BMP signalling differentially regulates distinct haematopoietic stem cell types.
Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they are first generated in the aorta-gonad-mesonephros region, but at later developmental stages, its role in HSCs is controversial. Here we show that HSCs in murine fetal liver and the bone marrow are of two types that can be prospectively isolated--BMP activated and non-BMP activated. Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs. Moreover, the two HSC types differ in intrinsic genetic programs, thus supporting a role for the BMP signalling axis in the regulation of HSC heterogeneity and lineage output. Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.
1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Mihaela
M
Crisan
1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Parham Solaimani
PS
Kartalaei
1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Chris S
CS
Vink
1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Chris
C
Vink
Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Tomoko
T
Yamada-Inagawa
Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Karine
K
Bollerot
Center for Biomics, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, Netherlands.
Wilfred
0000000204218301
W
van IJcken
Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Reinier
R
van der Linden
Department of Anatomy and Embryology, Leiden University Medical Center, Building 2, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
Susana M Chuva
SM
de Sousa Lopes
Department of Anatomy and Embryology, Leiden University Medical Center, Building 2, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
Rui
0000000242238506
R
Monteiro
Department of Anatomy and Embryology, Leiden University Medical Center, Building 2, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
Christine
C
Mummery
1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Elaine
E
Dzierzak
D000818:Animals; D001572:Benzofurans; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011804:Quinolines; D015398:Signal Transduction / Q000502:physiology*
C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; C484261:Babam2 protein, mouse; D001572:Benzofurans; D019485:Bone Morphogenetic Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011804:Quinolines; D049452:Green Fluorescent Proteins