Molecular signatures of proliferation and quiescence in hematopoietic stem cells

Teresa V. Bowman, Akil A. Merchant, Carlos A. Ramos, Nathan L. Whitehouse, Andrew S. Young, Chad A. Shaw, Margaret A. Goodell

Research output: Contribution to journalArticle

238 Citations (Scopus)

Abstract

Stem cells resident in adult tissues are principally quiescent, yet harbor enormous capacity for proliferation to achieve self renewal and to replenish their tissue constituents. Although a single hematopoietic stem cell (HSC) can generate sufficient primitive progeny to repopulate many recipients, little is known about the molecular mechanisms that maintain their potency or regulate their self renewal. Here we have examined the gene expression changes that occur over a time course when HSCs are induced to proliferate and return to quiescence in vivo. These data were compared to data representing differences between naturally proliferating fetal HSCs and their quiescent adult counterparts. Bioinformatic strategies were used to group time-ordered gene expression profiles generated from microarrays into signatures of quiescent and dividing stem cells. A novel method for calculating statistically significant enrichments in Gene Ontology groupings for our gene lists revealed elemental subgroups within the signatures that underlie HSC behavior, and allowed us to build a molecular model of the HSC activation cycle. Initially, quiescent HSCs evince a state of readiness. The proliferative signal induces a preparative state, which is followed by active proliferation divisible into early and late phases. Re-induction of quiescence involves changes in migratory molecule expression, prior to reestablishment of homeostasis. We also identified two genes that increase in both gene and protein expression during activation, and potentially represent new markers for proliferating stem cells. These data will be of use in attempts to recapitulate the HSC self renewal process for therapeutic expansion of stem cells, and our model may correlate with acquisition of self renewal characteristics by cancer stem cells.

Original languageEnglish (US)
JournalPLoS Biology
Volume2
Issue number10
DOIs
StatePublished - Oct 2004
Externally publishedYes

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Hematopoietic Stem Cells
Stem cells
stem cells
Stem Cells
gene expression
Gene Expression
molecular models
Gene Ontology
Molecular Models
genes
Neoplastic Stem Cells
Genes
Computational Biology
Transcriptome
bioinformatics
Gene expression
homeostasis
Cell Cycle
Homeostasis
protein synthesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Bowman, T. V., Merchant, A. A., Ramos, C. A., Whitehouse, N. L., Young, A. S., Shaw, C. A., & Goodell, M. A. (2004). Molecular signatures of proliferation and quiescence in hematopoietic stem cells. PLoS Biology, 2(10). https://doi.org/10.1371/journal.pbio.0020301

Molecular signatures of proliferation and quiescence in hematopoietic stem cells. / Bowman, Teresa V.; Merchant, Akil A.; Ramos, Carlos A.; Whitehouse, Nathan L.; Young, Andrew S.; Shaw, Chad A.; Goodell, Margaret A.

In: PLoS Biology, Vol. 2, No. 10, 10.2004.

Research output: Contribution to journalArticle

Bowman, TV, Merchant, AA, Ramos, CA, Whitehouse, NL, Young, AS, Shaw, CA & Goodell, MA 2004, 'Molecular signatures of proliferation and quiescence in hematopoietic stem cells', PLoS Biology, vol. 2, no. 10. https://doi.org/10.1371/journal.pbio.0020301
Bowman, Teresa V. ; Merchant, Akil A. ; Ramos, Carlos A. ; Whitehouse, Nathan L. ; Young, Andrew S. ; Shaw, Chad A. ; Goodell, Margaret A. / Molecular signatures of proliferation and quiescence in hematopoietic stem cells. In: PLoS Biology. 2004 ; Vol. 2, No. 10.
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