Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronisation in cell proliferation

AbstractWe present a suite of experimental data showing that cell proliferation assays, prepared using standard methods thought to produce asynchronous cell populations, persistently exhibit inherent synchronisation. Our experiments use fluorescent cell cycle indicators to reveal the normally-hidden cell synchronisation by highlighting oscillatory subpopulations within the total cell population. These oscillatory subpopulations would never be observed without these cell cycle indicators. On the other hand, our experimental data show that the total cell population appears to grow exponentially, as in an asynchronous population. We reconcile these seemingly inconsistent observations by employing a multi-stage mathematical model of cell proliferation that can replicate the oscillatory subpopulations. Our study has important implications for understanding and improving experimental reproducibility. In particular, inherent synchronisation may affect the experimental reproducibility of studies aiming to investigate cell cycle-dependent mechanisms, including changes in migration and drug response.

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Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation

Journal of The Royal Society Interface ◽

10.1098/rsif.2019.0382 ◽

2019 ◽

Vol 16 (157) ◽

pp. 20190382 ◽

Cited By ~ 7

Author(s):

Sean T. Vittadello ◽

Scott W. McCue ◽

Gency Gunasingh ◽

Nikolas K. Haass ◽

Matthew J. Simpson

Keyword(s):

Experimental Data ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Population ◽

Total Cell ◽

Fluorescent Cell ◽

Multi Stage ◽

Total Cell Population ◽

Cycle Dependent ◽

Proliferation Assays

We present a suite of experimental data showing that cell proliferation assays, prepared using standard methods thought to produce asynchronous cell populations, persistently exhibit inherent synchronization. Our experiments use fluorescent cell cycle indicators to reveal the normally hidden cell synchronization, by highlighting oscillatory subpopulations within the total cell population. These oscillatory subpopulations would never be observed without these cell cycle indicators. On the other hand, our experimental data show that the total cell population appears to grow exponentially, as in an asynchronous population. We reconcile these seemingly inconsistent observations by employing a multi-stage mathematical model of cell proliferation that can replicate the oscillatory subpopulations. Our study has important implications for understanding and improving experimental reproducibility. In particular, inherent synchronization may affect the experimental reproducibility of studies aiming to investigate cell cycle-dependent mechanisms, including changes in migration and drug response.

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In vitro evidence that LHRH stimulates the recruitment of prolactin mRNA-expressing cells during the postnatal period in the rat

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0120107 ◽

1994 ◽

Vol 12 (1) ◽

pp. 107-118 ◽

Cited By ~ 21

Author(s):

A Van Bael ◽

R Huygen ◽

B Himpens ◽

C Denef

Keyword(s):

Cell Cycle ◽

Cell Population ◽

Blot Hybridization ◽

Postnatal Period ◽

S Phase ◽

Female Rats ◽

Mrna Levels ◽

Dot Blot ◽

Total Cell Population

ABSTRACT We have studied the effect of LHRH and neuropeptide Y (NPY) on prolactin (PRL) mRNA levels in pituitary reaggregate cell cultures from 14-day-old female rats, by means of in situ hybridization and Northern blot analysis. As estimated by computer-image analysis, addition of LHRH on day 5 in culture for 40 h resulted in a 37% increase in the total cytoplasmic areas of cells containing PRL mRNA, visualized using a digoxigenin-labelled PRL cRNA. The size of individual PRL-expressing cells was not influenced, nor was the content of PRL mRNA per cell. A similar effect of LHRH was found by dot blot hybridization of extracted RNA. PRL mRNA levels were not affected by NPY. LHRH induced a 29% increase in the number of PRL mRNA-expressing cells processing through the S phase of the cell cycle, visualized by the incorporation of [3H]thymidine ([3H]T) into DNA over 16 h. The fraction of [3H]T-labelled cells was 10–12% of the total cell population. NPY did not influence the number of [3H]T-positive cells expressing PRL mRNA, but completely blocked the effect of LHRH on the latter population. The present data suggest that LHRH, probably via a paracrine action of gonadotrophs, stimulates the recruitment of new lactotrophs, an action which is negatively modulated by NPY. Since the magnitude of this effect was the same in the total pituitary cell population as in cells processing through the S phase of the cell cycle and presumably mitosis, recruitment of lactotrophs seems to be based on differentiation of progenitor or immature cells into PRL-expressing cells, rather than on a mitogenic action on pre-existing lactotrophs alone.

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Total Cell Counts of the Bone Marrow of Normal Albino Rats from 1 to 50 Weeks of Age

Blood ◽

10.1182/blood.v14.4.409.409 ◽

1959 ◽

Vol 14 (4) ◽

pp. 409-414 ◽

Cited By ~ 15

Author(s):

WILLIAM T. BURKE ◽

CHARLES HARRIS

Keyword(s):

Bone Marrow ◽

Cell Population ◽

Normal Values ◽

Age Groups ◽

Considerable Change ◽

Total Cell ◽

Albino Rats ◽

Cell Counts ◽

Total Cell Population ◽

Femoral Bone Marrow

Abstract A method is described by which the total nucleated cell count of femoral bone marrow of the rat can be estimated and cell population expressed in terms of differential counts. Normal values of total nucleated cell counts and the cellular distributions are given for seven age groups. These data indicate considerable change in bone marrow total cell population in rats one to 10 weeks of age.

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Cell cycle-dependent phosphorylation and regulation of cellular differentiation

Biochemical Society Transactions ◽

10.1042/bst20180276 ◽

2018 ◽

Vol 46 (5) ◽

pp. 1083-1091 ◽

Cited By ~ 5

Author(s):

Laura J.A. Hardwick ◽

Roberta Azzarelli ◽

Anna Philpott

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Diverse Range ◽

Cyclin Dependent Kinases ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Stem And Progenitor Cells ◽

Cycle Dependent ◽

Cell Cycle Dynamics ◽

Bidirectional Interactions

Embryogenesis requires an exquisite regulation of cell proliferation, cell cycle withdrawal and differentiation into a massively diverse range of cells at the correct time and place. Stem cells also remain to varying extents in different adult tissues, acting in tissue homeostasis and repair. Therefore, regulated proliferation and subsequent differentiation of stem and progenitor cells remains pivotal throughout life. Recent advances have characterised the cell cycle dynamics, epigenetics, transcriptome and proteome accompanying the transition from proliferation to differentiation, revealing multiple bidirectional interactions between the cell cycle machinery and factors driving differentiation. Here, we focus on a direct mechanistic link involving phosphorylation of differentiation-associated transcription factors by cell cycle-associated Cyclin-dependent kinases. We discuss examples from the three embryonic germ layers to illustrate this regulatory mechanism that co-ordinates the balance between cell proliferation and differentiation.

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Pendulin, a Drosophila protein with cell cycle-dependent nuclear localization, is required for normal cell proliferation.

The Journal of Cell Biology ◽

10.1083/jcb.129.6.1491 ◽

1995 ◽

Vol 129 (6) ◽

pp. 1491-1507 ◽

Cited By ~ 79

Author(s):

P Küssel ◽

M Frasch

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Nuclear Localization ◽

Growth Regulation ◽

Tandem Repeats ◽

Sequence Similarity ◽

Intracellular Localization ◽

Abnormal Development ◽

Embryonic Cells ◽

Cycle Dependent

We describe the dynamic intracellular localization of Drosophila Pendulin and its role in the control of cell proliferation. Pendulin is a new member of a superfamily of proteins which contains Armadillo (Arm) repeats and displays extensive sequence similarities with the Srp1 protein from yeast, with RAG-1 interacting proteins from humans, and with the importin protein from Xenopus. Almost the entire polypeptide chain of Pendulin is composed of degenerate tandem repeats of approximately 42 amino acids each. A short NH2-terminal domain contains adjacent consensus sequences for nuclear localization and cdc2 kinase phosphorylation. The subcellular distribution of Pendulin is dependent on the phase of cell cycle. During interphase, Pendulin protein is exclusively found in the cytoplasm of embryonic cells. At the transition between G2 and M-phase, Pendulin rapidly translocates into the nuclei where it is distributed throughout the nucleoplasm and the areas around the chromosomes. In the larval CNS, Pendulin is predominantly expressed in the dividing neuroblasts, where it undergoes the same cell cycle-dependent redistribution as in embryos. Pendulin is encoded by the oho31 locus and is expressed both maternally and zygotically. We describe the phenotypes of recessive lethal mutations in the oho31 gene that result in a massive decrease or loss of zygotic Pendulin expression. Hematopoietic cells of mutant larvae overproliferate and form melanotic tumors, suggesting that Pendulin normally acts as a blood cell tumor suppressor. In contrast, growth and proliferation in imaginal tissues are reduced and irregular, resulting in abnormal development of imaginal discs and the CNS of the larvae. This phenotype shows that Pendulin is required for normal growth regulation. Based on the structure of the protein, we propose that Pendulin may serve as an adaptor molecule to form complexes with other proteins. The sequence similarity with importin indicates that Pendulin may play a role in the nuclear import of karyophilic proteins and some of these may be required for the normal transmission and function of proliferative signals in the cells.

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miR-431-5p regulates cell proliferation and apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis by targeting XIAP

10.21203/rs.3.rs-30605/v3 ◽

2020 ◽

Author(s):

Yuejiao Wang ◽

Kailin Zhang ◽

Xiaowei Yuan ◽

Neili Xu ◽

Shuai Zhao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Cycle ◽

Cell Proliferation ◽

Real Time ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Proliferation And Apoptosis ◽

Synovial Tissues ◽

Proliferation Assays ◽

Fibroblast Like Synoviocytes

Abstract Background miR-431-5p is dysregulated in various cancers and plays an important function in the development of cancer. However, its role in fibroblast-like synoviocytes (FLSs) in patients with rheumatoid arthritis (RA) remains to be understood.Methods Quantitative real-time polymerase chain reaction was used to detect the relative expression of miR-431-5p in synovial tissues and FLSs. Cell proliferation assays helped examine RA FLS proliferation. Flow cytometry was performed to determine apoptosis and cell cycle progression in RA FLSs. We used dual-luciferase assays to determine the correlation between miR-431-5p and its putative target, X-linked inhibitor of apoptosis (XIAP). Quantitative real-time PCR and western blotting were used to measure XIAP levels in synovial tissues and transfected RA FLSs.Results miR-431-5p was downregulated in synovial tissues and FLSs of patients with RA. Upregulation of miR-431-5p prohibited cell proliferation and the G0/G1-to-S phase transition, but promoted apoptosis in RA FLSs; while miR-431-5p inhibition showed the opposite results. miR-431-5p directly targeted XIAP in RA FLSs, and reversely correlated with XIAP levels in synovial tissues. Notably, XIAP silencing partially restored the effects of miR-431-5p inhibition in RA FLSs.Conclusion miR-431-5p regulates cell proliferation, apoptosis，and cell cycle of RA FLSs by targeting XIAP, suggesting its potential in the treatment of RA.

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Studies on the kinetics of expression of cell cycle dependent proto-oncogenes during mitogen-induced liver cell proliferation

Cancer Letters ◽

10.1016/0304-3835(89)90186-9 ◽

1989 ◽

Vol 47 (1-2) ◽

pp. 115-119 ◽

Cited By ~ 13

Author(s):

P. Coni ◽

F.A. Bignone ◽

G. Pichiri ◽

G.M. Ledda-Columbano ◽

A. Columbano ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Liver Cell ◽

Cycle Dependent ◽

Kinetics Of

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Erythropoiesis in peripheral blood of tuatara (Sphenodon punctatus) and turtle (Malaclemys terrapin)

Canadian Journal of Zoology ◽

10.1139/z70-033 ◽

1970 ◽

Vol 48 (2) ◽

pp. 209-212 ◽

Cited By ~ 1

Author(s):

Vibeke E. Engelbert ◽

Ann Dorothy Young

Keyword(s):

Cell Population ◽

Peripheral Blood ◽

Total Cell ◽

Red Cells ◽

Malaclemys Terrapin ◽

Domestic Birds ◽

Total Cell Population ◽

Sphenodon Punctatus ◽

Clone Cells

Erythropoiesis in peripheral blood of domestic birds was shown earlier to arise directly from the nucleus of mature erythrocytes as nuclear protuberations that later broke free. Three to seven percent of new red cells originated in this way from clone cells.Investigations of peripheral blood in reptiles has further demonstrated formation of nucleated red cells as clones from nuclear buds of mature erythrocytes. Clone cells plus new immature red cells constitute, in Sphenodon punctatus, 8–18% and, in turtle, Malaclemys terrapin, 18–25% of the total cell population. Some lymphocytes and granulocytes appear also to arise from nuclear buds. Thrombocytes were present in some animals, absent in others, but were not counted in the present work.

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Investigation on Cell Proliferation with a New Antibody against Thymidine Kinase 1

Analytical Cellular Pathology ◽

10.1155/2001/658312 ◽

2001 ◽

Vol 23 (1) ◽

pp. 11-19 ◽

Cited By ~ 26

Author(s):

Naining Wang ◽

Qimin He ◽

Sven Skog ◽

Staffan Eriksson ◽

Bernhard Tribukait

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thymidine Kinase ◽

Specific Marker ◽

Thymidine Kinase 1 ◽

C Terminus ◽

Proliferation Activity ◽

Cycle Dependent ◽

Cellular Dna ◽

Archival Specimens

The cytosolic thymidine kinase 1 (TK1) is one of the enzymes involved in DNA replication. Based on biochemical studies, TK1 is activated at late G1 of cell cycle, and its activity correlates with the cell proliferation. We have developed a polyclonal anti‐TK1 antibody against a synthetic peptide from the C‐terminus of human TK1. Using this antibody, here we demonstrate the exclusive location of TK1 in the cytoplasm of cells. Cell cycle dependent TK1 expression was studied by simultaneous fluorescence staining for TK1 and bromodeoxyuridine, by using elutriated cells, and by quantitation of the amount TK1 in relation to the cellular DNA content. TK1, which was strongly expressed in the cells in S+G2 period, raised at late G1 and decreased during mitosis. The amount of TK1 increased three folds from late G1 to G2. TK1 positive cells were demonstrated in areas of proliferation activity of various normal and malignant tissues. The new anti‐TK1 antibody works in archival specimens and is a specific marker of cell proliferation.

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