title: 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 Atg7flox/floxPF4-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.
authors.affiliation: a Cyrus Tang Hematology Center , Soochow University , Suzhou , China.|b Collaborative Innovation Center of Hematology , Soochow University , Suzhou , China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: a Cyrus Tang Hematology Center , Soochow University , Suzhou , China.|d Jiangsu Institute of Hematology of The First Affiliated Hospital , Soochow University , Suzhou , China.
authors.forename: Tao
authors.initials: T
authors.lastname: You
authors.affiliation: a Cyrus Tang Hematology Center , Soochow University , Suzhou , China.
authors.forename: Hongqiong
authors.initials: H
authors.lastname: Fan
authors.affiliation: a Cyrus Tang Hematology Center , Soochow University , Suzhou , China.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Cyrus Tang Hematology Center , Soochow University , Suzhou , China.|d Jiangsu Institute of Hematology of The First Affiliated Hospital , Soochow University , Suzhou , China.
authors.forename: Tinatian
authors.initials: T
authors.lastname: Chu
authors.affiliation: f Department of Pediatrics, Children's Hospital of Philadelphia , Perelman School of Medicine at the University of Pennsylvania , Philadelphia , Pennsylvania , USA.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: a Cyrus Tang Hematology Center , Soochow University , Suzhou , China.|b Collaborative Innovation Center of Hematology , Soochow University , Suzhou , China.|c MOH Key Lab of Thrombosis and Hemostasis , Soochow University , Suzhou , China.|e Jiangsu Key Lab of Preventive and translational Medicine for Geriatric Diseases , Soochow University , Suzhou , China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers; D001792:Blood Platelets / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010976:Platelet Count; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics / Q000378:metabolism; D011003:Ploidies; D020123:Sirolimus / Q000494:pharmacology*; D034061:Thrombopoiesis / Q000187:drug effects* / Q000235:genetics
chemical_list: D015415:Biomarkers; D039661:Integrin beta3; D018942:Macrolides; D040201:Platelet Membrane Glycoprotein IIb; C040929:bafilomycin A1; D020123:Sirolimus
keywords: Autophagy; megakaryopoiesis; thrombopoiesis