Clonal dominance and transplantation dynamics in hematopoietic stem cell compartments

@article{Ashcroft2017ClonalDA,
  title={Clonal dominance and transplantation dynamics in hematopoietic stem cell compartments},
  author={Peter Ashcroft and Markus G. Manz and Sebastian Bonhoeffer},
  journal={PLoS Computational Biology},
  year={2017},
  volume={13}
}
Hematopoietic stem cells in mammals are known to reside mostly in the bone marrow, but also transitively passage in small numbers in the blood. Experimental findings have suggested that they exist in a dynamic equilibrium, continuously migrating between these two compartments. Here we construct an individual-based mathematical model of this process, which is parametrised using existing empirical findings from mice. This approach allows us to quantify the amount of migration between the bone… 

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References

SHOWING 1-10 OF 68 REFERENCES

Clonal dynamics of native haematopoiesis

This work has established a novel experimental model in mice where cells can be uniquely and genetically labelled in situ to address the question of how a large number of long-lived progenitors are the main drivers of steady-state haematopoiesis during most of adulthood.

The kinetics of clonal dominance in myeloproliferative disorders.

The results can explain the absence of clonal myeloproliferative disorders in mice, are consistent with clinical observations in cats, and provide insight into the progression of chronic myelogenous leukemia in humans, and demonstrate that competition for microenvironmental support can lead to the suppression of normal hematopoiesis as neoplasia evolves.

Niche recycling through division-independent egress of hematopoietic stem cells

Insight is provided as to how HSC replacement can occur despite the residence of endogenous HSCs in niches, and therapeutic interventions that capitalize upon physiological HSC egress are suggested.

Evidence that hematopoiesis may be a stochastic process in vivo

It is proved that stochastic differentiation can result in the wide spectrum of discrete outcomes observed in vivo, and that clonal dominance can occur by chance, as large–animal data challenge clinical strategies for marrow transplantation and gene therapy.

The replication rate of human hematopoietic stem cells in vivo.

This report analyzes the changing ratio with age of maternal/paternal X-chromosome phenotypes in blood cells from females and infer that human HSCs replicate on average once every 40 weeks, and uses the estimate to simulate human hematopoiesis, and shows that the simulations accurately reproduce marrow transplantation data.

Unperturbed vs. post-transplantation hematopoiesis: both in vivo but different

Noninvasive genetic experiments in mice have identified a major role of stem and progenitor cells downstream from HSCs as drivers of adult hematopoiesis, and revealed that post-transplantation hematopoliesis differs quantitatively from normal steady-state hematosynthesis.

Stochastic Dynamics of Hematopoietic Tumor Stem Cells

It is unequivocally demonstrated that stochastic effects related to the finite size of the active stem-cell population have a profound influence on the dynamics of cancer evolution.

Stem Cell Engraftment Strategies

Evidence overwhelmingly supports the concept that syngeneic engraftment is determined by stem cell competition and can be extended to H‐2 mismatched allogeneic mouse combination when antigen pre‐exposure and CD40‐CD40 ligand antibody blockage are employed.

Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning

These experiments provide a general mechanism by which transplanted HSCs can correct hematopoietic deficiencies without any host conditioning or with only highly specific and transient lymphoablation.
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