Osteoblasts support megakaryopoiesis through production of interleukin-9

Min Xiao  ^{1   2} , Yongkui Wang  ^{1   2} , Chen Tao  ¹ , Zhenyu Wang  ² , Jun Yang  ¹ , Zhenguo Chen  ¹ , Zhipeng Zou  ¹ , Mangmang Li  ¹ , Anling Liu  ¹ , Chunhong Jia  ¹ , Bin Huang  ² , Bo Yan  ² , Pinglin Lai  ² , Changhai Ding  ¹ , Daozhang Cai  ² , Guozhi Xiao  ^{3   4} , Yu Jiang  ⁵ , Xiaochun Bai  ^{1   2}

Affiliations

• ¹ State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences and.
• ² Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
• ³ Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
• ⁴ Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL; and.
• ⁵ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Abstract

Severe thrombocytopenia is a significant challenge in patients undergoing myelosuppressive chemotherapy for malignancies. Understanding the biology of platelet-producing megakaryocytes development in the bone marrow microenvironment may facilitate the development of novel therapies to stimulate platelet production and prevent thrombocytopenia. We report here that osteoblasts supported megakaryopoiesis by secreting interleukin-9 (IL-9), which stimulated IL-9 receptor (IL-9R)/Stat3 signaling in promoting megakaryopoiesis. IL-9 production in osteoblasts was negatively regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signaling in a NF-κB-dependent manner. Constitutive activation of mTORC1 inhibited IL-9 production in osteoblasts and suppressed megakaryocytic cells expansion, whereas mTORC1 inactivation increased IL-9 production and enhanced megakaryocyte and platelet numbers in mice. In mouse models, we showed that IL-9 administration stimulated megakaryopoiesis, whereas neutralizing endogenous IL-9 or IL-9R depletion inhibited the process. Importantly, we found that low doses of IL-9 efficiently prevented chemotherapy-induced thrombocytopenia (CIT) and accelerated platelet recovery after CIT. These data indicate that IL-9 is an essential regulator of megakaryopoiesis and a promising therapeutic agent for treatment of thrombocytopenia such as CIT.