8,558 research outputs found
(A)Symmetric Stem Cell Replication and Cancer
Most tissues in metazoans undergo continuous turnover due to cell death or epithelial shedding. Since cellular replication is associated with an inherent risk of mutagenesis, tissues are maintained by a small group of stem cells (SCs) that replicate slowly to maintain their own population and that give rise to differentiated cells. There is increasing evidence that many tumors are also maintained by a small population of cancer stem cells that may arise by mutations from normal SCs. SC replication can be either symmetric or asymmetric. The former can lead to expansion of the SC pool. We describe a simple model to evaluate the impact of (a)symmetric SC replication on the expansion of mutant SCs and to show that mutations that increase the probability of asymmetric replication can lead to rapid mutant SC expansion in the absence of a selective fitness advantage. Mutations in several genes can lead to this process and may be at the root of the carcinogenic process
Effect of Dedifferentiation on Time to Mutation Acquisition in Stem Cell-Driven Cancers
Accumulating evidence suggests that many tumors have a hierarchical
organization, with the bulk of the tumor composed of relatively differentiated
short-lived progenitor cells that are maintained by a small population of
undifferentiated long-lived cancer stem cells. It is unclear, however, whether
cancer stem cells originate from normal stem cells or from dedifferentiated
progenitor cells. To address this, we mathematically modeled the effect of
dedifferentiation on carcinogenesis. We considered a hybrid
stochastic-deterministic model of mutation accumulation in both stem cells and
progenitors, including dedifferentiation of progenitor cells to a stem
cell-like state. We performed exact computer simulations of the emergence of
tumor subpopulations with two mutations, and we derived semi-analytical
estimates for the waiting time distribution to fixation. Our results suggest
that dedifferentiation may play an important role in carcinogenesis, depending
on how stem cell homeostasis is maintained. If the stem cell population size is
held strictly constant (due to all divisions being asymmetric), we found that
dedifferentiation acts like a positive selective force in the stem cell
population and thus speeds carcinogenesis. If the stem cell population size is
allowed to vary stochastically with density-dependent reproduction rates
(allowing both symmetric and asymmetric divisions), we found that
dedifferentiation beyond a critical threshold leads to exponential growth of
the stem cell population. Thus, dedifferentiation may play a crucial role, the
common modeling assumption of constant stem cell population size may not be
adequate, and further progress in understanding carcinogenesis demands a more
detailed mechanistic understanding of stem cell homeostasis
Congenital microcephaly
The underlying etiologies of genetic congenital microcephaly are complex and multifactorial. Recently, with the exponential growth in the identification and characterization of novel genetic causes of congenital microcephaly, there has been a consolidation and emergence of certain themes concerning underlying pathomechanisms. These include abnormal mitotic microtubule spindle structure, numerical and structural abnormalities of the centrosome, altered cilia function, impaired DNA repair, DNA Damage Response signaling and DNA replication, along with attenuated cell cycle checkpoint proficiency. Many of these processes are highly interconnected. Interestingly, a defect in a gene whose encoded protein has a canonical function in one of these processes can often have multiple impacts at the cellular level involving several of these pathways. Here, we overview the key pathomechanistic themes underlying profound congenital microcephaly, and emphasize their interconnected nature
DNA methyltransferase-3-dependent nonrandom template segregation in differentiating embryonic stem cells.
Asymmetry of cell fate is one fundamental property of stem cells, in which one daughter cell self-renews, whereas the other differentiates. Evidence of nonrandom template segregation (NRTS) of chromosomes during asymmetric cell divisions in phylogenetically divergent organisms, such as plants, fungi, and mammals, has already been shown. However, before this current work, asymmetric inheritance of chromatids has never been demonstrated in differentiating embryonic stem cells (ESCs), and its molecular mechanism has remained unknown. Our results unambiguously demonstrate NRTS in asymmetrically dividing, differentiating human and mouse ESCs. Moreover, we show that NRTS is dependent on DNA methylation and on Dnmt3 (DNA methyltransferase-3), indicating a molecular mechanism that regulates this phenomenon. Furthermore, our data support the hypothesis that retention of chromatids with the old template DNA preserves the epigenetic memory of cell fate, whereas localization of new DNA strands and de novo DNA methyltransferase to the lineage-destined daughter cell facilitates epigenetic adaptation to a new cell fate
Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques.
BACKGROUND:How a potentially diverse population of hematopoietic stem cells (HSCs) differentiates and proliferates to supply more than 10(11) mature blood cells every day in humans remains a key biological question. We investigated this process by quantitatively analyzing the clonal structure of peripheral blood that is generated by a population of transplanted lentivirus-marked HSCs in myeloablated rhesus macaques. Each transplanted HSC generates a clonal lineage of cells in the peripheral blood that is then detected and quantified through deep sequencing of the viral vector integration sites (VIS) common within each lineage. This approach allowed us to observe, over a period of 4-12 years, hundreds of distinct clonal lineages. RESULTS:While the distinct clone sizes varied by three orders of magnitude, we found that collectively, they form a steady-state clone size-distribution with a distinctive shape. Steady-state solutions of our model show that the predicted clone size-distribution is sensitive to only two combinations of parameters. By fitting the measured clone size-distributions to our mechanistic model, we estimate both the effective HSC differentiation rate and the number of active HSCs. CONCLUSIONS:Our concise mathematical model shows how slow HSC differentiation followed by fast progenitor growth can be responsible for the observed broad clone size-distribution. Although all cells are assumed to be statistically identical, analogous to a neutral theory for the different clone lineages, our mathematical approach captures the intrinsic variability in the times to HSC differentiation after transplantation
Bifurcation in epigenetics: implications in development, proliferation and diseases
Cells often exhibit different and stable phenotypes from the same DNA
sequence. Robustness and plasticity of such cellular states are controlled by
diverse transcriptional and epigenetic mechanisms, among them the modification
of biochemical marks on chromatin. Here, we develop a stochastic model that
describes the dynamics of epigenetic marks along a given DNA region. Through
mathematical analysis, we show the emergence of bistable and persistent
epigenetic states from the cooperative recruitment of modifying enzymes. We
also find that the dynamical system exhibits a critical point and displays, in
presence of asymmetries in recruitment, a bifurcation diagram with hysteresis.
These results have deep implications for our understanding of epigenetic
regulation. In particular, our study allows to reconcile within the same
formalism the robust maintenance of epigenetic identity observed in
differentiated cells, the epigenetic plasticity of pluripotent cells during
differentiation and the effects of epigenetic misregulation in diseases.
Moreover, it suggests a possible mechanism for developmental transitions where
the system is shifted close to the critical point to benefit from high
susceptibility to developmental cues.Comment: accepted in Physical Review E as a Rapid Communicatio
Differential sensitivity of Glioma stem cells to Aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics
Glioma stem-cell-like cells are considered to be responsible for treatment resistance and tumour recurrence following chemo-radiation in glioblastoma patients, but specific targets by which to kill the cancer stem cell population remain elusive. A characteristic feature of stem cells is their ability to undergo both symmetric and asymmetric cell divisions. In this study we have analysed specific features of glioma stem cell mitosis. We found that glioma stem cells appear to be highly prone to undergo aberrant cell division and polyploidization. Moreover, we discovered a pronounced change in the dynamic of mitotic centrosome maturation in these cells. Accordingly, glioma stem cell survival appeared to be strongly dependent on Aurora A activity. Unlike differentiated cells, glioma stem cells responded to moderate Aurora A inhibition with spindle defects, polyploidization and a dramatic increase in cellular senescence, and were selectively sensitive to Aurora A and Plk1 inhibitor treatment. Our study proposes inhibition of centrosomal kinases as a novel strategy to selectively target glioma stem cells
A multi-phenotypic cancer model with cell plasticity
The conventional cancer stem cell (CSC) theory indicates a hierarchy of CSCs
and non-stem cancer cells (NSCCs), that is, CSCs can differentiate into NSCCs
but not vice versa. However, an alternative paradigm of CSC theory with
reversible cell plasticity among cancer cells has received much attention very
recently. Here we present a generalized multi-phenotypic cancer model by
integrating cell plasticity with the conventional hierarchical structure of
cancer cells. We prove that under very weak assumption, the nonlinear dynamics
of multi-phenotypic proportions in our model has only one stable steady state
and no stable limit cycle. This result theoretically explains the phenotypic
equilibrium phenomena reported in various cancer cell lines. Furthermore,
according to the transient analysis of our model, it is found that cancer cell
plasticity plays an essential role in maintaining the phenotypic diversity in
cancer especially during the transient dynamics. Two biological examples with
experimental data show that the phenotypic conversions from NCSSs to CSCs
greatly contribute to the transient growth of CSCs proportion shortly after the
drastic reduction of it. In particular, an interesting overshooting phenomenon
of CSCs proportion arises in three-phenotypic example. Our work may pave the
way for modeling and analyzing the multi-phenotypic cell population dynamics
with cell plasticity.Comment: 29 pages,6 figure
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