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Generation of Large Numbers of Myeloid Progenitors and Dendritic Cell Precursors from Murine Bone Marrow Using a Novel Cell Sorting Strategy
Published on: August 10, 2018
Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity
Marie-France Grasset1, Stéphanie Gobert-Gosse, Guy Mouchiroud
1Universite de Lyon, Universite Lyon 1, Centre de Genetique Moleculaire et Cellulaire, CNRS UMR5534, Villeurbanne, France.
Abstract:
M-CSF regulates the production, survival, and function of monocytes and macrophages. The MAPKs ERK1/2 are key elements for signal integration downstream of the M-CSFR, and their sustained activation is essential for macrophage differentiation. In this study, we sought to isolate genes whose induction by M-CSF is dependent on persistent MAPK activation, thereby being possibly involved in the commitment of myeloid progenitors to macrophage differentiation. Following SSH between cDNA libraries from FD-Fms cells stimulated by M-CSF for 8 h in the presence or the absence of the MEK inhibitor U0126, we isolated DUSP5. DUSP5 expression is induced by M-CSF in various myeloid cells and acts as a specific negative-feedback regulator of ERK1/2. In FD-Fms cells that proliferate and differentiate toward macrophages in response to M-CSF, overexpression of DUSP5 increased M-CSF-dependent proliferation and strongly decreased differentiation. Similarly, overexpression of DUSP5 in the multipotent EGER-Fms cells not only significantly increased M-CSF-induced proliferation and prevented macrophage differentiation but also favored granulocytic differentiation. Altogether, experiments demonstrated that DUSP5 is implicated in M-CSF signaling and suggested that it may influence myeloid cell fate.
Insights
Macrophage colony-stimulating factor (M-CSF) signaling involves mitogen-activated protein kinases (MAPKs). This study identifies DUSP5 as a key regulator, influencing myeloid cell proliferation and differentiation.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Macrophage colony-stimulating factor (M-CSF) is crucial for monocyte and macrophage development.
- Mitogen-activated protein kinases (MAPKs), particularly ERK1/2, are vital for M-CSF receptor (M-CSFR) signaling and macrophage differentiation.
Purpose of the Study:
- To identify genes induced by M-CSF that depend on sustained MAPK activation.
- To investigate the role of such genes in myeloid progenitor commitment to macrophage differentiation.
Main Methods:
- Subtractive hybridization (SSH) was used to compare gene expression in FD-Fms cells stimulated with M-CSF with or without MEK inhibitor U0126.
- DUSP5 expression and function were analyzed in myeloid cell lines (FD-Fms and EGER-Fms) with DUSP5 overexpression.
Main Results:
- DUSP5 was identified as a M-CSF-induced gene and a negative-feedback regulator of ERK1/2.
- Overexpression of DUSP5 enhanced M-CSF-induced proliferation and inhibited macrophage differentiation in FD-Fms cells.
- In EGER-Fms cells, DUSP5 overexpression increased proliferation, blocked macrophage differentiation, and promoted granulocytic differentiation.
Conclusions:
- DUSP5 plays a significant role in M-CSF signaling pathways.
- DUSP5 influences myeloid cell fate decisions, impacting proliferation and differentiation toward specific lineages.
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