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MafB Restricts M-CSF-Dependent Myeloid Commitment Divisions of Hematopoietic Stem Cells
Sandrine Sarrazin1,2,3,Noushine Mossadegh-Keller1,2,3,9,Taro Fukao1,2,3,5,9,Athar Aziz1,2,3,6,Frederic Mourcin1,2,3,7,Laurent Vanhille1,2,3,Louise Kelly Modis1,2,3,8,Philippe Kastner4,Susan Chan4,Estelle Duprez1,2,3,Claas Otto1,2,3andMichael H. Sieweke1,2,3,,
1 Centre d'Immunologie de Marseille-Luminy (CIML), Université Aix-Marseille, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France
2 Institut National de la Santé et de la Recherche Médicale (INSERM), U631, Marseille, France
3 Centre National de la Recherche Scientifique (CNRS), UMR6102, Marseille, France
4 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg F-67000, France
5 Present address: Max-Planck Institute of Immunobiology, Stübeweg 51, D-79108 Freiburg, Germany
6 Present address: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK
7 Present address: INSERM U917, Faculté de Médecine, Université de Rennes, Rennes F-35043, France
8 Present address: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
9 These authors contributed equally to this work
While hematopoietic stem cell (HSC) self-renewal is well studied, it remains unknown whether distinct control mechanisms enable HSC divisions that generate progeny cells with specific lineage bias. Here, we report that the monocytic transcription factor MafB specifically restricts the ability of M-CSF to instruct myeloid commitment divisions in HSCs. MafB deficiency specifically enhanced sensitivity to M-CSF and caused activation of the myeloid master-regulator PU.1 in HSCs in vivo. Single-cell analysis revealed that reduced MafB levels enabled M-CSF to instruct divisions producing asymmetric daughter pairs with one PU.1+ cell. As a consequence, MafB HSCs showed a PU.1 and M-CSF receptor-dependent competitive repopulation advantage specifically in the myelomonocytic, but not T lymphoid or erythroid, compartment. Lineage-biased repopulation advantage was progressive, maintained long term, and serially transplantable. Together, this indicates that an integrated transcription factor/cytokine circuit can control the rate of specific HSC commitment divisions without compromising other lineages or self-renewal.
