Divisional History and Hematopoietic Stem Cell Function during Homeostasis

• Published in: Stem cell reports 2014-04, Vol.2 (4), p.473-490
• Main Authors: Qiu, Jiajing, Papatsenko, Dmitri, Niu, Xiaohong, Schaniel, Christoph, Moore, Kateri
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cell Division; Cell Proliferation; Cluster Analysis; Gene Expression Profiling; Gene Expression Regulation; Genes, Reporter; Green Fluorescent Proteins - genetics; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeostasis; Immunophenotyping; Mice; Mice, Transgenic; Phenotype; Resting Phase, Cell Cycle
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.01.016

We investigated the homeostatic behavior of hematopoietic stem and progenitor cells (HSPCs) temporally defined according to their divisional histories using an HSPC-specific GFP label-retaining system. We show that homeostatic hematopoietic stem cells (HSCs) lose repopulating potential after limited cell divisions. Once HSCs exit dormancy and accrue divisions, they also progressively lose the ability to return to G0 and functional activities associated with quiescent HSCs. In addition, dormant HSPCs phenotypically defined as multipotent progenitor cells display robust stem cell activity upon transplantation, suggesting that temporal quiescence is a greater indicator of function than cell-surface phenotype. Our studies suggest that once homeostatic HSCs leave dormancy, they are slated for extinction. They self-renew phenotypically, but they lose self-renewal activity. As such, they question self-renewal as a characteristic of homeostatic, nonperturbed HSCs in contrast to self-renewal demonstrated under stress conditions. •Homeostatic HSCs progressively lose self-renewal ability with cell division•G0 homeostatic HSCs lose functional ability in relation to their divisional history•Temporally defined quiescence reflects HSC functional abilities better than phenotype•Once dormant HSCs are activated without stress, they lose self-renewal activity Moore and colleagues suggest that, during normal homeostasis, once HSCs exit dormancy, they lose robust repopulating activity in proportion to the number of times they divide, irrespective of cell-surface phenotype. They also lose the ability to return to quiescence in relationship to their divisional history as well as functional activity as G0 HSC.