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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

H2S protects against fatal myelosuppression by promoting the generation of megakaryocytes/platelets

Authors: Huan-Di Liu, Ai-Jie Zhang, Jing-Jing Xu, Ying Chen, Yi-Chun Zhu

Published in: Journal of Hematology & Oncology | Issue 1/2016

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Abstract

Background

Our previous pilot studies aimed to examine the role of hydrogen sulfide (H2S) in the generation of endothelial progenitor cells led to an unexpected result, i.e., H2S promoted the differentiation of certain hematopoietic stem/progenitor cells in the bone marrow. This gave rise to an idea that H2S might promote hematopoiesis.

Methods

To test this idea, a mice model of myelosuppression and cultured fetal liver cells were used to examine the role of H2S in hematopoiesis.

Results

H2S promoted the generation of megakaryocytes, increased platelet levels, ameliorate entorrhagia, and improved survival. These H2S effects were blocked in both in vivo and in vitro models with thrombopoietin (TPO) receptor knockout mice (c-mpl−/− mice). In contrast, H2S promoted megakaryocytes/platelets generation in both in vivo and in vitro models with TPO knockout mice (TPO−/− mice).

Conclusions

H2S is a novel promoter for megakaryopoiesis by acting on the TPO receptors but not TPO to generate megakaryocytes/platelets.
Appendix
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Literature
1.
Henry MK, Lynch JT, Eapen AK, Quelle FW. DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway. Blood. 2001;98(3):834–41.CrossRefPubMed
2.
Mauch P, Constine L, Greenberger J, et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys. 1995;31(5):1319–39.CrossRefPubMed
3.
Wang Y, Schulte BA, LaRue AC, Ogawa M, Zhou D. Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood. 2006;107(1):358–66.PubMedCentralCrossRefPubMed
4.
Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12):3241–8.CrossRefPubMed
5.
Schrezenmeier H, Seifried E. Buffy-coat-derived pooled platelet concentrates and apheresis platelet concentrates: which product type should be preferred? Vox Sang. 2010;99(1):1–15.CrossRefPubMed
6.
Li C, Zheng L. The pharmacology and clinical application of thrombopoietin receptor agonists. Int J Hematol. 2014;100(6):529–39.CrossRefPubMed
7.
Wormann B. Clinical indications for thrombopoietin and thrombopoietin-receptor agonists. Transfus Med Hemother. 2013;40(5):319–25.PubMedCentralPubMed
8.
Stasi R. Eltrombopag: the discovery of a second generation thrombopoietin-receptor agonist. Expert Opin Drug Discov. 2009;4(1):85–93.CrossRefPubMed
9.
Jeong JY, Levine MS, Abayasekara N, Berliner N, Laubach J, Vanasse GJ. The non-peptide thrombopoietin receptor agonist eltrombopag stimulates megakaryopoiesis in bone marrow cells from patients with relapsed multiple myeloma. J Hematol Oncol. 2015;8:37.PubMedCentralCrossRefPubMed
10.
de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369(6481):533–8.CrossRefPubMed
11.
Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369(6481):568–71.CrossRefPubMed
12.
Wendling F, Maraskovsky E, Debili N, et al. cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994;369(6481):571–4.CrossRefPubMed
13.
Solar GP, Kerr WG, Zeigler FC, et al. Role of c-mpl in early hematopoiesis. Blood. 1998;92(1):4–10.PubMed
14.
Kaushansky K, Lin N, Grossmann A, Humes J, Sprugel KH, Broudy VC. Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol. 1996;24(2):265–9.PubMed
15.
Sitnicka E, Lin N, Priestley GV, et al. The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood. 1996;87(12):4998–5005.PubMed
16.
Kaushansky K, Broudy VC, Grossmann A, et al. Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. J Clin Invest. 1995;96(3):1683–7.PubMedCentralCrossRefPubMed
17.
Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M. Recombinant human thrombopoietin (Mpl ligand) enhances proliferation of erythroid progenitors. Blood. 1995;86(7):2494–9.PubMed
18.
19.
20.
Olson KR, Straub KD. The role of Hydrogen sulfide in Evolution and the Evolution of Hydrogen Sulfide in Metabolism and Signaling. Physiology (Bethesda). 2016; 31(1): 60–72.
21.
Hosoki R, Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997;237(3):527–31.CrossRefPubMed
22.
Ma SF, Luo Y, Ding YJ, et al. Hydrogen sulfide targets the Cys320/Cys529 motif in Kv4.2 to inhibit the Ito potassium channels in cardiomyocytes and regularizes fatal arrhythmia in myocardial infarction. Antioxid Redox Signal. 2015;23(2):129–47.CrossRefPubMed
23.
24.
Sun YG, Cao YX, Wang WW, Ma SF, Yao T, Zhu YC. Hydrogen sulphide is an inhibitor of L-type calcium channels and mechanical contraction in rat cardiomyocytes. Cardiovasc Res. 2008;79(4):632–41.CrossRefPubMed
25.
Garcia-Bereguiain MA, Samhan-Arias AK, Martin-Romero FJ, Gutierrez-Merino C. Hydrogen sulfide raises cytosolic calcium in neurons through activation of L-type Ca2+ channels. Antioxid Redox Signal. 2008;10(1):31–42.CrossRefPubMed
26.
27.
Partlo LA, Sainsbury RS, Roth SH. Effects of repeated hydrogen sulphide (H2S) exposure on learning and memory in the adult rat. Neurotoxicology. 2001;22(2):177–89.CrossRefPubMed
28.
Ali MY, Whiteman M, Low CM, Moore PK. Hydrogen sulphide reduces insulin secretion from HIT-T15 cells by a KATP channel-dependent pathway. J Endocrinol. 2007;195(1):105–12.CrossRefPubMed
29.
Kaneko Y, Kimura Y, Kimura H, Niki I. L-cysteine inhibits insulin release from the pancreatic beta-cell: possible involvement of metabolic production of hydrogen sulfide, a novel gasotransmitter. Diabetes. 2006;55(5):1391–7.CrossRefPubMed
30.
Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. Faseb J. 2006;20(12):2118–20.CrossRefPubMed
31.
Li L, Bhatia M, Moore PK. Hydrogen sulphide--a novel mediator of inflammation? Curr Opin Pharmacol. 2006;6(2):125–9.CrossRefPubMed
32.
Li L, Bhatia M, Zhu YZ, et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. Faseb J. 2005;19(9):1196–8.PubMed
33.
Dunn WR, Alexander SP, Ralevic V, Roberts RE. Effects of hydrogen sulphide in smooth muscle. Pharmacol Ther. 2016; 158: 101–13.CrossRefPubMed
34.
Denizalti M, Bozkurt TE, Akpulat U, Sahin-Erdemli I, Abacioglu N. The vasorelaxant effect of hydrogen sulfide is enhanced in streptozotocin-induced diabetic rats. Naunyn Schmiedebergs Arch Pharmacol. 2011;383(5):509–17.CrossRefPubMed
35.
Bir SC, Kolluru GK, McCarthy P, et al. Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1alpha and vascular endothelial growth factor-dependent angiogenesis. J Am Heart Assoc. 2012;1(5):e4093.CrossRef
36.
Qipshidze N, Metreveli N, Mishra PK, Lominadze D, Tyagi SC. Hydrogen sulfide mitigates cardiac remodeling during myocardial infarction via improvement of angiogenesis. Int J Biol Sci. 2012;8(4):430–41.PubMedCentralCrossRefPubMed
37.
Lilyanna S, Peh MT, Liew OW, et al. GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia. J Mol Cell Cardiol. 2015;87:27–37.CrossRefPubMed
38.
Ji Y, Pang QF, Xu G, Wang L, Wang JK, Zeng YM. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J Pharmacol. 2008;587(1-3):1–7.CrossRefPubMed
39.
Sivarajah A, Collino M, Yasin M, et al. Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock. 2009;31(3):267–74.CrossRefPubMed
40.
Moustafa A, Habara Y. Hydrogen sulfide: a novel gaseous signaling molecule and intracellular Ca2+ regulator in rat parotid acinar cells. Am J Physiol Cell Physiol. 2015;309(7):C480–90.CrossRefPubMed
41.
Cai WJ, Wang MJ, Moore PK, Jin HM, Yao T, Zhu YC. The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res. 2007;76(1):29–40.CrossRefPubMed
42.
Wang MJ, Cai WJ, Zhu YC. Mechanisms of angiogenesis: role of hydrogen sulphide. Clin Exp Pharmacol Physiol. 2010;37(7):764–71.CrossRefPubMed
43.
Papapetropoulos A, Pyriochou A, Altaany Z, et al. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci U S A. 2009;106(51):21972–7.PubMedCentralCrossRefPubMed
44.
Tao BB, Liu SY, Zhang CC, et al. VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel Cys1045-Cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells. Antioxid Redox Signal. 2013;19(5):448–64.PubMedCentralCrossRefPubMed
45.
Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, Zhu YC. The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antioxid Redox Signal. 2010;12(9):1065–77.CrossRefPubMed
46.
Lessard J, Faubert A, Sauvageau G. Genetic programs regulating HSC specification, maintenance and expansion. Oncogene. 2004;23(43):7199–209.CrossRefPubMed
47.
Schulze H. Culture of murine megakaryocytes and platelets from fetal liver and bone marrow. Methods Mol Biol. 2012;788:193–203.CrossRefPubMed
48.
Chang Y, Bluteau D, Debili N, Vainchenker W. From hematopoietic stem cells to platelets. J Thromb Haemost. 2007;5 Suppl 1:318–27.CrossRefPubMed
49.
Kaushansky K, Broudy VC, Lin N, et al. Thrombopoietin, the Mp1 ligand, is essential for full megakaryocyte development. Proc Natl Acad Sci U S A. 1995;92(8):3234–8.PubMedCentralCrossRefPubMed
50.
Bowie MB, McKnight KD, Kent DG, McCaffrey L, Hoodless PA, Eaves CJ. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J Clin Invest. 2006;116(10):2808–16.PubMedCentralCrossRefPubMed
51.
Mirshekar-Syahkal B, Fitch SR, Ottersbach K. Concise review: from greenhouse to garden: the changing soil of the hematopoietic stem cell microenvironment during development. Stem Cells. 2014;32(7):1691–700.CrossRefPubMed
52.
53.
Dong-Feng Z, Ting L, Yong Z, Cheng C, Xi Z, Pei-Yan K. The TPO/c-MPL pathway in the bone marrow may protect leukemia cells from chemotherapy in AML patients. Pathol Oncol Res. 2014;20(2):309–17.CrossRefPubMed
54.
Matsumura I, Kanakura Y, Kato T, et al. Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin. Blood. 1995;86(2):703–9.PubMed
55.
Ninos JM, Jefferies LC, Cogle CR, Kerr WG. The thrombopoietin receptor, c-Mpl, is a selective surface marker for human hematopoietic stem cells. J Transl Med. 2006;4:9.PubMedCentralCrossRefPubMed
56.
Vigon I, Mornon JP, Cocault L, et al. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci U S A. 1992;89(12):5640–4.PubMedCentralCrossRefPubMed
57.
Ge SN, Zhao MM, Wu DD, et al. Hydrogen sulfide targets EGFR Cys797/Cys798 residues to induce Na(+)/K(+)-ATPase endocytosis and inhibition in renal tubular epithelial cells and increase sodium excretion in chronic salt-loaded rats. Antioxid Redox Signal. 2014;21(15):2061–82.PubMedCentralCrossRefPubMed
58.
Chan ER, Lavender H, Li G, Haviernik P, Bunting KD, Adams MD. An ENU-induced recessive mutation in Mpl leads to thrombocytopenia with overdominance. Exp Hematol. 2009;37(2):276–84.PubMedCentralCrossRefPubMed
59.
Murone M, Carpenter DA, de Sauvage FJ. Hematopoietic deficiencies in c-mpl and TPO knockout mice. Stem Cells. 1998;16(1):1–6.CrossRefPubMed
60.
de Sauvage FJ, Carver-Moore K, Luoh SM, et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med. 1996;183(2):651–6.CrossRefPubMed
61.
Shen X, Pattillo CB, Pardue S, Bir SC, Wang R, Kevil CG. Measurement of plasma hydrogen sulfide in vivo and in vitro. Free Radic Biol Med. 2011;50(9):1021–31.CrossRefPubMed
Metadata
Title
H2S protects against fatal myelosuppression by promoting the generation of megakaryocytes/platelets
Authors
Huan-Di Liu
Ai-Jie Zhang
Jing-Jing Xu
Ying Chen
Yi-Chun Zhu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0244-7

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