Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells
Abstract 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 bifurcat...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01575-y |
| _version_ | 1797769630992826368 |
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| author | Meichao Zhang Yiling Meng Yingxia Ying Pingting Zhou Suning Zhang Yong Fang Yuan Yao Dong Li |
| author_facet | Meichao Zhang Yiling Meng Yingxia Ying Pingting Zhou Suning Zhang Yong Fang Yuan Yao Dong Li |
| author_sort | Meichao Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T21:11:48Z |
| format | Article |
| id | doaj.art-4c49f55633c5433bbe8ddb84bd7e9456 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-12T21:11:48Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-4c49f55633c5433bbe8ddb84bd7e94562023-07-30T11:07:44ZengNature Publishing GroupCell Death Discovery2058-77162023-07-019111110.1038/s41420-023-01575-ySelective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cellsMeichao Zhang0Yiling Meng1Yingxia Ying2Pingting Zhou3Suning Zhang4Yong Fang5Yuan Yao6Dong Li7Department of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Burns and Plastic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineAbstract 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.https://doi.org/10.1038/s41420-023-01575-y |
| spellingShingle | Meichao Zhang Yiling Meng Yingxia Ying Pingting Zhou Suning Zhang Yong Fang Yuan Yao Dong Li Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells Cell Death Discovery |
| title | Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells |
| title_full | Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells |
| title_fullStr | Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells |
| title_full_unstemmed | Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells |
| title_short | Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells |
| title_sort | selective activation of stat3 and stat5 dictates the fate of myeloid progenitor cells |
| url | https://doi.org/10.1038/s41420-023-01575-y |
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