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Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU


Stem cells are proposed to segregate chromosomes asymmetrically during self-renewing divisions so that older (‘immortal’) DNA strands are retained in daughter stem cells whereas newly synthesized strands segregate to differentiating cells1,2,3,4,5,6. Stem cells are also proposed to retain DNA labels, such as 5-bromo-2-deoxyuridine (BrdU), either because they segregate chromosomes asymmetrically or because they divide slowly5,7,8,9. However, the purity of stem cells among BrdU-label-retaining cells has not been documented in any tissue, and the ‘immortal strand hypothesis’ has not been tested in a system with definitive stem cell markers. Here we tested these hypotheses in haematopoietic stem cells (HSCs), which can be highly purified using well characterized markers. We administered BrdU to newborn mice, mice treated with cyclophosphamide and granulocyte colony-stimulating factor, and normal adult mice for 4 to 10 days, followed by 70 days without BrdU. In each case, less than 6% of HSCs retained BrdU and less than 0.5% of all BrdU-retaining haematopoietic cells were HSCs, revealing that BrdU has poor specificity and poor sensitivity as an HSC marker. Sequential administration of 5-chloro-2-deoxyuridine and 5-iodo-2-deoxyuridine indicated that all HSCs segregate their chromosomes randomly. Division of individual HSCs in culture revealed no asymmetric segregation of the label. Thus, HSCs cannot be identified on the basis of BrdU-label retention and do not retain older DNA strands during division, indicating that these are not general properties of stem cells.

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Figure 1: Contrasting predictions regarding stem cell labelling on the basis of the immortal strand model versus random chromosome segregation.
Figure 2: Six per cent of HSCs stochastically enter the cell cycle each day.
Figure 3: Few HSCs retain BrdU, and most BrdU-retaining bone marrow cells are not HSCs.
Figure 4: HSCs segregate chromosomes randomly in vivo and in vitro.

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This work was supported by the Howard Hughes Medical Institute, the National Institute on Aging (NIH), and the US Army Research Laboratory/Office. Flow cytometry was partially supported by the UM-Comprehensive Cancer Centre and the UM-Multipurpose Arthritis Centre. Antibody production was partially supported by the Rheumatic Core Disease Centre. M.J.K. was supported by a University of Michigan Cancer Biology Training Grant. The authors thank D. Adams and M. White for flow cytometry and E. Smith (Hybridoma Core Facility) for antibody production.

Author Contributions M.J.K. performed all experiments and interpreted results. S.H. assisted in the design and interpretation of many experiments and helped to perform some experiments. R.A., S.N.G. and T.L.J. generated the mathematical model of BrdU retention over time (Fig. 3a). M.T. and J.A.K. developed the protocol for double-labelling cells with CldU and IdU. S.J.M. participated in the design and interpretation of experiments, and wrote the paper with M.J.K. and S.H.

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Correspondence to Sean J. Morrison.

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Kiel, M., He, S., Ashkenazi, R. et al. Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449, 238–242 (2007).

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