Fundamental properties of unperturbed haematopoiesis from stem cells in vivo

• Published in: Nature (London) 2015-02, Vol.518 (7540), p.542-546
• Main Authors: Busch, Katrin, Klapproth, Kay, Barile, Melania, Flossdorf, Michael, Holland-Letz, Tim, Schlenner, Susan M., Reth, Michael, Höfer, Thomas, Rodewald, Hans-Reimer
• Format: Article
• Language: English
• Subjects: 13/31; 14/35; 42/41; 631/532/1542; 64/60; Aging; Animal models in research; Animals; Animals, Newborn; Blood; Bone marrow; Bone Marrow Transplantation; Cell Lineage - physiology; Cell Proliferation; Cell Tracking; Cellular biology; Female; Fetus - cytology; Fetus - embryology; Fluorouracil; Genetic aspects; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humanities and Social Sciences; letter; Male; Mice; multidisciplinary; Observations; Physiological aspects; Properties; Receptor, TIE-2 - metabolism; Rodents; Science; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Transplantation; Transplants & implants
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14242

Inducible genetic labelling of haematopoietic stem cells (HSCs) and linked mathematical modelling show that at least 30% of all HSCs are productive, and that adult haematopoiesis is largely sustained by ‘short-term’ downstream stem cells that operate near self-renewal in the steady state; HSC fate mapping provides a quantitative model for better understanding of HSC functions in health and disease. Following haematopoiesis in vivo Most of what we know of the properties of haematopoietic stem cells (HSCs) is derived from transplantation and reconstitution of an emptied blood and immune system. Relatively little is known about how HSCs behave under physiological conditions. It was reported recently that normal haematopoeisis in adults is driven by thousands of long-lived progenitors rather than classic HSCs. Hans-Reimer Rodewald and colleagues have used inducible genetic labelling of primitive HSCs in a mouse model, combined with mathematical modelling, to show that although HSCs participate in establishment of the blood system in early life, steady-state haematopoiesis depends mainly on progenitors that are able to self-renew but also receive rare input from long-term HSCs. This input is increased following physiological challenges. 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 1 , 2 , 3 , 4 , 5 . Chromosomal marking 6 , viral integration 7 , 8 , 9 and barcoding 10 , 11 , 12 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