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At least 19 recordsLinked to original sources
PubMed1985

Mucous cells and cell migration in the mouse duodenal epithelium.

The distribution of mucous cells in the mouse duodenum was used to determine whether or not intestinal epithelial cells move as a sheet during their migration from crypts to villi. The experiments took advantage of the probable symmetry of mucous-cell divisions (symmetry in the sense that each mucous-cell division produces two mucous cells). Since approximately 50% of newly formed mucous cells are derived from mucous-cell divisions, at least 50% of newly formed mucous cells in the crypt should be found in mucous-cell pairs. It follows that if the epithelium moves as a firmly interconnected sheet, at least 50% of mucous cells found in the villus should also be in pairs. On the other hand, if a significant amount of cell mixing occurs during migration, the pairing tendency of mucous cells would be lost. Mucous-cell pairing was determined by two independent methods: 1) direct observation of mucous-cell pairs and 2) the application of Poisson statistics to the mucous-cell distribution to determine a "pairing tendency." We found that in the crypt at least 75-80% of newly formed mucous cells occur in pairs, while in all regions of the villus (base, middle, and top) mucous cells are distributed randomly. These results strongly indicate the existence of a significant amount of cell mixing in the epithelium at some point between the site of mucous-cell formation in the crypts and the villus base. Since the mucous-cell population was randomly distributed in all regions of the villus we were unable to determine whether or not additional cell mixing occurs in the villus epithelium.

Animals↗
PubMed2025

Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.

Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.

Hematopoietic Stem Cells↗
PubMed1999

Symmetry of initial cell divisions among primitive hematopoietic progenitors is independent of ontogenic age and regulatory molecules.

We have developed a time-lapse camera system to follow the replication history and the fate of hematopoietic stem cells (HSC) at a single-cell level. Combined with single-cell culture, we correlated the early replication behavior with colony development after 14 days. The membrane dye PKH26 was used to monitor cell division. In addition to multiple, synchronous, and symmetric divisions, single-sorted CD34(+)/CD38(-) cells derived from fetal liver (FLV) also gave rise to a daughter cell that remained quiescent for up to 8 days, whereas the other daughter cell proliferated exponentially. Upon separation and replating as single cells onto medium containing a cytokine cocktail, 60.6% +/- 9.8% of the initially quiescent cells (PKH26 bright) gave rise again to colonies and 15.8% +/- 7.8% to blast colonies that could be replated. We have then determined the effects of various regulatory molecules on symmetry of initial cell divisions. After single-cell sorting, the CD34(+)/CD38(-) cells derived from FLV were exposed to flt3-ligand, thrombopoietin, stem cell factor (SCF), or medium containing a cytokine cocktail (with SCF, interleukin-3, interleukin-6, granulocyte-macrophage colony-stimulating factor, and erythropoietin). Whereas mitotic rate, colony efficiency, and asymmetric divisions could be altered using various regulatory molecules, the asymmetric division index, defined as the number of asymmetric divisions versus the number of dividing cells, was not altered significantly. This observation suggests that, although lineage commitment and cell proliferation can be skewed by extrinsic signaling, symmetry of early divisions is probably under the control of intrinsic factors.

Adult↗
PubMed2006

Human mesenchymal stromal cells regulate initial self-renewing divisions of hematopoietic progenitor cells by a beta1-integrin-dependent mechanism.

In previous reports, we have demonstrated that only direct cell-cell contact with stromal cells, such as the murine stromal cell line AFT024, was able to alter the cell division kinetics and self-renewing capacity of hematopoietic progenitor cells (HPC). Because beta(1)-integrins were shown to be crucial for the interaction of HPC with the bone marrow microenvironment, we have studied the role of beta(1)-integrins in the regulation of self-renewing cell divisions. For this purpose, we used primary human mesenchymal stromal (MS) cells as in vitro surrogate niche and monitored the division history and subsequent functional fate of individually plated CD34(+)133(+) cells in the absence or presence of an anti-beta(1)-integrin blocking antibody by time-lapse microscopy and subsequent long-term culture-initiating cell (LTC-IC) assays. beta(1)-Integrin-mediated contact with MS cells significantly increased the proportion of asymmetrically dividing cells and led to a substantial increase of LTC-IC. Provided that beta(1)-integrin-mediated contact was available within the first 72 hours, human MS cells were able to recruit HPC into cell cycle and accelerate their division kinetics without loss of stem cell function. Activation of beta(1)-integrins by ligands alone (e.g., fibronectin and vascular cell adhesion molecule-1) was not sufficient to alter the cell division symmetry and promote self-renewal of HPC, thus indicating an indirect effect. These results have provided evidence that primary human MS cells are able to induce self-renewing divisions of HPC by a beta(1)-integrin-dependent mechanism.

Antibodies↗
PubMed2000

Control of cell divisions in the nervous system: symmetry and asymmetry.

The diverse cell types in the nervous system are derived from neural progenitor cells. Neural progenitors can undergo symmetric divisions to expand cell population or asymmetric divisions to generate diverse cell types. Furthermore, neural progenitors must exit the cell cycle in a developmentally regulated manner to allow for terminal differentiation. The patterns of neural progenitor divisions have been characterized in vertebrates and invertebrates. During the course of nervous system development, extrinsic and intrinsic cues dictate the division patterns of neural progenitors by influencing their cell cycle behavior and cellular polarity. The identification in Drosophila of asymmetrically distributed fate determinants, adapter molecules, and polarity organizing molecules that participate in asymmetric neural progenitor divisions should provide points of entry for studying similar asymmetric divisions in vertebrates.

Animals↗
PubMed1995

The Significance of Microspore Division and Division Symmetry for Vegetative Cell-Specific Transcription and Generative Cell Differentiation.

The significance of the onset and symmetry of pollen mitosis I (PMI) for the subsequent differentiation of the vegetative and generative cells was investigated by the in vitro maturation of isolated microspores of transgenic tobacco. Free uninucleate microspores of transgenic plants harboring the vegetative cell (VC)-specific late anther tomato lat52 promoter fused to the [beta]-glucuronidase (gus) gene showed normal asymmetric cell division at PMI and activated the lat52 promoter specifically in the nascent VC during in vitro maturation. In vitro maturation in the presence of high levels of colchicine effectively blocked PMI, resulting in the formation of uninucleate pollen grains in which the lat52 promoter was activated. Furthermore, matured uninucleate pollen grains were capable of germination and pollen tube growth despite the absence of a functional generative cell (GC). Lower levels of colchicine induced symmetric division at PMI, producing two similar daughter cells in which typical GC chromatin condensation was prevented. Similar cultures of transgenic microspores harboring the lat52 promoter driving the expression of a nuclear-targeted GUS fusion protein showed that lat52 promoter activation occurred in both symmetric daughter cells. These results directly demonstrate that division asymmetry at PMI is essential for correct GC differentiation and that activation of VC-specific transcription and functional VC maturation may be uncoupled from cytokinesis at PMI. These results are discussed in relation to models proposed to account for the role and distribution of factors controlling the differing fates of the vegetative and generative cells.

Journal Article↗
PubMed2001

Fission yeast Pom1p kinase activity is cell cycle regulated and essential for cellular symmetry during growth and division.

Schizosaccharomyces pombe cells grow from both ends during most of interphase and divide symmetrically into two daughter cells. The pom1 gene, encoding a member of the Dyrk family of protein kinases, has been identified through a mutant showing abnormal cellular morphogenesis. Here we show that Pom1p kinase activity is cell cycle regulated in correlation with the state of cellular symmetry: the activity is high during symmetrical growth and division, but lower when cells grow at just one end. Point mutations in the catalytic domain lead to asymmetry during both cell growth and division, whilst cells overexpressing Pom1p form additional growing ends. Manipulations of kinase activity indicate a negative role for Pom1p in microtubule growth at cell ends. Pom1p is present in a large protein complex and requires its non-catalytic domain to localize to the cell periphery and its kinase activity to localize to cell ends. These data establish that Pom1p kinase activity plays an important role in generating cellular symmetry and suggest that there may be related roles of homologous protein kinases ubiquitously present in all eukaryotes.

Blotting, Western↗
PubMed1981

Heterocyst differentiation and cell division in the cyanobacterium Anabaena cylindrica: effect of high light intensity.

Heterocyst differentiation in the cyanobacterium Anabaena cylindrica is initiated by the removal of fixed nitrogen from the medium. These specialized cells occur singly at regular intervals within filaments of vegetative cells. Incubation of cultures for periods of up to 12 h immediately prior to or following removal of fixed nitrogen, at a light intensity (500 mi Einsteins cm-2 s-1) approximately 10-fold higher than that required for optimum growth, resulted in the differentiation of pairs of adjacent (double) heterocysts. The frequency of double heterocysts was proportional to the length of the period of high light intensity. During growth at normal light intensity approximately 5% of cell divisions were symmetrical, but this increased more than 3-fold during 10-h incubation at high light intensity. The frequency of dividing cells remained constant during this period, but increased rapidly on return to normal light. The frequency of double heterocysts was reduced if a period of incubation at normal light intensity was interposed between the 12-h period at high light intensity and transfer to nitrogen-free medium. A period of 8 h normal light was required to reduce the frequency of double heterocysts to control values, and this corresponded to the length of time needed for the frequency of symmetrical divisions to return to control levels following 12 h at high light intensity. We confirm that cell division in Anabaena cylindrica is asymmetrical and conclude that the presence of double heterocysts results from an increase in the symmetry of cell division during incubation at high light intensity. The results also support the finding of previous workers that a cell is only susceptible to differentiation during a short period following its formation. During the period of high light the rate of doubling of the absorbance of the culture at 750 mn increased from 24 h to approximately 10 h and decreased to more than 100 h on return to normal light. The very high rate could be explained by increases in the volume and granular content of cells during incubation at high light intensity and did not represent an equivalent increase in the rate of cell division.

Cell Differentiation↗
PubMed1996

Unequal cleavage in leech embryos: zygotic transcription is required for correct spindle orientation in subset of early blastomeres.

Leech embryos undergo invariant sequences of equal and unequal cell divisions to give rise to identifiable progeny cells. While many of the early cleavages are under maternal control, the divisions of a subset of early blastomeres (the large cells of the D' lineage) are perturbed after the inhibition of zygotic transcription. Analysis of the different types of cells produced in embryos injected with the transcriptional inhibitor, alpha-amanitin, revealed that the symmetry of cell division is perturbed in these large D'-derived cells during this early period of development. These cells, which would normally undergo a series of equal and unequal cleavages, always undergo equal cleavages after the inhibition of zygotic transcription. It appears that zygotically transcribed gene product(s) are required in the large cells of the D' lineage to orient the mitotic spindles properly for these unequal cell cleavages.

Amanitins↗
PubMed1995

A Monte Carlo simulation of the Escherichia coli cell cycle.

A Monte-Carlo simulation of the division cycle of an individual bacterium has been developed to test theories concerning the control of cell cycle events and for the analysis of cell cycle data. The model is based on the work of Cooper and Helmstetter and other theories concerning the control of DNA replication initiation, chromosome segregation and cell division. Variability in the molecular events that initiate a particular cell cycle event is incorporated using a Monte Carlo approach. The model results are compared with experimental data from a number of different sources and collected using a number of different analytical techniques. This model is able to accurately represent the cell size distributions of an exponentially growing population as determined by a Coulter Counter and the DNA distributions as determined by flow cytometry. The model is also able to accurately simulate the cell age distribution and chromosome replication and segregation patterns as determined by the membrane-elution technique. Results from parameter sensitivity analysis indicate that variability in the symmetry of cell division and in the cell size at initiation of chromosome replication have the most significant impact on the cell size, age and DNA distributions. Results from the membrane-elution simulation support the hypothesis that total cell protein is synthesized exponentially during the division cycle and that cell size control is a plausible explanation for control of DNA replication. The simulation results for chromosome segregation agree with experimental data and support chromosome strand segregation models. In the future, this simulation should be useful in testing complex theories about molecular control of cell cycle events against experimental data.

Bacterial Proteins↗
PubMed2005

Kinetics and symmetry of divisions of hematopoietic stem cells.

To fulfill the dual abilities to self-renew and to differentiate into cells of multiple lineages, stem cells must undergo, at some stage, asymmetric divisions to generate cells to sustain the stem cell pool as well as the various progeny cells of the distinct lineages. A central question in developmental biology is how a single cell can divide to produce two progeny cells that adopt different fates. Different daughter cells can theoretically arise by uneven distribution of determinants upon cell division, i.e., due to intrinsic factors, or become different upon subsequent exposure to environmental signals, i.e., due to extrinsic factors. Recent advances in the understanding of stem cell biology in Drosophila and murine models have served as a model for hematopoietic stem cell (HSC) development. Provided with advances in molecular and cellular biology, we have gained insight into the mechanisms governing self-renewing asymmetric divisions of primitive HSC. Direct contact with cellular determinants in the niche has been shown to play an essential role in the balance between self-renewing asymmetric division versus differentiation. Identification of the molecular interactions between stem cells and their niche will lead to an understanding of the mechanisms controlling the long-term destiny of stem cells. Ultimately, molecular signals triggered by adhesion and junction complexes are probably responsible for the specific adoption of differentiation pathways.

Animals↗
PubMed2005

The fate of isolated blastomeres with respect to germ cell formation in the amphipod crustacean Parhyale hawaiensis.

Germ cells may be specified through the localization of germ line determinants to specific cells in early embryogenesis, or by inductive signals from neighboring cells to germ cell precursors in later embryogenesis. Such determinants can be produced and localized during or after oogenesis, either autonomously by oocytes or by associated nutritive cells. In Drosophila, each oocyte is connected to nurse cells by cytoplasmic bridges, and determinants synthesized in nurse cells are transported through these bridges to the oocyte. However, the Drosophila model may not be applicable to all arthropods, since in many species of all four extant arthropod classes, gametogenesis functions without nurse cells. In this paper, I use immunodetection of Vasa protein to study germ cell development in the amphipod crustacean Parhyale hawaiensis, a species whose ovaries lack nurse cells and whose eggs lack obvious polarity. Previous cell lineage analyses have shown that all three germ layers and the germ line are exclusively specified by third cleavage. In the present study, I use a molecular marker to follow germ cell development during P. hawaiensis embryogenesis. I determine the capacity of individual blastomeres to form germ cells by isolating blastomeres at early cleavage stages and provide experimental evidence for localized germ cell determinants at the two-cell stage in P. hawaiensis. These experiments indicate that many aspects of early amphipod development, including timing and symmetry of cell division, the transition from holoblastic to superficial cleavage, and possibly some gastrulation movements, are cell autonomous following first cleavage.

Amphipoda↗
PubMed2006

Fission yeast cytoskeletons and cell polarity factors: connecting at the cortex.

Cell polarity is a fundamental property of cells from unicellular to multicellular organisms. Most of the time, it is essential so that the cells can achieve their function. The fission yeast Schizosaccharomyces pombe is a powerful genetic model organism for studying the molecular mechanisms of the cell polarity process. Indeed, S. pombe cells are rod-shaped and cell growth is restricted at the poles. The accurate localization of the cell growth machinery at the cell cortex, which involves the actin cytoskeleton, depends on cell polarity pathways that are temporally and spatially regulated. The importance of interphase microtubules and cell polarity factors acting at the cortex of cell ends in this process has been shown. Here, we review recent advances in knowledge of molecular pathways leading to the establishment of a cellular axis in fission yeast. We also describe the role of cortical proteins and mitotic cytoskeletal rearrangements that control the symmetry of cell division.

Actin Cytoskeleton↗
PubMed1994

A model of DNA aneuploidization and evolution in colorectal cancer.

BACKGROUND: Extensive chromosome and DNA content heterogeneity within and between human solid tumors has been observed using both classical karyotype and DNA cytometry. Experimental evidence suggests, at least in some tumor types, that DNA stemline heterogeneity in tumor progression is according to a three-compartment model with diploidy shifting to tetraploidy and then to hypotetraploidy. EXPERIMENTAL DESIGN: The human colorectal adenoma-carcinoma sequence appears as one of the most potentially informative systems for the study of DNA stemline heterogeneity in human tumors since adenomas, adenomas with early cancer, and adenocarcinomas in nontreated patients represent clear morphologically distinct stages of tumor progression. The quantitative measurement of DNA content in the G0.1 phase of the cell cycle was performed by high resolution flow cytometry in a large number of cases using multiple fresh or frozen samples. RESULTS: The distribution of the degree of DNA aneuploidy values, also known as DNA index, (DI not equal to 1) among 467 human precancer and cancer colorectal lesions was clearly nonrandom and showed modes at DI = 0.9, 1.2, 1.5, 1.8, and 2.2 with a clear valley at DI = 1.3. Whereas DNA aneuploid subclones within early lesions were up to about 80% near-diploid (DI < or = 1.3), DNA subclones within advanced cancer were in the vast majority with DI = 1.5-1.8 and, in a small fraction, with DI > 2. In addition, in adenomas with early cancer, which represent a link in colorectal tumor progression, early and late DNA stemlines often coexisted. CONCLUSIONS: The natural history of the colorectal adenoma-carcinoma sequence appears to be characterized by near-diploid subclones as early events and by late-stage hypotetraploidy. A new model is proposed that predicts the origin of the near-diploid subclones by "loss of symmetry" in cell division and their evolution (in particular hypodiploid) to the late-stage hypotetraploidy by tetraploidization. This model agrees with recent data associating molecular biology events, cytogenetic data, and DNA stemline heterogeneity in colorectal and other tumor systems.

Adenocarcinoma↗
PubMed2007

Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe.

BACKGROUND: The choice of a stem cell to divide symmetrically or asymmetrically has profound consequences for development and disease. Unregulated symmetric division promotes tumor formation, whereas inappropriate asymmetric division affects organ morphogenesis. Despite its importance, little is known about how spindle positioning is regulated. In some tissues cell fate appears to dictate the type of cell division, whereas in other tissues it is thought that stochastic variation in spindle position dictates subsequent sibling cell fate. RESULTS: Here we investigate the relationship between neural progenitor identity and spindle positioning in the Drosophila optic lobe. We use molecular markers and live imaging to show that there are two populations of progenitors in the optic lobe: symmetrically dividing neuroepithelial cells and asymmetrically dividing neuroblasts. We use genetically marked single cell clones to show that neuroepithelial cells give rise to neuroblasts. To determine if a change in spindle orientation can trigger a neuroepithelial to neuroblast transition, we force neuroepithelial cells to divide along their apical/basal axis by misexpressing Inscuteable. We find that this does not induce neuroblasts, nor does it promote premature neuronal differentiation. CONCLUSION: We show that symmetrically dividing neuroepithelial cells give rise to asymmetrically dividing neuroblasts in the optic lobe, and that regulation of spindle orientation and division symmetry is a consequence of cell type specification, rather than a mechanism for generating cell type diversity.

Animals↗
PubMed1994

Tumour stem cells: the biological concept and its application in cancer treatment.

Experiments in different transplantable mouse tumours suggest that a proportion ranging from 0.1% to 100% of all tumour cells in these different tumours meet the functional definition criteria of tumour stem cells, i.e. regrowth of the tumour proceeded by clonal expansion from a single cell with unlimited proliferative potential. It is concluded that the proliferative organization of many or most human tumours may resemble that of the tissue of origin with a small proportion of stem cells and the majority of transit cells, both proliferating or resting. Cell loss and accelerated repopulation are due to regulated changes in the symmetry constraint of stem cell divisions.

Animals↗
PubMedDate not supplied

Morphology and development of mirror-image doublets of Stylonychia mytilus.

This paper describes the cortical anatomy and development of mirror-image doublets of Stylonychia mytilus, analyzed using the protargol technique. The reversed, or "left-handed" (LH) component of these doublets is a mirror image of the normal or "right handed" (RH) component with regard to the arrangement of cortical structures. The mirror-image patterning is imperfect, however, as the individual ciliary structures of the LH component all are of normal internal asymmetry, and the orientation of membranelles is inverted. Certain structures that would be expected to form near the line of symmetry are absent. During cell division and cortical reorganization, ciliary primordia arise and become arranged in a mirror-image pattern that is more perfect than that exhibited by the mature structures. Deviations from a mirror-image pattern appear at late stages when organelle sets differentiate within ciliary primordia: for example, the membranelle set differentiates within the oral primordium of the LH component in a sequence that is an inversion rather than a mirror image of the corresponding sequence of the RH component. This mixed control of oral development by different cortical "informational systems" accounts for some of the characteristic abnormalities of the mature oral structures of the LH component.

Animals↗
PubMed2002

The induced sector Arabidopsis apical embryonic fate map.

Creation of an embryonic fate map may provide insight into the patterns of cell division and specification contributing to the apical region of the early Arabidopsis embryo. A fate map has been constructed by inducing genetic chimerism during the two-apical-cell stage of embryogenesis to determine if the orientation of the first anticlinal cell division correlates with later developmental axes. Chimeras were also used to map the relative locations of precursors of the cotyledon and leaf primordia. Genetic chimeras were induced in embryos doubly heterozygous for a heat shock regulated Cre recombinase and a constitutively expressed beta-glucuronidase (GUS) gene flanked by the loxP binding sites for Cre. Individual cells in the two-apical-cell stage embryo responding to heat shock produce GUS-negative daughter cells. Mature plants grown from seed derived from treated embryos were scored for GUS-negative sector extent in the cotyledons and leaves. The GUS-negative daughters of apical cells had a strong tendency to contribute primarily to one cotyledon or the other and to physically adjacent true leaf margins. This result indicated that patterns of early cell division correlate with later axes of symmetry in the embryo and that these patterns partially limit the fates available for adoption by daughter cells. However, GUS-negative sectors were shared between all regions of the mature plant, suggesting that there is no strict fate restriction imposed on the daughters of the first apical cells.

Arabidopsis↗