Endothelial microparticles delivering microRNA-155 into T lymphocytes are involved in the initiation of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

// Ran Zhang 1, * , Xiaoxiao Wang 1, * , Mei Hong 1, * , Ting Luo 1 , Miaomiao Zhao 1 , Haorui Shen 1 , Jun Fang 1 , Xiaojie Li 1 , Sibin Zang 1 , Ping Chen 1 , Dimin Nie 1 , Peng Zheng 1 , Qiuling Wu 1 and Linghui Xia 1 1 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China * These authors contributed equally to this work Correspondence to: Linghui Xia, email: Linghuixia@mail.hust.edu.cn Qiuling Wu, email: wuqiuling927@hotmail.com Keywords: acute graft-versus-host disease, endothelial microparticles, microRNA-155, T lymphocytes, differentiation Received: October 24, 2016      Accepted: February 12, 2017      Published: February 21, 2017 ABSTRACT Endothelial microparticles (EMPs) upregulation has been observed in acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the role of EMPs remains unclear. We found that EMPs derived from TNF-α-stimulated human umbilical vein endothelial cells (EA.hy926) concentrated more microRNA-155 (miR-155) compared with maternal cells. The miR-155 levels in MPs from peripheral blood of aGVHD patients and mice were remarkably elevated and significantly higher than the levels in plasma. Moreover, the rising peak of miR-155 in MPs occurred significantly prior to the peak in T lymphocytes. Additionally, we observed fluorescently-labeled miR-155 in EMPs actively transported into recipient T lymphocytes. Inhibition of miR-155 in EMPs by antagomir-155 did not influence the proliferation and apoptosis of T lymphocytes, but induced defective differentiation toward Th1, Th9 and Th17 cells and skewed differentiation toward Th2 and Treg cells. Furthermore, intravenous injection of miR-155-deficient-EMPs into aGVHD mice significantly attenuated the exacerbation of aGVHD manifestations and abnormal T lymphocytes differentiation induced by high concentration EMPs. Taken together, these data provide a mechanistic framework in which miR-155 delivered by EMPs is involved in aGVHD pathogenesis by activating specific T lymphocytes functions. The results may provide new therapeutic approaches for aGVHD while preserving graft-versus-leukemia (GVL) effect.