Evolutionary dynamics of adult stem cells: Comparison of random and immortal-strand segregation mechanisms

Tannenbaum, Emmanuel; Sherley, James L.; Shakhnovich, Eugene I.

doi:10.1103/physreve.71.041914

Cited by 18 publications

(8 citation statements)

References 12 publications

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“…This laboratory provided the first quantitative modeling of the potential effect of nonrandom segregation on DSC genetic fidelity [3]. It was estimated to afford a 100‐ to 1,000‐fold reduction in DSC mutation rate, but ideally to require suspended DNA repair [5], as suggested earlier [6, 7]. We also confirmed that nonrandom segregation occurs specifically during asymmetric self‐renewal [8, 9] as originally envisioned [2].…”

Section: Introductionsupporting

confidence: 83%

Molecular Cloaking of H2A.Z on Mortal DNA Chromosomes During Nonrandom Segregation

Huh

Sherley

2011

Stem Cells

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Although nonrandom sister chromatid segregation is a singular property of distributed stem cells (DSCs) that are responsible for renewing and repairing mature vertebrate tissues, both its cellular function and its molecular mechanism remain unknown. This situation persists in part because of the lack of facile methods for detecting and quantifying nonrandom segregating cells and for identifying chromosomes with immortal DNA strands, the cellular molecules that signify nonrandom segregation. During nonrandom segregation, at each mitosis, asymmetrically selfrenewing DSCs continuously cosegregate to themselves the set of chromosomes that contain immortal DNA strands, which are the oldest DNA strands. Here, we report the discovery of a molecular asymmetry between segregating sets of immortal chromosomes and opposed mortal chromosomes (i.e., containing the younger set of DNA template strands) that constitutes a new convenient biomarker for detection of cells undergoing nonrandom segregation and direct delineation of chromosomes that bear immortal DNA strands. In both cells engineered with DSC-specific properties and ex vivo-expanded mouse hair follicle stem cells, the histone H2A variant H2A.Z shows specific immunodetection on immortal DNA chromosomes. Cell fixation analyses indicate that H2A.Z is present on mortal chromosomes as well but is cloaked from immunodetection, and the cloaking entity is acid labile. The H2A.Z chromosomal asymmetry produced by molecular cloaking provides a first direct assay for nonrandom segregation and for chromosomes with immortal DNA strands. It also seems likely to manifest an important aspect of the underlying mechanism(s) responsible for nonrandom sister chromatid segregation in DSCs.

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Section: Introductionsupporting

confidence: 83%

Molecular Cloaking of H2A.Z on Mortal DNA Chromosomes During Nonrandom Segregation

Huh

Sherley

2011

Stem Cells

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“…Motivated by the immortal strand hypothesis [ 59 ] and non-random DNA strand co-segregation [ 60 ] we model mutation events in the malignant subpopulation of CSCs during symmetric division ( Fig. 5C ).…”

Section: Methodsmentioning

confidence: 99%

Evolution and Phenotypic Selection of Cancer Stem Cells

2015

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Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can change, and favorable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. We set out to investigate the emerging intratumoral heterogeneity and to determine the evolutionary trajectories of the combination of cell-intrinsic kinetics that yield aggressive tumor growth. We develop a cellular automaton model that tracks the temporal evolution of the malignant subpopulation of so-called cancer stem cells(CSC), as these cells are exclusively able to initiate and sustain tumors. We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of non-stem cancer cells(CC) that compete with CSC and thus inhibit CSC division while a reduction in proliferation potential loosens such inhibition and facilitates frequent CSC division. The sub-population of cancer stem cells in itself becomes highly heterogeneous dictating population level dynamics that vary from long-term dormancy to aggressive progression. Our study suggests that the clonal diversity that is captured in single tumor biopsy samples represents only a small proportion of the total number of phenotypes.

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“…Given the constant demand for proliferation and the error-prone nature of DNA replication, these cells possess a high risk for malignant transformation [3] . As a consequence, it has long been postulated that ASCs might have acquired specialized features to protect their genome [4] , [5] . A highly efficient DNA-repair system is commonly described as a stem cell trait, which would serve this purpose [2] .…”

Section: Introductionmentioning

confidence: 99%

Stem Cells Propagate Their DNA by Random Segregation in the Flatworm Macrostomum lignano

et al. 2012

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Adult stem cells are proposed to have acquired special features to prevent an accumulation of DNA-replication errors. Two such mechanisms, frequently suggested to serve this goal are cellular quiescence, and non-random segregation of DNA strands during stem cell division, a theory designated as the immortal strand hypothesis. To date, it has been difficult to test the in vivo relevance of both mechanisms in stem cell systems. It has been shown that in the flatworm Macrostomum lignano pluripotent stem cells (neoblasts) are present in adult animals. We sought to address by which means M. lignano neoblasts protect themselves against the accumulation of genomic errors, by studying the exact mode of DNA-segregation during their division.In this study, we demonstrated four lines of in vivo evidence in favor of cellular quiescence. Firstly, performing BrdU pulse-chase experiments, we localized ‘Label-Retaining Cells’ (LRCs). Secondly, EDU pulse-chase combined with Vasa labeling demonstrated the presence of neoblasts among the LRCs, while the majority of LRCs were differentiated cells.We showed that stem cells lose their label at a slow rate, indicating cellular quiescence. Thirdly, CldU/IdU− double labeling studies confirmed that label-retaining stem cells showed low proliferative activity. Finally, the use of the actin inhibitor, cytochalasin D, unequivocally demonstrated random segregation of DNA-strands in LRCs.Altogether, our data unambiguously demonstrated that the majority of neoblasts in M. lignano distribute their DNA randomly during cell division, and that label-retention is a direct result of cellular quiescence, rather than a sign of co-segregation of labeled strands.

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Evolutionary dynamics of adult stem cells: Comparison of random and immortal-strand segregation mechanisms

Cited by 18 publications

References 12 publications

Molecular Cloaking of H2A.Z on Mortal DNA Chromosomes During Nonrandom Segregation

Molecular Cloaking of H2A.Z on Mortal DNA Chromosomes During Nonrandom Segregation

Evolution and Phenotypic Selection of Cancer Stem Cells

Stem Cells Propagate Their DNA by Random Segregation in the Flatworm Macrostomum lignano

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