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Thromb Haemost 2020; 120(04): 647-657
DOI: 10.1055/s-0040-1705117
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Heparanase Facilitates PMA-Induced Megakaryocytic Differentiation in K562 Cells via Interleukin 6/STAT3 Pathway

Lu Ming Wan
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
2   Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China
,
Shi Kun Zhang
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Su Bo Li
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Wen Li
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Shou Ping Ji
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Lin Gong
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
3   Department of Hepatobiliary Surgery, No.971 Hospital of Chinese PLA, Qingdao, Shandong, China
,
Zhi Min Yun
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Xue Zhang
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Hong Wei Gao
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Hui Zhong
2   Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China
,
Cong Wen Wei
2   Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China
,
Li Hong Bian
4   Department of Gynecology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
,
Hai Long Zhuo
5   Department of Transfusion, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
,
Qun Luo
5   Department of Transfusion, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
,
Jin Ping Li
6   Department of Medical Biochemistry and Microbiology, SciLifeLab Uppsala, The Biomedical Center, University of Uppsala, Uppsala, Sweden
,
Ying Xia Tan
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
,
Feng Gong
1   Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China
› Author Affiliations Funding The authors would like to thank the financial supports from Swedish Research Council (2018–02503) and Swedish Cancer Foundation (CAN2018/541).
Further Information

Publication History

17 July 2019

15 January 2020

Publication Date:
14 April 2020 (online)

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Abstract

Heparanase (HPSE) is an endo-β-D-glucuronidase that cleaves heparan sulfate and hence participates in remodeling of the extracellular matrix, leading to release of cytokines that are immobilized by binding to heparan sulfate proteoglycans (HSPGs), and consequently activating signaling pathways. This function of HPSE is correlated to its expression level that is normally very low in majority of the tissues. Exceptionally, human platelets express high level of HPSE, suggesting a unique physiological role in this cell. Using K562 cell line, we found a progressive increase of HPSE during the megakaryocytic differentiation. Analysis of a series of megakaryocytic differentiation-related heparin-binding proteins (HBPs) in the cell culture medium revealed an exclusive positive correlation between the level of interleukin 6 (IL-6) and HPSE expression. IL-6 modulated megakaryocytic differentiation through activation of STAT3. Further, we demonstrated that overexpression of HPSE potentiates megakaryocytic differentiation, whereas elimination of HPSE led to a delayed differentiation. This function of HPSE is associated with its activity, as overexpression of inactive HPSE had no effect on IL-6 production and megakaryocytic differentiation. The role of HPSE is further supported by the observation in an umbilical cord blood CD34+ cells megakaryocytic differentiation model. Our data propose a novel role for HPSE in platelets production by a HPSE/IL-6/STAT3 positive feedback loop that specifically regulates megakaryocytes maturation.

Keywords

heparanase - megakaryocytic differentiation - interleukin 6 - STAT3

Supplementary Material

 

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