Nature - USA (2020-02-13)

Nature | Vol 578 | 13 February 2020 | 283

gradient^32 and the downstream effects of osteoclast degradation^33. To
fully characterize the regulatory factors that govern HSC quiescence
versus proliferation, it will be necessary to develop molecular profiling
technology^34 that can spatially map distinct bone cavities.

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1. Sun, J. et al. Clonal dynamics of native haematopoiesis. Nature 514 , 322–327 (2014).


2. Busch, K. & Rodewald, H. R. Unperturbed vs. post-transplantation hematopoiesis: both
   in vivo but different. Curr. Opin. Hematol. 23 , 295–303 (2016).


3. Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells
   in their niche. Nature 457 , 92–96 (2009).


4. Lo Celso, C., Lin, C. P. & Scadden, D. T. In vivo imaging of transplanted hematopoietic
   stem and progenitor cells in mouse calvarium bone marrow. Nat. Protoc. 6 , 1–14 (2011).


5. Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains
   for tumour engraftment. Nature 435 , 969–973 (2005).


6. Cao, X. et al. Irradiation induces bone injury by damaging bone marrow
   microenvironment for stem cells. Proc. Natl Acad. Sci. USA 108 , 1609–1614 (2011).


7. Acar, M. et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly
   perisinusoidal. Nature 526 , 126–130 (2015).


8. Chen, J. Y. et al. Hoxb5 marks long-term haematopoietic stem cells and reveals a
   homogenous perivascular niche. Nature 530 , 223–227 (2016).


9. Gazit, R. et al. Fgd5 identifies hematopoietic stem cells in the murine bone marrow. J. Exp.
   Med. 211 , 1315–1331 (2014).


10. Zhang, Y. et al. PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic
    stem cell function. Blood 118 , 3853–3861 (2011).


11. Métais, J. Y. & Dunbar, C. E. The MDS1-EVI1 gene complex as a retrovirus integration site:
    impact on behavior of hematopoietic cells and implications for gene therapy. Mol. Ther.
    16 , 439–449 (2008).


12. Oguro, H., Ding, L. & Morrison, S. J. SLAM family markers resolve functionally distinct
    subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell
    13 , 102–116 (2013).


13. Pietras, E. M. et al. Functionally distinct subsets of lineage-biased multipotent progenitors
    control blood production in normal and regenerative conditions. Cell Stem Cell 17 , 35–46
    (2015).


14. Boyer, S. W., Schroeder, A. V., Smith-Berdan, S. & Forsberg, E. C. All hematopoietic cells
    develop from hematopoietic stem cells through Flk2/Flt3-positive progenitor cells. Cell
    Stem Cell 9 , 64–73 (2011).
    15. Buza-Vidas, N. et al. FLT3 expression initiates in fully multipotent mouse hematopoietic
    progenitor cells. Blood 118 , 1544–1548 (2011).
    16. Cabezas-Wallscheid, N. et al. Vitamin A-retinoic acid signaling regulates hematopoietic
    stem cell dormancy. Cell 169 , 807–823.e819 (2017).
    17. Zilionis, R. et al. Single-cell barcoding and sequencing using droplet microfluidics. Nat.
    Protocols 12 , 44–73 (2017).
    18. Rodriguez-Fraticelli, A. E. et al. Clonal analysis of lineage fate in native haematopoiesis.
    Nature 553 , 212–216 (2018).
    19. Sanjuan-Pla, A. et al. Platelet-biased stem cells reside at the apex of the haematopoietic
    stem-cell hierarchy. Nature 502 , 232–236 (2013).
    20. Guo, G. et al. Mapping cellular hierarchy by single-cell analysis of the cell surface
    repertoire. Cell Stem Cell 13 , 492–505 (2013).
    21. Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature
    502 , 637–643 (2013).
    22. Nombela-Arrieta, C. et al. Quantitative imaging of haematopoietic stem and progenitor
    cell localization and hypoxic status in the bone marrow microenvironment. Nat. Cell Biol.
    15 , 533–543 (2013).
    23. Lassailly, F., Foster, K., Lopez-Onieva, L., Currie, E. & Bonnet, D. Multimodal imaging
    reveals structural and functional heterogeneity in different bone marrow compartments:
    functional implications on hematopoietic stem cells. Blood 122 , 1730–1740 (2013).
    24. Coutu, D. L., Kokkaliaris, K. D., Kunz, L. & Schroeder, T. Multicolor quantitative confocal
    imaging cytometry. Nat. Methods 15 , 39–46 (2018).
    25. Takubo, K. & Suda, T. Roles of the hypoxia response system in hematopoietic and
    leukemic stem cells. Int. J. Hematol. 95 , 478–483 (2012).
    26. Parmar, K., Mauch, P., Vergilio, J. A., Sackstein, R. & Down, J. D. Distribution of
    hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl
    Acad. Sci. USA 104 , 5431–5436 (2007).
    27. Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone
    marrow of live animals. Nature 508 , 269–273 (2014).
    28. Morrison, S. J., Wright, D. E. & Weissman, I. L. Cyclophosphamide/granulocyte colony-
    stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization.
    Proc. Natl Acad. Sci. USA 94 , 1908–1913 (1997).
    29. Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition
    between symmetrically dividing Lgr5 stem cells. Cell 143 , 134–144 (2010).
    30. Yeh, S. A., Wilk, K., Lin, C. P. & Intini, G. In vivo 3D histomorphometry quantifies bone
    apposition and skeletal progenitor cell differentiation. Sci. Rep. 8 , 5580 (2018).
    31. Rashidi, N. M. et al. In vivo time-lapse imaging shows diverse niche engagement by
    quiescent and naturally activated hematopoietic stem cells. Blood 124 , 79–83 (2014).
    32. Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the
    calcium-sensing receptor. Nature 439 , 599–603 (2006).
    33. Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of
    hematopoietic progenitor cells. Nat. Med. 12 , 657–664 (2006).
    34. Medaglia, C. et al. Spatial reconstruction of immune niches by combining
    photoactivatable reporters and scRNA-seq. Science 358 , 1622–1626 (2017).
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