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@ARTICLE{Busch:126215,
      author       = {K. Busch$^*$ and K. Klapproth$^*$ and M. Barile$^*$ and M.
                      Flossdorf$^*$ and T. Holland-Letz$^*$ and S. M.
                      Schlenner$^*$ and M. Reth$^*$ and T. Höfer$^*$ and H.-R.
                      Rodewald$^*$},
      title        = {{F}undamental properties of unperturbed haematopoiesis from
                      stem cells in vivo.},
      journal      = {Nature},
      volume       = {518},
      number       = {7540},
      issn         = {1476-4687},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-02330},
      pages        = {542 - 546},
      year         = {2015},
      abstract     = {Haematopoietic stem cells (HSCs) are widely studied by HSC
                      transplantation into immune- and blood-cell-depleted
                      recipients. Single HSCs can rebuild the system after
                      transplantation. Chromosomal marking, viral integration and
                      barcoding of transplanted HSCs suggest that very low numbers
                      of HSCs perpetuate a continuous stream of differentiating
                      cells. However, the numbers of productive HSCs during normal
                      haematopoiesis, and the flux of differentiating progeny
                      remain unknown. Here we devise a mouse model allowing
                      inducible genetic labelling of the most primitive Tie2(+)
                      HSCs in bone marrow, and quantify label progression along
                      haematopoietic development by limiting dilution analysis and
                      data-driven modelling. During maintenance of the
                      haematopoietic system, at least $30\%$ or ∼5,000 HSCs are
                      productive in the adult mouse after label induction.
                      However, the time to approach equilibrium between labelled
                      HSCs and their progeny is surprisingly long, a time scale
                      that would exceed the mouse's life. Indeed, we find that
                      adult haematopoiesis is largely sustained by previously
                      designated 'short-term' stem cells downstream of HSCs that
                      nearly fully self-renew, and receive rare but polyclonal HSC
                      input. By contrast, in fetal and early postnatal life, HSCs
                      are rapidly used to establish the immune and blood system.
                      In the adult mouse, 5-fluoruracil-induced leukopenia
                      enhances the output of HSCs and of downstream compartments,
                      thus accelerating haematopoietic flux. Label tracing also
                      identifies a strong lineage bias in adult mice, with
                      several-hundred-fold larger myeloid than lymphoid output,
                      which is only marginally accentuated with age. Finally, we
                      show that transplantation imposes severe constraints on HSC
                      engraftment, consistent with the previously observed
                      oligoclonal HSC activity under these conditions. Thus, we
                      uncover fundamental differences between the normal
                      maintenance of the haematopoietic system, its regulation by
                      challenge, and its re-establishment after transplantation.
                      HSC fate mapping and its linked modelling provide a
                      quantitative framework for studying in situ the regulation
                      of haematopoiesis in health and disease.},
      keywords     = {Receptor, TIE-2 (NLM Chemicals) / Tek protein, mouse (NLM
                      Chemicals) / Fluorouracil (NLM Chemicals)},
      cin          = {B086 / C060 / D110},
      ddc          = {070},
      cid          = {I:(DE-He78)B086-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)D110-20160331},
      pnm          = {314 - Tumor immunology (POF3-314)},
      pid          = {G:(DE-HGF)POF3-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25686605},
      doi          = {10.1038/nature14242},
      url          = {https://inrepo02.dkfz.de/record/126215},
}