M2 macrophages,but not Ml macrophages,support megakaryopoiesis by upregulating PI3K-AKT pathway activity  

作　　者：Hong-Yan Zhao Yuan-Yuan Zhang Tong Xing Shu-Qian Tang Qi Wen Zhong-Shi Lyu Meng Lv Yu Wang Lan-Ping Xu Xiao-Hui Zhang Yuan Kong Xiao-Jun Huang 

机构地区：[1]Peking University People’s Hospital,Peking University Institute of Hematology,National Clinical Research Center for Hematologic Disease,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation,Collaborative Innovation Center of Hematology,Peking University,Beijing,China [2]Peking-Tsinghua Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第7期2196-2209,共14页信号转导与靶向治疗（英文）

基　　金：This work was supported by the National Key Research and Development Program(2017YFA0104500 and 2019YFC0840606);National Natural Science Foundation of China(82070188,81870139,81930004);the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81621001);the Science and Technology Project of Guangdong Province of China(2016B030230003).

摘　　要：Dysfunctional megakaryopoiesis hampers platelet production,which is closely associated with thrombocytopenia(PT).Macrophages(MΦs)are crucial cellular components in the bone marrow(BM)microenvironment.However,the specific effects of M1 MΦs or M2 MΦs on regulating megakaryocytes(MKs)are largely unknown.In the current study,aberrant BM-M1/M2 MO polarization,characterized by increased M1 MΦs and decreased M2 MΦs and accompanied by impaired megakaryopoiesis-supporting abilities,was found in patients with PT post-allotransplant.RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MΦs of PT patients.Moreover,in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MΦs from PT patients.Furthermore,we found M1 MΦs suppress,whereas M2 MCDs support MK maturation and platelet formation In humans.Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MΦs,as indicated by decreased MK count,colony-forming unit number,high-ploidy distribution,and platelet count.Importantly,genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MΦs both in vitro and in a MO-specific PI3K-knockdown murine model,indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 M(Ds.Furthermore,our preliminary data indicated that TGF-β released by M2 MΦs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs.Taken together,our data reveal that M1 and M2 MΦs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner,which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

关 键 词：PI3K IMPAIRED supporting 

分 类 号：R392[医药卫生—免疫学]