Page 169 - 2019_08-Haematologica-web

Platelet Biology & its DIsorders
All-trans retinoic acid protects mesenchymal stem cells from immune thrombocytopenia by regulating the complement–interleukin-1β loop
Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1661-1675
Partial results of this research were presented as an oral presentation at the 58th American Society of Hematology Annual Meeting
and Exposition (ASH), San Diego, CA,
3 December 2016 (“Crucial Role of Complement Activation and IL-1β in Bone Marrow Niche of Immune Thrombocytopenia”, n. 166).
Xiaolu Zhu,1 Yanan Wang,1 Qian Jiang,1 Hao Jiang,1 Jin Lu,1 Yazhe Wang,1 Yuan Kong,1 Yingjun Chang,1 Lanping Xu,1 Jun Peng,2 Ming Hou,2 Xiaojun Huang1 and Xiaohui Zhang1
1Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Beijing and 2Department of Hematology, Qilu Hospital, Shandong University, Jinan, P.R. China
ABSTRACT
Enhanced peripheral complement activation has long been considered as one of the major pathogenic elements of immune thrombocytope- nia. A dysfunctional bone marrow microenvironment, especially with regards to mesenchymal stem cells, has been observed in patients with immune thrombocytopenia. However, the potential role of the comple- ment system in the dysfunctional bone marrow microenvironment remains poorly understood. In this study, bone marrow samples from patients with immune thrombocytopenia were divided into two groups based on whether or not complement components were deposited on the surfaces of their mesenchymal stem cells. The mesenchymal cells from the group with complement deposition were less numerous, dysfunctional, had a reduced capacity to proliferate, and showed increased apoptosis as well as abnormal secretion of interleukin-1β and C-X-C motif chemokine ligand 12. In vitro treatment with all-trans retinoic acid increased the number and improved the function of the complement-positive bone marrow mesenchymal stem cells by upregulating DNA hypermethylation of the interleukin-1β promot- er. In vivo studies showed that all-trans retinoic acid could rescue the impaired mesenchymal stem cells to support the thrombopoietic niche in both patients with immune thrombocytopenia and a murine model of this disease. Taken together, these results indicate that impairment of mes- enchymal stem cells, mediated by the complement–interleukin-1β loop, plays a role in the pathogenesis of immune thrombocytopenia. All-trans retinoic acid represents a promising therapeutic approach in patients with immune thrombocytopenia through its effect of repairing mesenchymal stem cell impairment.
Introduction
Immune thrombocytopenia (ITP) is a common autoimmune disorder character- ized by severe isolated thrombocytopenia.1 Increasing evidence suggests a role for complement activation in ITP.1-3 We previously characterized the abnormal enhanced complement activation in plasma samples from patients with ITP, as well as enhanced plasma complement activation/fixation capacity on immobilized het- erologous platelets.4 Moreover, we confirmed the activation of both the classical and alternative complement pathways in the peripheral blood of patients with ITP.4 However, our knowledge regarding the involvement of the complement sys- tem in the bone marrow of patients with ITP is still very limited.
Emerging evidence indicates that complement affects not only B-cell responses5,6 but also T-cell immunity during the induction, effector and contraction phases of an immune response.7-10 Interestingly, we and others have identified an imbalance between B-effector and T-regulatory networks involved in the pathogenesis of ITP.1,11-14 Mesenchymal stem cells (MSC) have been documented to play crucial
Correspondence:
XIAOHUI ZHANG
zhangxh100@sina.com
Received: August 13, 2018. Accepted: January 21, 2019. Pre-published: January 24, 2019.
doi:10.3324/haematol.2018.204446
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/8/1661
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(8)
1661
ARTICLE