Modelling cell lifespan and proliferation: is likelihood to die or to divide independent of age?

Dowling, Mark R.; Milutinović, Dejan; Hodgkin, Philip D.

doi:10.1098/rsif.2005.0069

Cited by 31 publications

(44 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We refer to this as the log-normal-senescent (LS) model. 4,25,26 It is apparent from Figure 2 that the LS model offers a natural interpretation of the differences between the genotypes: the mean log life span is (24 hours). The efficiency of labeling (ϳ 90% for X488 and ϳ 60% for biotin) and the half-life of biotin were accounted for in the fitting procedure ("Methods" and supplemental data).…”

Section: Resultsmentioning

confidence: 99%

“…We refer to this as the log-normal-senescent (LS) model. 4,25,26 It is apparent from Figure 2 that the LS model offers a natural interpretation of the differences between the genotypes: the mean log life span is Bcl-x ϩ/Plt20 , (B) wild-type, and (C) Bak Ϫ/Ϫ mice. Data points are the mean of replicates (4 for Bcl-x ϩ/Plt20 , 6 for wild-type and Bak Ϫ/Ϫ ), and error bars represent one SD.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Platelet senescence is regulated by an internal timer, not damage inflicted by hits

Dowling¹,

Josefsson

Henley

et al. 2010

Blood

View full text Add to dashboard Cite

The mechanisms responsible for the brief life span of blood platelets have been a subject of speculation since the 1950s. The most popular hypothesis to date has been the "multiple-hit" model, whereby damage inflicted by external "hits" triggers recognition and clearance by the reticuloendothelial system. Recently, it was demonstrated that platelets contain an apoptotic pathway that mediates their survival in vivo. Using a novel labeling technique to measure population and cohort survival in mice carrying mutations in this pathway, combined with mathematical modeling, we have studied the internal and external control of platelet fate. Our results cast doubt on the veracity of the multiple-hit model. An alternative model, under which platelets are born with an internal "timer," provides a more parsimonious interpretation of the data. Thus, at steady state, platelet senescence is probably the product of internal processes rather than external hits. (Blood. 2010;116(10): 1776-1778) IntroductionPlatelets are small anucleate blood cells whose primary function is to facilitate clot formation at sites of vascular injury. They are the progeny of megakaryocytes, large polyploid cells that develop in the bone marrow and release platelets into the circulation. Although a small fraction of human platelets fulfill their raison d'être by being consumed in blood clots, 1 the majority become senescent and are cleared by the reticuloendothelial system in the liver and spleen after approximately 10 days in the circulation. This finite existence was first noted in the 1950s when platelet transfusions were given to leukemia patients. 2 The most popular hypothesis to explain platelet senescence at steady state has been the "multiple-hit" model proposed by Mustard et al in 1966. 3 In this model, platelets accumulate damage over time via "hits" inflicted by the circulatory environment. Each platelet is able to endure a certain number of hits before being recognized and cleared by the reticuloendothelial system. In a groundbreaking series of papers, Murphy and Francis formulated the multiple-hit model into a mathematical form. [4][5][6] The 2 mechanistic assumptions of the model, that (1) platelets can withstand a fixed number of hits and (2) hits occur at a constant rate, lead to a gamma distribution of life span. The multiple-hit model provides an elegant explanation for why platelets age; however, the precise nature of the hits and the veracity of the model have never been established. New light on the problem came from recent work demonstrating that platelets contain an apoptotic pathway that controls life span at steady state. 7 The key components of the pathway are the Bcl-2 family proteins Bcl-x L and Bak. The balance between them dictates whether a platelet lives or dies: mutations in prosurvival Bcl-x L reduce life span in vivo, whereas mutations in prodeath Bak extend it. Transfusion experiments demonstrated that these effects are cell-intrinsic, so it is clear that the transition from life to death is mediated by an interna...

show abstract

Section: Resultsmentioning

confidence: 99%

“…We refer to this as the log-normal-senescent (LS) model. 4,25,26 It is apparent from Figure 2 that the LS model offers a natural interpretation of the differences between the genotypes: the mean log life span is Bcl-x ϩ/Plt20 , (B) wild-type, and (C) Bak Ϫ/Ϫ mice. Data points are the mean of replicates (4 for Bcl-x ϩ/Plt20 , 6 for wild-type and Bak Ϫ/Ϫ ), and error bars represent one SD.…”

Section: Resultsmentioning

confidence: 99%

Platelet senescence is regulated by an internal timer, not damage inflicted by hits

Dowling¹,

Josefsson

Henley

et al. 2010

Blood

View full text Add to dashboard Cite

show abstract

“…This model is based on previous work, where we derived an expression for the joint distribution of total division time, T div , and remaining time until next division, δ, within an asynchronous and exponentially growing population of cells (29). When supplemented with a further assumption about the duration of S phase, T S , this model can be used to calculate the proportion of cells found to be BrdU(−ve) DNA(×2), p(l), as a function of pulse length, l. The full mathematical details of this model are described in SI Appendix, Text 3, and Fig.…”

Section: Resultsmentioning

confidence: 99%

Stretched cell cycle model for proliferating lymphocytes

Dowling

Kan

Heinzel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

134

View full text Add to dashboard Cite

Stochastic variation in cell cycle time is a consistent feature of otherwise similar cells within a growing population. Classic studies concluded that the bulk of the variation occurs in the G 1 phase, and many mathematical models assume a constant time for traversing the S/G 2 /M phases. By direct observation of transgenic fluorescent fusion proteins that report the onset of S phase, we establish that dividing B and T lymphocytes spend a near-fixed proportion of total division time in S/G 2 /M phases, and this proportion is correlated between sibling cells. This result is inconsistent with models that assume independent times for consecutive phases. Instead, we propose a stretching model for dividing lymphocytes where all parts of the cell cycle are proportional to total division time. Data fitting based on a stretched cell cycle model can significantly improve estimates of cell cycle parameters drawn from DNA labeling data used to monitor immune cell dynamics.he kinetic relationship between phases of the cell cycle first came to attention with the advent of autoradiographic techniques for detecting DNA synthesis in the 1950s (1, 2). It was realized that such data could be used to resolve the dynamics of the proliferating population if combined with an appropriate cell cycle model. However, direct filming of times to divide revealed remarkable variation, even among cloned, presumed identical, cells (3-6), eliminating simple deterministic models as the basis for cell cycle control. Working toward developing a general model, Smith and Martin made the striking observation that plotting the proportion of undivided cells versus time (so-called "alpha plots"), gave curves suggestive of two distinct phases, one relatively constant and another stochastic (7). They proposed that the two phases mapped to discrete states of the cell cycle. A resting "A state," they suggested, was contained within the G 1 phase from which cells could exit with constant probability per unit time (analogous to radioactive decay). The cells then entered the "B phase," which includes that part of G 1 not included in A state, as well as the entirety of S/G 2 /M. In B phase, cells' activities were first described to be "deterministic, and directed towards replication," implying a constant B phase. However, in the same paper, this assumption was relaxed and the duration of B phase was described with a relatively constant random variable (7).Although details of the quantitative relationship and biological interpretation have been debated (7-12), the rule that the bulk of kinetic variation is in G 1 phase, and that time in S/G 2 /M is relatively fixed, is widely accepted. Furthermore, mathematical models adopting this mechanical description (so-called "transition probability" or "compartment" models) remain popular and form the basis of many studies of lymphocyte and cancer kinetics in vitro and in vivo today (13-21).More recently, a molecular description of cell cycle regulation, including the discovery of key regulatory proteins such as cyclins a...

show abstract

“…However, this approach implicitly assumes that all platelets ("new" and "old" platelets) have the same chance of destruction, and provides a poor fit to the observed platelet decay kinetics. 16 An alternative approach is to consider that platelets have an "average life span" when they are produced. When we sample platelets we obtain a mix of cells of different ages, which have different remaining life spans.…”

Section: Mathematical Modelingmentioning

confidence: 99%

Drug-induced thrombocytopenia: development of a novel NOD/SCID mouse model to evaluate clearance of circulating platelets by drug-dependent antibodies and the efficacy of IVIG

Liang

Pinkevych

Khachigian

et al. 2010

Blood

View full text Add to dashboard Cite

Modelling cell lifespan and proliferation: is likelihood to die or to divide independent of age?

Cited by 31 publications

References 18 publications

Platelet senescence is regulated by an internal timer, not damage inflicted by hits

Platelet senescence is regulated by an internal timer, not damage inflicted by hits

Stretched cell cycle model for proliferating lymphocytes

Drug-induced thrombocytopenia: development of a novel NOD/SCID mouse model to evaluate clearance of circulating platelets by drug-dependent antibodies and the efficacy of IVIG

Contact Info

Product

Resources

About