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Eltrombopag, a Thrombopoietin Receptor Agonist, Enhances Human

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Eltrombopag, a Thrombopoietin Receptor Agonist, Enhances Human View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Stem Cell Research (2012) 9,77–86 Available online at www.sciencedirect.com www.elsevier.com/locate/scr REGULAR ARTICLE Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis☆ Hongliang Sun a, Ying Tsai a, Irena Nowak a, Jane Liesveld b, Yuhchyau Chen a,⁎ a Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Ave, Box 647, Rochester, NY 14642, USA b Department of Medicine, Division of Hematology Oncology, University of Rochester Medical Center, 601 Elmwood Ave, Box 704, Rochester, NY 14642, USA Received 22 February 2012; received in revised form 5 May 2012; accepted 7 May 2012 Available online 14 May 2012 Abstract Umbilical cord blood (UCB) transplantation has emerged as a promising therapy, but it is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated eltrombopag's effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/ SCID mice xenotransplant model. Consequently, eltrombopag increased peripheral human platelets and white blood cells. We Abbreviations: FBS, fetal bovine serum; FL, flt-3 ligand; G (M)-CSF, granulocyte (macrophage) colony-stimulating factor; GVHD, graft versus host disease; HLA, human leukocyte antigen; HPC, hematopoietic progenitor cell; HSC, hematopoietic stem cell; ITP, idiopathic thrombocytopenic purpura; MNCs, mononuclear cells; NOD/SCID, Non-obese diabetic/severe combined immunodeficiency; PEG-rHuMGDF, pegylated recombinant megakaryocyte growth and development factor; PBSC, peripheral blood stem cells; RBC, red blood cells; rhTPO, recombinant human thrombopoietin; UCB(T), umbilical cord blood (transplantation); TPO, thrombopoietin; TPO-R, thrombopoietin receptor; WBC, white blood cells. ☆ Funding: This work was funded in part by a grant from Center for Medical Countermeasures against Radiation Program (CMCR) (Y.C.; No. U19A1067733) from the National Institute of Health (NIH)/National Institute of Allergy and Infectious Disease (NIAID). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID. The study was also funded in part by federal funds from the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services (HHS), under Contract No. HHSO100200800058C (Y.C.). GlaxoSmithKline has provided the supply of eltrombopag. None of the funding agencies or GSK provided input in the study design; collection, analysis, and interpretation of data; writing of the report; and decision to submit this report for publication. ⁎ Corresponding author. E-mail addresses: [email protected] (H. Sun), [email protected] (Y. Tsai), [email protected] (I. Nowak), [email protected] (J. Liesveld), [email protected] (Y. Chen). 1873-5061/$ - see front matter. Published by Elsevier B.V. doi:10.1016/j.scr.2012.05.001 78 H. Sun et al. further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+ CD38−, CD34+, and CD41+ cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41−, CD34− CD41+, and CD34− CD41− cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34 − C41+ cells, while eltrombopag had no effects on pSTAT3. In conclusion, eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/ HPC populations. Published by Elsevier B.V. Introduction 1996; Luens et al., 1998; Ramsfjell et al., 1997; Petzer et al., 1996; Sitnicka et al., 1996; Young et al., 1996). TPO is also Umbilical cord blood transplantation (UCBT) holds great known to be critical for the replenishment of HSCs after bone promise with apparent clinical advantages, but the trans- marrow transplantation (Fox et al., 2002; Qian et al., 2007). plant success rate remains much poorer than peripheral These observations established the crucial roles of TPO blood stem cell (PBSC) or bone marrow stem cell sources. receptor (c-Mpl) signaling on not only megakaryocytopoiesis, This is due to the scarcity of stem cells in each unit, thus ex but also early hematopoiesis including regulation of HSCs. vivo expansion of UBC continues to be an area of active While TPO holds promise in thrombopoiesis and in promoting research (Koestenbauer et al., 2009). Nonetheless, human stem cell proliferation and differentiation, phase II–III clinical UCB stem cells are useful for patients without matched trials of rhTPO and its shorter polyethylene glycol-conjugated related or unrelated donors, because an estimated 40%–80% form, PEG-rHuMGDF yielded mixed results. This was due to the of patients will not be able to find an acceptable adult stem fact that both were associated with autoantibodies that cross- cell donor for stem cell transplantation (Ballen et al., 2007; reacted with and neutralized endogenous TPO, ultimately Barker et al., 2003; Brunstein et al., 2007; Misawa et al., leading to low platelet counts. Clinical trials of these agents 2006; Rocha et al., 2009). Human UCB offers practical were discontinued in the United States several years ago advantages as an alternative source of bone marrow stem (Basser et al., 2002; Li et al., 2001). Since then, a peptide cell or PBSC, which include (1) the relative ease of mimetic (romiplostim), and a few non-peptide, small molecule procurement (ability to store fully tested and HLA-typed c-Mpl agonists have been developed as alternatives to UCB available for immediate use); (2) the absence of risk to recombinant TPO (Erickson-Miller et al., 2009; Fukushima- the mother and the donors; (3) the reduced likelihood of Shintani et al., 2009; Inagaki et al., 2004; Nakamura et al., transmitting infections; (4) immaturity of immune cells, thus 2006; Nogami et al., 2008). Among these, eltrombopag (SB- reduced risk of GVHD; (5) less stringent criteria for HLA 497115) is an oral thrombopoietic receptor agonist, which matching for donor–recipient selection (with the potential interactswiththetransmembranedomainofthec-Mpl.The of finding donors for minority populations); (6) absence of latter confers unique species-specificity of eltrombopag, which donor attrition (Chao et al., 2004); and (7) availability: UCB binds to c-Mpl of humans and chimpanzees only (Erickson-Miller banks have been established for related and unrelated UCB et al., 2005, 2009). Eltrombopag selectively activates the c-Mpl transplantation with more than 100,000 units being avail- signaling pathway, stimulates the growth of TPO-dependent cell able based on published data (Barker et al., 2002; Gluckman lines, promotes isolated human CD34+ cells to become mega- et al., 2001; Kernan et al., 1993; Rocha et al., 2000). Thus karyocytes, and increases platelet count dose-dependently agents that can facilitate human UCB hematopoietic stem (Erickson-Miller et al., 2005, 2009; Jenkins et al., 2007). The cell (HSC) and hematopoietic progenitor cell (HPC) expan- treatment of chronic idiopathic thrombocytopenic purpura (ITP) sion are highly desirable. or chronic hepatitis C patients with eltrombopag effectively The cytokine thrombopoietin (TPO) plays a crucial role increased platelet number and reduces thrombocytopenia- in thrombopoiesis, in the regulation of HSCs, and in the related complications (Bussel et al., 2007, 2009; McHutchison proliferation of primitive HPCs. Both murine and human HSCs et al., 2007). are highly enriched in cells expressing the TPO receptor c-Mpl Eltrombopag is only capable of activating parts of the c-Mpl (Solar et al., 1998; Yoshihara et al., 2007). Administration of signaling pathways, but whether eltrombopag retains the TPO to myelosuppressed animals not only significantly allevi- function of TPO in enhancing stem cells and early progenitor ates thrombocytopenia, but also accelerates multiple lineage cells remains largely unknown (Erhardt et al., 2009; Will et recovery (Akahori et al., 1996; Farese et al., 1996; Grossmann al., 2009). As eltrombopag is a c-Mpl agonist, we hypothe- et al., 1996a, 1996b; Kaushansky et al., 1996; Neelis et al., size that eltrombopag can expand HSCs and HPCs of UCB, 1997), promotes the reconstitution of multiple-lineage imma- thus can enhance multi-lineage hematopoiesis. Given the ture progenitors/precursors in bone marrow and spleen (Farese species specificity of eltrombopag to only humans and et al., 1996; Grossmann et al., 1996a; Kaushansky et al., 1996; chimpanzees, our investigation utilized an in vitro serum- Neelis et al., 1997), and augments the responses to GM-CSF and free culture system, and an in vivo NOD/SCID xenotrans- G-CSF (Farese et al., 1996; Grossmann et al., 1996a; Neelis
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