An in silico investigation into the causes of telomere length heterogeneity and its implications for the Hayflick limit

Golubev, A. G.; Khrustalev, S.; Butov, A. A.

doi:10.1016/s0022-5193(03)00229-7

Cited by 19 publications

(17 citation statements)

References 62 publications

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“…45 The relative importance of telomere shortening, oxidative stress, and genomic stability in defining the proliferative capacity of cells is unclear and controversial. 46,47 Our results indirectly support the concept that HSCs (similar to other somatic cells) undergo a finite number of replications before cellular senescence. 48 Because mice, cats, and baboons can be ordered not only by longevity but also by size, we cannot rule out the possibility that the biologic mechanism that drives slower HSC-replication rates in primates is size.…”

Section: Discussionsupporting

confidence: 75%

Hematopoietic stem-cell behavior in nonhuman primates

Shepherd

Kiem

Lansdorp

et al. 2007

Blood

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Little is known about the behavior of hematopoietic stem cells (HSCs) in primates because direct observations and competitive-repopulation assays are not feasible. Therefore, we used 2 different and independent experimental strategies, the tracking of transgene expression after retroviral-mediated gene transfer (N ‫؍‬ 11 baboons; N ‫؍‬ 7 rhesus macaques) and quantitation of the average telomere length of granulocytes (N ‫؍‬ 132 baboons; N ‫؍‬ 14 macaques), together with stochastic methods, to study HSC kinetics in vivo. The average replication rate for baboon HSCs is once per 36 weeks according to gene-marking analyses and once per 23 weeks according to telomere-shortening analyses. Comparable results were derived from the macaque data. These rates are substantially slower than the average replication rates previously reported for HSCs in mice (once per 2.5 weeks) and cats (once per 8.3 weeks). Because baboons and macaques live for 25 to 45 years, much longer than mice (ϳ2 years) and cats (12-18 years), we can compute that HSCs undergo a relatively constant number (ϳ80-200) of lifetime replications. Thus, our data suggest that the self-renewal capacity of mammalian stem cells in vivo is defined and evolutionarily conserved. IntroductionHematopoiesis is the ordered process by which hematopoietic stem cells (HSCs) proliferate and differentiate into mature blood cells. Through replication and differentiation, HSCs generate clones of progenitors, precursors, and mature cells, which support hematopoiesis throughout an animal's life. HSCs cannot be directly observed and are generally defined and identified by their function (their ability to reconstitute and maintain hematopoiesis).The most informative experimental approach for studying HSC kinetics is limiting-dilution competitive-repopulation experiments. Small numbers of cells with distinguishable phenotypes are transplanted into a recipient animal in which hematopoiesis has been ablated. After the HSCs engraft and restore blood cell production, the percentage of marrow progenitor cells or blood granulocytes of each phenotype is tracked over time, because this reflects the phenotype of contributing (differentiating) HSC clones. 1,2 Using such data, the frequency of HSCs in mice and cats was estimated, as were their average replication and differentiation rates. [3][4][5] Importantly, the estimated frequency of HSCs in mice derived with stochastic analyses was similar to frequencies estimated with independent methods. [6][7][8][9] In addition, the results from transplantation studies overlapped the results from studies of unperturbed hematopoiesis, including 5-bromodeoxyuridine (BrdU)-labeling experiments. 6,9,10 Given the significant differences in estimates of the frequency of HSCs (number of HSCs/number of nucleated marrow cells; 4-8/10 5 vs. 6/10 7 ) and the average HSC-replication rate (once/2.5 weeks vs once/8-10 weeks) between mice and cats, we hypothesized that underlying biologic principles might explain these discrepancies. For example, our data and addit...

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Section: Discussionsupporting

confidence: 75%

Hematopoietic stem-cell behavior in nonhuman primates

Shepherd

Kiem

Lansdorp

et al. 2007

Blood

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“…Nonstem cells also remember their relative senescence (i.e., their "mitotic age" causing the Hayflick limit in cell culture; this essential vitality indicator has a loose correlation with the overall age of the organism) through telomere-independent as well as telomere-shorteningdependent mechanisms (Fig. 1, level I) (87,88). Thus, senescence assays may become an important tool in tissue engineering to avoid premature ageing and loss of engineered implants.…”

Section: Developmental Programs In Cellsmentioning

confidence: 99%

Memory Encoded Throughout Our Bodies: Molecular and Cellular Basis of Tissue Regeneration

et al. 2008

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When a sheep loses its tail, it cannot regenerate it in the manner of lizards. On the other hand, it is possible to clone mammals from somatic cells, showing that a complete developmental program is intact in a wounded sheep's tail the same way it is in a lizard. Thus, there is a requirement for more than only the presence of the entire genetic code in somatic cells for regenerative abilities. Thoughts like this have motivated us to assemble more than just a factographic synopsis on tissue regeneration. As a model, we review skin wound healing in chronological order, and when possible, we use that overview as a framework to point out possible mechanisms of how damaged tissues can restore their original structure. This article postulates the existence of tissue structural memory as a complex distributed homeostatic mechanism. We support such an idea by referring to an extremely fragmented literature base, trying to synthesize a broad picture of important principles of how tissues and organs may store information about their own structure for the purposes of regeneration. Selected developmental, surgical, and tissue engineering aspects are presented and discussed in the light of recent findings in the field. (Pediatr Res 63: 502-512, 2008)

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“…As a result, it may be that the induction of some genes occurs only in a part of cycling cells, whereas other genes may be induced in the other part. This relationship was suggested to be the common mechanistic base of the stochastic mode of cell differentiation and the transition probability model of cell cycle, and was used in the discrete event model of cell behaviour described in Golubev et al (2003), Golubev (2010) and the present paper.…”

Section: Stochasticity-based Approaches To Cell Behaviourmentioning

confidence: 99%

“…The computer-assisted realisation of this model was initially developed to explore relationships between intermitotic time (IMT) and telomere length (L) variabilities, as described in Golubev et al (2003).…”

Section: Discrete Event Model Of Cell Behaviourmentioning

confidence: 99%

An in silico investigation into the causes of telomere length heterogeneity and its implications for the Hayflick limit

Cited by 19 publications

References 62 publications

Hematopoietic stem-cell behavior in nonhuman primates

Hematopoietic stem-cell behavior in nonhuman primates

Memory Encoded Throughout Our Bodies: Molecular and Cellular Basis of Tissue Regeneration

Random discrete competing events vs. dynamic bistable switches in cell proliferation in differentiation

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