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M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity

Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are lar...

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Autores principales: Zhao, Hong-Yan, Zhang, Yuan-Yuan, Xing, Tong, Tang, Shu-Qian, Wen, Qi, Lyu, Zhong-Shi, Lv, Meng, Wang, Yu, Xu, Lan-Ping, Zhang, Xiao-Hui, Kong, Yuan, Huang, Xiao-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211642/
https://www.ncbi.nlm.nih.gov/pubmed/34140465
http://dx.doi.org/10.1038/s41392-021-00627-y
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author Zhao, Hong-Yan
Zhang, Yuan-Yuan
Xing, Tong
Tang, Shu-Qian
Wen, Qi
Lyu, Zhong-Shi
Lv, Meng
Wang, Yu
Xu, Lan-Ping
Zhang, Xiao-Hui
Kong, Yuan
Huang, Xiao-Jun
author_facet Zhao, Hong-Yan
Zhang, Yuan-Yuan
Xing, Tong
Tang, Shu-Qian
Wen, Qi
Lyu, Zhong-Shi
Lv, Meng
Wang, Yu
Xu, Lan-Ping
Zhang, Xiao-Hui
Kong, Yuan
Huang, Xiao-Jun
author_sort Zhao, Hong-Yan
collection PubMed
description Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs 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 MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, 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 MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs 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.
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spelling pubmed-82116422021-07-01 M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity Zhao, Hong-Yan Zhang, Yuan-Yuan Xing, Tong Tang, Shu-Qian Wen, Qi Lyu, Zhong-Shi Lv, Meng Wang, Yu Xu, Lan-Ping Zhang, Xiao-Hui Kong, Yuan Huang, Xiao-Jun Signal Transduct Target Ther Article Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs 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 MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, 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 MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs 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. Nature Publishing Group UK 2021-06-18 /pmc/articles/PMC8211642/ /pubmed/34140465 http://dx.doi.org/10.1038/s41392-021-00627-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhao, Hong-Yan
Zhang, Yuan-Yuan
Xing, Tong
Tang, Shu-Qian
Wen, Qi
Lyu, Zhong-Shi
Lv, Meng
Wang, Yu
Xu, Lan-Ping
Zhang, Xiao-Hui
Kong, Yuan
Huang, Xiao-Jun
M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity
title M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity
title_full M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity
title_fullStr M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity
title_full_unstemmed M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity
title_short M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity
title_sort m2 macrophages, but not m1 macrophages, support megakaryopoiesis by upregulating pi3k-akt pathway activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211642/
https://www.ncbi.nlm.nih.gov/pubmed/34140465
http://dx.doi.org/10.1038/s41392-021-00627-y
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