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

Jiaqian Qi; Tao You; Tingting Pan; Qi Wang; Li Zhu; Yue Han

doi:10.1160/TH17-03-0155

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(10): 1875-1886
DOI: 10.1160/TH17-03-0155

Cellular Haemostasis and Platelets

Schattauer GmbH

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

Jiaqian Qi

¹The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, Suzhou, China

²Cyrus Tang Hematology Center, Soochow University, Suzhou, China

³Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Suzhou, China

⁴Soochow University, Collaborative Innovation Centre of Haematology, Suzhou, China

,

Tao You

¹The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, Suzhou, China

²Cyrus Tang Hematology Center, Soochow University, Suzhou, China

,

Tingting Pan

¹The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, Suzhou, China

²Cyrus Tang Hematology Center, Soochow University, Suzhou, China

³Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Suzhou, China

⁴Soochow University, Collaborative Innovation Centre of Haematology, Suzhou, China

,

Qi Wang

⁴Soochow University, Collaborative Innovation Centre of Haematology, Suzhou, China

,

Li Zhu

²Cyrus Tang Hematology Center, Soochow University, Suzhou, China

³Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Suzhou, China

⁴Soochow University, Collaborative Innovation Centre of Haematology, Suzhou, China

,

Yue Han

¹The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, Suzhou, China

²Cyrus Tang Hematology Center, Soochow University, Suzhou, China

³Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Suzhou, China

› Author Affiliations

Abstract

Summary

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.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

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

Full Text

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Supplementary Material