Estimating dormant and active hematopoietic stem cell kinetics through extensive modeling of bromodeoxyuridine label-retaining cell dynamics.

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Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Estimating dormant and active hematopoietic stem cell kinetics through extensive modeling of bromodeoxyuridine label-retaining cell dynamics.
Journal
PLoS One
Author(s)
van der Wath R.C., Wilson A., Laurenti E., Trumpp A., Liò P.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
4
Number
9
Pages
e6972
Language
english
Abstract
Bone marrow hematopoietic stem cells (HSCs) are responsible for both lifelong daily maintenance of all blood cells and for repair after cell loss. Until recently the cellular mechanisms by which HSCs accomplish these two very different tasks remained an open question. Biological evidence has now been found for the existence of two related mouse HSC populations. First, a dormant HSC (d-HSC) population which harbors the highest self-renewal potential of all blood cells but is only induced into active self-renewal in response to hematopoietic stress. And second, an active HSC (a-HSC) subset that by and large produces the progenitors and mature cells required for maintenance of day-to-day hematopoiesis. Here we present computational analyses further supporting the d-HSC concept through extensive modeling of experimental DNA label-retaining cell (LRC) data. Our conclusion that the presence of a slowly dividing subpopulation of HSCs is the most likely explanation (amongst the various possible causes including stochastic cellular variation) of the observed long term Bromodeoxyuridine (BrdU) retention, is confirmed by the deterministic and stochastic models presented here. Moreover, modeling both HSC BrdU uptake and dilution in three stages and careful treatment of the BrdU detection sensitivity permitted improved estimates of HSC turnover rates. This analysis predicts that d-HSCs cycle about once every 149-193 days and a-HSCs about once every 28-36 days. We further predict that, using LRC assays, a 75%-92.5% purification of d-HSCs can be achieved after 59-130 days of chase. Interestingly, the d-HSC proportion is now estimated to be around 30-45% of total HSCs - more than twice that of our previous estimate.
Keywords
Algorithms, Animals, Antimetabolites/pharmacology, Bromodeoxyuridine/pharmacology, Cell Cycle, Cell Proliferation, Computational Biology/methods, Hematopoietic Stem Cells/cytology, Hematopoietic Stem Cells/drug effects, Kinetics, Mice, Models, Biological, Models, Theoretical, Software, Stochastic Processes, Time Factors
Pubmed
Web of science
Open Access
Yes
Create date
15/01/2010 15:25
Last modification date
20/08/2019 15:08
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