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- Title
Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia.
- Authors
He, Yun; Xu, Lin‐Lin; Feng, Fei‐Er; Wang, Qian‐Ming; Zhu, Xiao‐Lu; Wang, Chen‐Cong; Zhang, Jia‐Min; Fu, Hai‐Xia; Xu, Lan‐Ping; Liu, Kai‐Yan; Huang, Xiao‐Jun; Zhang, Xiao‐Hui
- Abstract
Summary: Immune thrombocytopenia (ITP) is an autoimmune disease. Mesenchymal stem cells (MSCs) play important roles in the physiology and homeostasis of the haematopoietic system, including supporting megakaryocytic differentiation from CD34+ haematopoietic progenitor cells. Tumour necrosis factor alpha‐induced protein 3 (TNFAIP3, also termed A20) plays a key role in terminating NF‐κB signalling. Human genetic studies showed that the polymorphisms of the <italic>TNFAIP3</italic> gene may contribute to ITP susceptibility. In this study, we showed a significant decrease in TNFAIP3 and increase in NF‐κB/SMAD7 in ITP‐MSCs. In co‐cultures with CD34+ cells, NF‐κB was overexpressed in MSCs from healthy controls (HC‐MSCs) after transfection with <italic>NFKBIA</italic> (<italic>I</italic>κ<italic>B</italic>)‐specific short hairpin (sh)RNAs, resulting in MSC deficiency and a reduction in megakaryocytic differentiation and thrombopoiesis. Knockdown of TNFAIP3 expression using <italic>TNFAIP3</italic>‐specific shRNAs in HC‐MSCs affected megakaryocytopoiesis. However, <italic>IKBKB</italic> knockdown corrected megakaryocytopoiesis inhibition in the ITP‐MSCs by decreasing NF‐κB expression. Amplified TNFAIP3 expression in ITP‐MSCs by <italic>TNFAIP3 </italic>cDNA can facilitate megakaryocyte differentiation. shRNA‐mediated knockdown of <italic>SMAD7</italic> expression rescued the impaired MSC function in ITP patients. Therefore, we demonstrate that a pathological reduction in TNFAIP3 levels induced NF‐κB/SMAD7 pathway activation, causing a deficiency in MSCs in ITP patients. The ability of ITP‐MSCs to support megakaryocytic differentiation and thrombopoiesis of CD34+ cells was impaired.
- Subjects
MESENCHYMAL stem cells; MULTIPOTENT stem cells; HEMATOPOIETIC system; HOMEOSTASIS; IDIOPATHIC thrombocytopenic purpura; TUMOR necrosis factors
- Publication
British Journal of Haematology, 2018, Vol 180, Issue 3, p395
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.15034