Molecular Signatures of Proliferation and Quiescence in Hematopoietic Stem Cells

作者：Teresa A. Venezia, Akil Abid Merchant, Carlos A. Ramos, Nathan L. Whitehouse, Andrew Young, Chad A. Shaw, Margaret A. Goodell · 发表于：PLoS Biology · 年份：2004 · DOI：10.1371/journal.pbio.0020301 · 被引用次数：369 · 研究领域：Hematopoietic Stem Cell Transplantation、Epigenetics and DNA Methylation

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 prote...