MafB restricts M-CSF-dependent myeloid commitment divisions of hematopoietic stem cells.
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.
Sarrazin
Sandrine
S
Centre d'Immunologie de Marseille-Luminy, Université Aix-Marseille, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France.
Mossadegh-Keller
Noushine
N
Fukao
Taro
T
Aziz
Athar
A
Mourcin
Frederic
F
Vanhille
Laurent
L
Kelly Modis
Louise
L
Kastner
Philippe
P
Chan
Susan
S
Duprez
Estelle
E
Otto
Claas
C
Sieweke
Michael H
MH
D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D019070:Cell Lineage; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D051258:MafB Transcription Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D016173:Macrophage Colony-Stimulating Factor; D051258:MafB Transcription Factor; D011518:Proto-Oncogene Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C490406:Mafb protein, mouse