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-C...

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Bibliographic Details
Published in:Cell 2009-07, Vol.138 (2), p.300-313
Main Authors: Sarrazin, Sandrine, Mossadegh-Keller, Noushine, Fukao, Taro, Aziz, Athar, Mourcin, Frederic, Vanhille, Laurent, Kelly Modis, Louise, Kastner, Philippe, Chan, Susan, Duprez, Estelle, Otto, Claas, Sieweke, Michael H.
Format: Article
Language:English
Subjects:
Animals
Cell Culture Techniques
Cell Differentiation
Cell Lineage
CELLCYCLE
DEVBIO
Hematopoietic Stem Cells
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Macrophage Colony-Stimulating Factor
Macrophage Colony-Stimulating Factor - metabolism
MafB Transcription Factor
MafB Transcription Factor - metabolism
Mice
Mice, Inbred C57BL
Myeloid Cells
Myeloid Cells - cytology
Proto-Oncogene Proteins
Proto-Oncogene Proteins - metabolism
Receptor, Macrophage Colony-Stimulating Factor
Receptor, Macrophage Colony-Stimulating Factor - metabolism
STEMCELL
Trans-Activators
Trans-Activators - metabolism
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2009.04.057