Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells

The molecular programs that govern the directed differentiation of myeloid progenitor cells are still poorly defined. Using a previously established immortalized, phenotypically normal myeloid progenitor cell model mEB8-ER, we unveil a new mechanism mediated by STAT5 and STAT3 at a bifurcation point...

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Bibliographic Details
Published in:Cell death discovery 2023-07, Vol.9 (1), p.274-274, Article 274
Main Authors: Zhang, Meichao, Meng, Yiling, Ying, Yingxia, Zhou, Pingting, Zhang, Suning, Fang, Yong, Yao, Yuan, Li, Dong
Format: Article
Language:English
Subjects:
631/532/1542
631/80/83
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell differentiation
Granulocyte colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor
Leukocytes (neutrophilic)
Life Sciences
Macrophages
Monocytes
Neutrophils
Overexpression
Phosphorylation
Progenitor cells
Stat3 protein
Stat5 protein
Stem Cells
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Summary:The molecular programs that govern the directed differentiation of myeloid progenitor cells are still poorly defined. Using a previously established immortalized, phenotypically normal myeloid progenitor cell model mEB8-ER, we unveil a new mechanism mediated by STAT5 and STAT3 at a bifurcation point of myeloid progenitor cell-fate specification. We find that myeloid progenitor cells can spontaneously differentiate into neutrophils with a basal level of STAT3 phosphorylation, which is enhanced by G-CSF treatment or STAT3 over-expression, leading to elevated neutrophil differentiation. Reduced STAT3 phosphorylation caused by GM-CSF treatment, STAT3 specific inhibitor, or STAT3 depletion leads to attenuated myeloid differentiation into neutrophils, while elevating differentiation into monocytes/macrophages. In contrast, STAT5 appears to have an antagonistic function to STAT3. When activated by GM-CSF, STAT5 promotes myeloid differentiation into monocytes/macrophages but inhibits neutrophil differentiation. At the mechanistic level, GM-CSF activates STAT5 to up-regulate SOCS3, which attenuates STAT3 phosphorylation and consequently neutrophil differentiation, while enhancing monocyte/macrophage differentiation. Furthermore, inhibition of STAT5 and STAT3 in primary myeloid progenitors recapitulates the results from the mEB8-ER model. Together, our findings provide new mechanistic insights into myeloid differentiation and may prove useful for the diagnosis and treatment of diseases related to abnormal myeloid differentiation.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-023-01575-y