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Thromb Haemost. 2017 Oct 5;117(10):1875-1886. doi: 10.1160/TH17-03-0155. Epub 2017 Aug 3.

Downregulation of hypoxia-inducible factor-1α contributes to impaired megakaryopoiesis in immune thrombocytopenia.

Author information

1
Yue Han, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, 188 Shizi Street, Suzhou, Jiangsu province, 215006 P.R. China, Tel.: +86 13901551669, E-mail: hanyue@suda.edu.cn, or, Li Zhu, Cyrus Tang Hematology Center, Soochow University, Rm 509, Bldg 703, 199 Ren'ai Road, Suzhou, Jiangsu, 215123 P.R. China, Tel.: +86 0512 65880899 ext. 3509, E-mail: zhul@suda.edu.cn.

Abstract

Impaired megakaryocyte maturation and exaggerated platelet destruction play a pivotal role in the pathogenesis of immune thrombocytopenia (ITP). Previous studies have shown that HIF-1α promotes the homing and engraftment of haematopoietic stem cells (HSCs), thereby stimulating HSC differentiation. However, whether HIF-1α plays a role in megakaryocytic maturation and platelet destruction in ITP remains elusive. Using enzyme-linked immunosorbent assays (ELISAs), we demonstrated that there were lower HIF-1α levels in the bone marrow (BM) of ITP patients than in that of healthy donors and patients with chemotherapy-related thrombocytopenia. Subjects with lower megakaryocyte (<100/slide) and platelet (<30 × 109/L) counts exhibited significantly decreased BM HIF-1α levels, compared to those with higher megakaryocyte (≥100/slide) and platelet (≥30 × 109/L) counts. To test whether HIF-1α regulates megakaryopoiesis and platelet production, megakaryocytes derived from mouse BM cells were treated with an HIF-1α activator (IOX-2; 50 µM) or inhibitor (PX-478; 50 µM). PX-478 significantly decreased HIF-1α expression, cell size, and the populations of CD41-positive and high-ploidy cells. Importantly, to evaluate the role of HIF-1α as a potential therapeutic target in ITP, mouse BM cells were incubated with plasma from ITP patients in the presence or absence of IOX-2. IOX-2 significantly attenuated the ITP plasma-induced decrease in cell size as well as the proportions of CD41-positive and high-ploidy cells. In addition, IOX-2 increased the number of megakaryocytes from mouse BM cells treated with ITP plasma. Our findings indicate that decreased HIF-1α may contribute to impaired megakaryopoiesis in ITP, and HIF-1α may provide a potential therapy for ITP patients.

KEYWORDS:

Hypoxia-inducible factor-1α; immune thrombocytopenia; megakaryocyte

PMID:
28771276
DOI:
10.1160/TH17-03-0155
[Indexed for MEDLINE]

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