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Stem Cells

The murine long-term multi-lineage renewal marrow stem cell is a cycling cell

Leukemia volume 28, pages 813–822 (2014)Cite this article

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Abstract

Prevailing wisdom holds that hematopoietic stem cells (HSCs) are predominantly quiescent. Although HSC cycle status has long been the subject of scrutiny, virtually all marrow stem cell research has been based on studies of highly purified HSCs. Here we explored the cell cycle status of marrow stem cells in un-separated whole bone marrow (WBM). We show that a large number of long-term multi-lineage engraftable stem cells within WBM are in S/G2/M phase. Using bromodeoxyuridine, we show rapid transit through the cell cycle of a previously defined relatively dormant purified stem cell, the long-term HSC (LT-HSC; Lineage−/c-kit+/Sca-1+/Flk-2−). Actively cycling marrow stem cells have continually changing phenotype with cell cycle transit, likely rendering them difficult to purify to homogeneity. Indeed, as WBM contains actively cycling stem cells, and highly purified stem cells engraft predominantly while quiescent, it follows that the population of cycling marrow stem cells within WBM are lost during purification. Our studies indicate that both the discarded lineage-positive and lineage-negative marrow cells in a stem cell separation contain cycling stem cells. We propose that future work should encompass this larger population of cycling stem cells that is poorly represented in current studies solely focused on purified stem cell populations.

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Acknowledgements

This project was supported by the National Center for Research Resources (NCRR) and the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health through Grant Number 8P20GM103468, and by the Herbert W. Savit 1949 Research Fellowship.

Author Contributions

PJQ supervised all the work presented in this manuscript and also was involved in the design of experiments, analysis of data and preparation of the manuscript. MSD and LRG contributed equally to this work, designing and performing the experiments, collecting and analyzing the data and preparing the manuscript. KJ performed the Pyronin and Hoechst separations for the purified LT-HSC experiments. JA provided technical and conceptual advice. EP, MP, DA and MD provided assistance with performing experiments, collecting and analyzing the data.

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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health or the Herbert W. Savit 1949 Research Fellowship.

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  1. L R Goldberg and M S Dooner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Rhode Island Hospital, Providence, RI, USA

    L R Goldberg, M S Dooner, K W Johnson, E F Papa, M G Pereira, M Del Tatto, D M Adler, J M Aliotta & P J Quesenberry

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  1. L R Goldberg
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Correspondence to L R Goldberg.

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Goldberg, L., Dooner, M., Johnson, K. et al. The murine long-term multi-lineage renewal marrow stem cell is a cycling cell. Leukemia 28, 813–822 (2014). https://doi.org/10.1038/leu.2013.252

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