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Nature. 2014 Oct 16;514(7522):322-7. doi: 10.1038/nature13824. Epub 2014 Oct 5.

Clonal dynamics of native haematopoiesis.

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1] Stem Cell Program, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Stem Cell Program, Children's Hospital, Boston, Massachusetts 02115, USA.
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Department of Immunology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.


It is currently thought that life-long blood cell production is driven by the action of a small number of multipotent haematopoietic stem cells. Evidence supporting this view has been largely acquired through the use of functional assays involving transplantation. However, whether these mechanisms also govern native non-transplant haematopoiesis is entirely unclear. Here we have established a novel experimental model in mice where cells can be uniquely and genetically labelled in situ to address this question. Using this approach, we have performed longitudinal analyses of clonal dynamics in adult mice that reveal unprecedented features of native haematopoiesis. In contrast to what occurs following transplantation, steady-state blood production is maintained by the successive recruitment of thousands of clones, each with a minimal contribution to mature progeny. Our results demonstrate that a large number of long-lived progenitors, rather than classically defined haematopoietic stem cells, are the main drivers of steady-state haematopoiesis during most of adulthood. Our results also have implications for understanding the cellular origin of haematopoietic disease.

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