expression ◽  
Whole Mount ◽  
Beta1 Integrin

In order to examine the spatial organisation of stem cells and their progeny in human epidermis, we developed a method for whole-mount epidermal immunofluorescence labelling using high surface beta1 integrin expression as a stem cell marker. We confirmed that there are clusters of high beta1 integrin-expressing cells at the tips of the dermal papillae in epidermis from several body sites, whereas alpha6 integrin expression is more uniform. The majority of actively cycling cells detected by Ki67 or bromodeoxyuridine labelling were found in the beta1 integrin-dull, transit amplifying population and integrin-negative, keratin 10-positive cells left the basal layer exclusively from this compartment. When we examined p53-positive clones in sun-exposed epidermis, we found two types of clone that differed in size and position in a way that was consistent with the founder cell being a stem or transit amplifying cell. The patterning of the basal layer implies that transit amplifying cells migrate over the basement membrane away from the stem cell clusters. In support of this, isolated beta1 integrin-dull keratinocytes were more motile on type IV collagen than beta1 integrin-bright keratinocytes and EGFP-labelled stem cell clones in confluent cultured sheets were compact, whereas transit amplifying clones were dispersed. The combination of whole-mount labelling and lineage marking thus reveals features of epidermal organisation that were previously unrecognised.

Lox2, a putative leech segment identity gene, is expressed in the same segmental domain in different stem cell lineages

Development ◽  
1992 ◽  
Vol 116 (3) ◽  
pp. 697-710 ◽  
Author(s):  
D. Nardelli-Haefliger ◽  
M. Shankland
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Gene Products ◽  
Cell Lineages ◽  
Stem Cell Lineage ◽  
Hybridization Reaction ◽  
Cell Segment

The segmented tissues of the adult leech arise from a set of five, bilaterally paired embryonic stem cells via a stereotyped sequence of cell lineage. Individual segments exhibit unique patterns of cell differentiation, and previous studies have suggested that each stem cell lineage establishes at least some aspects of its own segmental specificity autonomously. In this paper, we describe a putative leech segment identity gene, Lox2, and examine its expression in the various stem cell lineages. Both sequence analysis and the segmental pattern of Lox2 expression suggest a specific homology to the fruitfly segment identity genes Ubx and abdA. In situ hybridization reveals a cellular accumulation of Lox2 RNA over a contiguous domain of 16 midbody segments (M6-M21), including postmitotic neurons, muscles and the differentiating genitalia. Lox2 transcripts were not detected at the stage when segment identities are first established, suggesting that Lox2 gene products may not be part of the initial specification process. Individual stem cell lineages were labeled by intracellular injection of fluorescent tracers, and single cell colocalization of lineage tracer and hybridization reaction product revealed expression of Lox2 RNA in the progeny of four different stem cells. The segmental domain of Lox2 RNA was very similar in the various stem cell lineages, despite the fact that some stem cells generate one founder cell/segment, whereas other stem cells generate two founder cells/segment.

scholarly journals Progressive and Coordinated Mobilization of the Skeletal Muscle Niche throughout Tissue Repair Revealed by Single-Cell Proteomic Analysis

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 744
Author(s):  
Matthew Borok ◽  
Nathalie Didier ◽  
Francesca Gattazzo ◽  
Teoman Ozturk ◽  
Aurelien Corneau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Muscle Regeneration ◽  
Cell Types ◽  
Skeletal Muscle Regeneration ◽  
Muscle Repair ◽  
Muscle Stem Cell ◽  
Muscle Stem Cells ◽  
Cell Lineages

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon injury, muscle fibers undergo necrosis and muscle stem cells activate, proliferate and fuse to form new myofibers. In addition to myogenic cell populations, interaction with other cell types such as inflammatory cells, mesenchymal (fibroadipogenic progenitors—FAPs, pericytes) and vascular (endothelial) lineages are important for efficient muscle repair. While the role of the distinct populations involved in skeletal muscle regeneration is well characterized, the quantitative changes in the muscle stem cell and niche during the regeneration process remain poorly characterized. Methods: We have used mass cytometry to follow the main muscle cell types (muscle stem cells, vascular, mesenchymal and immune cell lineages) during early activation and over the course of muscle regeneration at D0, D2, D5 and D7 compared with uninjured muscles. Results: Early activation induces a number of rapid changes in the proteome of multiple cell types. Following the induction of damage, we observe a drastic loss of myogenic, vascular and mesenchymal cell lineages while immune cells invade the damaged tissue to clear debris and promote muscle repair. Immune cells constitute up to 80% of the mononuclear cells 5 days post-injury. We show that muscle stem cells are quickly activated in order to form new myofibers and reconstitute the quiescent muscle stem cell pool. In addition, our study provides a quantitative analysis of the various myogenic populations during muscle repair. Conclusions: We have developed a mass cytometry panel to investigate the dynamic nature of muscle regeneration at a single-cell level. Using our panel, we have identified early changes in the proteome of stressed satellite and niche cells. We have also quantified changes in the major cell types of skeletal muscle during regeneration and analyzed myogenic transcription factor expression in satellite cells throughout this process. Our results highlight the progressive dynamic shifts in cell populations and the distinct states of muscle stem cells adopted during skeletal muscle regeneration. Our findings give a deeper understanding of the cellular and molecular aspects of muscle regeneration.

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