Rapamycin and bafilomycin A1 alter autophagy and megakaryopoiesis

Abstract

Autophagy is an effective strategy for cell development by recycling cytoplasmic constituents. Genetic deletion of autophagy mediator Atg7 in hematopoietic stem cells (HSCs) can lead to failure of megakaryopoiesis and enhanced autophagy has been implicated in various hematological disorders such as immune thrombocytopenia and myelodysplastic syndrome. Here, we examined the hypothesis that optimal autophagy is essential for megakaryopoiesis and thrombopoiesis by altering autophagy using pharmacological approaches. When autophagy was induced by rapamycin or inhibited by bafilomycin A1 in fetal liver cells, we observed a significant decrease in high ploidy megakaryocytes, a reduction of CD41 and CD61 co-expressing cells, and less proplatelet or platelet formation. Additionally, reduced cell size was shown in megakaryocytes derived from rapamycin, but not bafilomycin A1-treated mouse fetal liver cells. However, when autophagy was altered in mature megakaryocytes, we observed no significant change in proplatelet formation, which was consistent with normal platelet counts, megakaryocyte numbers, and ploidy in Atg7^flox/flox PF4-Cre mice with megakaryocyte- and platelet-specific deletion of autophagy-related gene Atg7. Therefore, our findings suggest that either induction or inhibition of autophagy in the early stage of megakaryopoiesis suppresses megakaryopoiesis and thrombopoiesis.

Keywords:

• Autophagy
• megakaryopoiesis
• thrombopoiesis

Acknowledgment

We would like to thank Drs. Yu Hu and Heng Mei (Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China) for their valuable suggestions during the revision of the manuscript.

Funding

This work was supported by Natural Science Foundation of China [grant 81370373, 81170132, 91439112 to LZ]; the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) of China [to LZ]

Additional information

Funding

This work was supported by Natural Science Foundation of China [grant 81370373, 81170132, 91439112 to LZ]; the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) of China [to LZ]