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Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Review
Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche Fatemeh Norozi a , Saeid Shahrabi b , Avital Mendelson c , Saeideh Hajizamani d , Najmaldin Saki a,∗ a
Health Research Institute, Thalassemia and Hemoglobinopathies Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Department of biochemistry and hematology, faculty of medicine, Semnan University of medical sciences, Semnan, Iran c Albert Einstein College of Medicine, Bronx, NY, USA d Diagnostic Laboratory, Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran b
a r t i c l e
a b s t r a c t
i n f o
Article history: Available online xxx Keywords: Megakaryocyte CXCL4 Hematopoietic stem cell Quiescence
Platelet factor-4 (CXCL4/PF-4) is a member of CXC-chemokine family produced by megakaryocytic lineage and stored in platelet ␣-granules. Platelet stimulation by aggregating agents such as thrombin and ADP leads to CXCL4 secretion. CXCL4 plays several roles in coagulation, angiogenesis control, immune system modulation and spread of cancer. Megakaryocytes (Mks) are associated with the vascular niche in the bone marrow (BM) and are located in vicinity of BM sinusoids. Mk-derived CXCL4 is involved in several hematopoietic processes, including inhibition of megakaryopoiesis and maintenance of hematopoietic stem cell (HSC) quiescence. The major aim of this review article was to evaluate the role of CXCL4 in hematological malignancies, promotion of HSC quiescence as well as BM niche cells. © 2015 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Characteristics of CXCL4/PF-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Interaction of megakaryocytes and BM cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 CXCL4 and hematologic malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author. Fax: +98 611 3738330. E-mail address: [email protected] (N. Saki). http://dx.doi.org/10.1016/j.leukres.2015.12.012 0145-2126/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: F. Norozi, et al., Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche, Leuk Res (2016), http://dx.doi.org/10.1016/j.leukres.2015.12.012
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1. Introduction Megakaryocytes (Mks) are derived from hematopoietic stem cells (HSCs) and are recognized by their large size and specific morphological characteristics [1,2]. These cells are located in the vicinity of bone marrow (BM) sinusoids and are associated with the vascular niche [3–6]. Several studies indicate that MKs, which produce platelets, are involved in the regulation and protection of BM niches by production of cytokines and growth factors. Platelet-derived factors play important roles in many biological processes such as hematopoiesis, inflammatory and immune responses, angiogenesis and hemostasis [7]. CXCL4 (platelet factor 4/PF4) and CXCL7 are the most frequently released platelet-derived chemokines, which have been recognized as important markers of the megakaryocytic lineage [8,9]. Furthermore, they have been demonstrated to downregulate normal and abnormal megakaryopoiesis in vitro [10]. Mks are also the major source of proangiogenic and antiangiogenic factors such as VEGF in the BM, which cause survival and proliferation of BM-derived sinusoidal endothelial cells in vitro [11]. In vivo studies in mouse models showed that angiogenic processes in BM are regulated by secreted factors from Mks and platelets, including thrombospondins 1 and 2 [12,13]. In addition to the aforementioned factors, other chemokines including C–C motif ligand 5 (CCL5), macrophage migration inhibitory factor (MIF), CXCL12 (stromal cell derived factor 1/SDF-1), and CXCL5 (epithelial neutrophil-activating peptide/ENA-78) are produced and released by platelets in high levels [8,14,15]. Specific cytokines, including GM-CSF, IL-3, IL-6, IL-11, IL-12 and erythropoietin (EPO), stimulate the proliferation of Mk progenitors [16]. IL-1␣ and leukemia inhibitory factor (LIF) play a role in Mk maturation and platelet release [16,17]. Moreover, thrombopoietin (TPO) is the most potent stimulator of hematopoietic progenitor cell (HPC) differentiation to the Mk lineage, which is involved in the maintenance of HSCs quiescence [18]. TPO has synergistic functions with other hematopoietic cytokines (including SCF, IL-11 and EPO) to enhance the proliferation of progenitor cells in vitro [19,20]. CXCL12 by itself and in combination with TPO increases the formation of megakaryocytes [21]. As a chemotactic factor, it also acts through endothelial cells of BM to increase the migration of Mks via CXCR4 [22]. The major aim of this review article was to evaluate the function of CXCL4 in hematological malignancies as well as its impact on BM niche cells and promotion of HSC quiescence.
important feature of CXCL4. Nearly all chemokines are able to bind heparin and heparin-sulfates (HS) but the ability of CXCL4 to bind GAGs is about 100-1000 times higher than other CXC family members. CXCL4 is the only chemokine directly related to other GAGs such as chondroitin sulfates [32,33]. Therefore, CXCL4 may take advantage of this characteristic to induce quiescence in HSCs by binding heparin or other HSC surface GAGs, enhancing HSC adhesion to stromal cells. This in turn could result in cell cycle arrest and entrance into the quiescence phase [34–36]. In addition to CXCL4, expression of the non-allelic gene variant known as PF4alt (CXCL4L1) by platelets has been indicated [23,37]. Unlike the CXCL4 stored in granules and released by platelet activation, CXCL4L1 seems to be continuously produced and released [23]. Both variants affect the same target cells with different biological efficacy, half-life and affinity for glycosaminoglycans [32,38]. During the innate immune response, CXCL4 and CXCL4L1 increase monocyte differentiation to macrophages or antigen-presenting cells (APC) in presence of IL-4 [39]. CXCL4 is also able to inhibit the development and maturation of Mk progenitor cells and colony-forming unit-Mks (CFU-Mks) [35,40]. Therefore, CXCL4 intervention to reduce the colony-forming units and percentage of colonies containing mature cells raises CXCL4 as a negative regulator of megakaryopoiesis [40,41]. The ability of CXCL4 (>2.5 g/mL) to inhibit Mk progenitors, CFU-Mk (colony forming unit-megakaryocyte), mCFU-Mk (mixed CFUMk) and BFU-Mk (burst FU-Mk) has also been reported. CXCL4 (>5 g/mL in vitro) inhibits colony formation by human BM multipotential CFU-GEMM (CFU-granulocyte, erythrocyte, monocyte and megakaryocyte), BFU-E (BFU-erythroid) and CFU-GM (CFUgranulocyte/macrophage). CXCL4 (1 g/ml) plays an important role in hematopoiesis by binding to human CD34+ hematopoietic progenitor cells via chondroitin sulfate [24,42]. Moreover, CXCL4 plays a key role in hematopoiesis through regulation of hematopoiesis by increasing progenitor cell adhesion. It is also involved in quiescence via interaction between HPCs and the chondroitin sulfate-containing moiety [36]. CXCL4 may indirectly bind and interfere with IL-8. Therefore, IL-8-dependent signaling is abrogated in hematopoietic progenitor cells [36]. Several other biological function of CXCL4 have also been recognized and the most important functions are summarized in Table 1. Understanding the precise mechanisms involved in each of these processes can reveal the influence of CXCL4 on HSCs as well as other BM cells.
3. Interaction of megakaryocytes and BM cells 2. Characteristics of CXCL4/PF-4 CXCL4 is a member of CXC chemokine family produced by Mks, which plays several roles in coagulation, angiogenesis control, immune system modulation and spread of cancer (Fig. 1) [23]. The genes encoding human CXCL4 and other members of the CXC chemokine family, including interleukin-8 (CXCL8/IL8), granulocyte chemotactic protein-2 (CXCL6/GCP-2), growthrelated oncogene (CXCL1/GRO-␣), CXCL2/GRO-, CXCL3/GRO-␥, neutrophil-activating peptide-2 (CXCL7/NAP-2) and epithelial cell-derived neutrophil-activating peptide (CXCL5/ENA-78) are localized to q13.1 locus in the global run-on (GRO) region of chromosome 4 [24,25]. Unlike the majority of CXC chemokine genes, which usually consist of four exons and three introns, CXCL4 gene includes three exons and two introns similar to CC chemokine genes [26]. CXCL4 is produced by Mks, is internalized in vesicles and is then packed in platelet ␣-granules [27,28]. CXCL4 is released from granules after platelet activation by platelet aggregating agents such as thrombin, adenosine 5-diphosphate (ADP) or arachidonic acid [29–31]. The ability to bind glycosaminoglycans (GAGs) is an
The HSC niche is a specific anatomical location providing essential factors for survival, regulation and proliferation of hematopoietic stem cells. In addition to HSCs, mesenchymal stem cells (MSCs) are located in this site [43]. Overall, the BM consists of two supportive HSC niches: osteoblastic/endosteal and vascular/endothelial niches. Osteoblastic niche maintains HSCs in quiescence phase and provides a microenvironment for long-term HSCs involved in hematopoiesis [44,45]. In contrast, vascular niche, which is composed of sinusoidal endothelial cells, promotes the differentiation and proliferation of short-term HSCs [45–47]. The non-hematopoietic microenvironment surrounding HSCs plays an important role in regulating the function and fate of HSCs through the production of paracrine factors [34,48]. Most HSCs are in the G0 phase of the cell cycle in the adult BM, a phenomenon known as quiescence. Several factors such as stem cell factor (SCF), transforming growth factor beta-1 (TGF-1), angiopoietin (ANGPT1) and TPO are involved in HSC quiescence. Furthermore, CXCL12 and its receptor (CXCR4), adhesion molecules such as vascular cell adhesion protein 1 (VCAM-1), different selectins and extracellular matrix (ECM) proteins including fibronectin or
Please cite this article in press as: F. Norozi, et al., Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche, Leuk Res (2016), http://dx.doi.org/10.1016/j.leukres.2015.12.012
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Fig. 1. Overview of biological functions of CXCL4. CXCL4/PF-4 has been reported to be involved in different biological processes, including hematopoiesis and angiogenesis inhibition, platelet coagulation interference, and host inflammatory response promotion. In addition, numerous studies have indicated the angiostatic and anti-tumor effects of CXCL4. Table 1 Biological role of CXCL4. Systems
Functions
Hematopoiesis • CXCL4 inhibites the maturation of Mks progenitor cells and CFU-Mks • Increased progenitor adhesion and quiescence through interaction between HPC and chonroitin sulphate-containing moiety, and indirectly through binding or interfer with other signalings of hematopoietically active chemokines such as IL-8 Coagulation
References [36,43]
• CXCL4 prevents heparin-anti thrombin [44,45] complex formation and decrease heparin-dependent accelaration of thrombin inactivation through heparin inhibition. • Prevents factor XII activation • Activates protein C
Immune system • Activates granulocyte (releasing lysosomal [39,43,46–52] enzymes) • Has an ability to differentiate monocytes to special macrophage subtypes and APCs • Inhibits CD4+ CD25− T-cells proliferation and stimulates CD4+ CD25+ T-cells proliferation • Affects cytokines production by Th1 cells, Th2 cells, CD4+ CD25− T-cells and CD4+ CD25+ T-cells • Decreases IFN-␥ production by Th1 cells and increases IL-4, IL-5 and IL-13 in Th2 cells • Induces intracellular signaling in T lymphocyte Angiogenesis
• CXCL4 is able to bind FGFs and VEGF directly [23,53] and inhibits their binding to cell surface receptors
Abbreviations: Mks: megakaryocytes; CFU-Mks: colony-forming unit-Mks; HPC: hematopoietic progenitor cells; APC: antigene-presenting cells; FGFs: fibroblast growth factors; VEGF: vascular endothelial growth factor.
hyaluronic acid are required for HSC homing, regulation and anchoring in the niche [49,50]. In addition, cell-bound molecules
like notch ligands, IL-7 and Epo are important in regulation of HSC proliferation and differentiation [50,51]. Studies have shown that Mks are located near BM sinusoids and are associated with MSCs as well as vascular BM niche. MSCs play a role in the regulation of Mk function by producing cytokines and soluble factors (Table 2). In particular, IL-6, IL-11, SCF and LIF are considered as modulators of Mk development and maturation [19,52–54]. In addition to cytokine secretion, MSCs can directly interact with HSCs via expression of adhesion molecules such as intracellular adhesion molecule-1/2 (ICAM-1/2), VCAM1 and E-selectin [55]. Therefore, direct cell/cell interaction and paracrine-secreted cytokines may be involved in Mk differentiation and platelet production in the BM niche. Moreover, the effect of Mks on different BM niche cells such as osteoblasts (OBs) and osteoclasts (OCs) has been demonstrated (Table 2). In vitro studies have demonstrated that Mks inhibit OCs development through the production of different factors, including Osteoprotegerin (OPG), receptor activator of nuclear factor-B ligand (RANKL), TGF-1, GM-CSF, IL-10 and IL-3 [56–58]. On the other hand, the factors produced by megakaryocytes play a role in the proliferation and differentiation of OBs and bone formation [52]. Therefore, since the osteoblastic niche has been shown to play an important role in HSC maintenance and quiescence [44] as well as production of hematopoietic growth factors enhancing HSCs survival [59], Mks may be indirectly involved in the induction of HSC quiescence by increasing differentiation toward the osteoblastic cell lineage. Reduced number of Mks may be associated with increased proliferation and differentiation of HSCs in some hematological malignancies, which is a topic for further study. The majority of previous studies have focused on the role of OBs, reticular stromal cells, endothelial cells and nerve cells in HSC niche regulation. However, recent studies have indicated the direct contact between HSCs and Mks in BM, leading to the hypothesis that HSCs are regulated by Mks (Table 2). This concept has been confirmed by several studies [60,61]. For example, Zhao et al. [60] demonstrated that Mks are the major source of TGF-1 in BM and are able to maintain HSC quiescence through the TGF- signaling pathway. In addition to the above factors, Mks are able to secrete other quiescence-promoting factors such as CXCL4. CXCL4 leads to
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4 Table 2 Megakaryocyte and BM cells interaction. Cell type
Mediators
Final result
References
HSCs
Mks produce TGF-1 Mks produce TPO Mks produce CXCL4
[8,71]
MSCs
MSCs produce and secrete IL-6, IL-11, SCF, LIF MSCs express ICAM-1/2, VCAM and E-selectin Mks produce OPG, RANKL, TGF-1, GM-CSF, IL-10 and IL-13
Maintain HSCs quiescence due to TGF- signaling pathway Cause increased the Mks maturation and HSC quiescence maintenance Lead to cell cycle arrest and quiescence induction in HSCs via increasing HPCs and stromal cells binding Mks development, maturation and differentiation
OCs development inhibition, OBs proliferation and bone formation
[63,67–69]
OBs & OCs
[19,63–66]
Abbreviations: HSC: hematopoietic stem cells; TPO: thrombopoietin; HPCs: hematopoietic progenitor cells BM: bone marrow; Mks: megakaryocutes; MSCs: mesenchymal stem cells; SCF: stem cell factor; LIF: leukemia inhibitory factor; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion protein; OCs:osteoclasts; OBs: osteoblasts; OPG: osteoprotegrin; RANKL: receptor activator of nuclear factor-B ligand; GM-CSF: granulocyte monocyte-colony stimulating factor.
cell cycle arrest and quiescence in HSCs via increased binding of HPCs to stromal cells [18,36,61]. Several mechanisms inhibiting cell growth by CXCL4 have been demonstrated, including CXCL4 binding to growth factors such as fibroblast growth factors (FGFs) and vascular endothelial growth factor as well as inhibition of their binding to receptors [23,62]. This chemokine can also block growth factor receptors and inhibit cell growth and dimerization of the factor (Fig. 2). Recently, CXCR3B receptor for CXCL4 has been detected on endothelial cells, which mediates the antiangiogenic effects of CXCL4 as well as cell cycle-dependent manner [23,63]. This binding induces signaling pathways such as cAMP-dependent signaling, which may be responsible for phenotypic modifications of endothelial cells in CXCR3B expression. p38 (MAPK) seems to be the downstream effector induced by CXCL4 binding CXCR3B [64,65]. CXCL4 binding to CXCR3B increases the intracellular level of cAMP, cyclin-dependent kinase inhibitor (CKI) and p21CIP1/WAF . Activation of CXCR3B causes reduced DNA synthesis and increased apoptotic death of human micro-vascular endothelial cell line-1 (HMEC-1) through the activation of different signaling pathways (Fig. 2) [63]. Therefore,
CXCL4 effectively arrests cell cycle progression during S phase by inhibiting DNA synthesis in S phase as well as progress from G1 phase into S phase [66]. Molecular mechanisms of CXCL4 interference with cell cycle include maintenance of p21Cip1/WAF1 , increased binding of p21Cip1/WAF1 to E-cyclin-dependent kinase 2 (E-cdk2), decreased activity of E-cdk2 and reduced phosphorylation of retinoblastoma protein (pRb), which inhibit the EGF-induced proliferation of endothelial cells that can be effective in inhibition of angiogenesis [67]. Based on the above, CXCL4 might take advantage of this cell cycle arrest mechanism to induce HSCS quiescence, and further studies are needed to prove this hypothesis. Mks support HSC quiescence through CXCL4 production in a feedback loop. However, the mechanisms of CXCL4 involvement in this process have not been elucidated. Therefore, recognition of the characteristics and functions of CXCL4 may be helpful for better understanding of its involvement in HSCs quiescence. Furthermore, according to the role of Mks in HSC fate, the likelihood of a megakaryocytic niche is raised, which needs further comprehensive studies to prove.
Fig. 2. Mechanisms of cell cycle arrest by CXCL4. CXCL4 is able to directly bind some growth factors such as b-FGFs and VEGF or block the binding of b-FGF and VEGF to their receptors, which inhibits the cell proliferation pathways. Also, binding of CXCL4 to CXCR3B leads to increased intracellular cAMP, CKI and p21CIP1/WAF . These events reduce DNA synthesis and lead to cell cycle arrest. Abbreviation: bFGF: basic fibroblast growth factor; VEGF: vascular endothelial growth factor; cAMP: cyclic adenosine monophosphate; CKI: cyclin-dependent kinase inhibitor.
Please cite this article in press as: F. Norozi, et al., Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche, Leuk Res (2016), http://dx.doi.org/10.1016/j.leukres.2015.12.012
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4. CXCL4 and hematologic malignancies Altered CXCL4 level has been shown in a number of hematological malignancies but there are limited studies on its role in severity and prognosis of disease. For example, a low level of CXCL4 has been shown in BM of myelodysplastic syndrome (MDS) patients, which may be a reason for hypercellularity in patients according to its inhibitory role in hematopoiesis [24]; however, further studies are required to demonstrate its role. In addition, some studies demonstrated that CXCL4 and its variant have an anti-tumor role. It has been shown that the level of CXCL4 and CXCL7 chemokines is significantly decreased in serum of MDS patients progressing towards acute myeloid leukemia (AML) [68]. In addition to MDS patients, some studies have shown that the breakpoint in 4q21 involves CXCL4 gene in acute lymphoblastic leukemia (ALL) harboring translocation (4q21; 11q23) [69,70]. In addition to the above, a number of studies indicated the tumor suppressor role of CXCL4 gene. For example, Cheng et al. [71] studied chromosomal imbalances in multiple myeloma cell lines, BM CD138+ plasma cells from monoclonal gammopathy patients and different stages of multiple myeloma patients. They observed that the CXCL4 gene was frequently silenced by a common deletion region on 4q13.3, promoter hypermethylation in multiple myeloma cell lines as well as multiple myeloma patients. In this regard, they concluded a likely tumor suppressor role for CXCL4. In addition to the role of CXCL4 in malignancies, some studies have shown anti-tumor effects of CXCL4, CXCL4 variants and CXCL4-derived peptides [29]. Intravenous or subcutaneous injection of CXCL4 also been shown to significantly inhibit experimental lung metastases in animal models of B16-F10 melanoma [72]. Based on these findings, we can conclude that CXCL4 inhibits the metastasis of tumor cells as well as their growth and may be used as a factor to prevent metastasis of malignant cells in future. 5. Conclusions and future directions Mks are important cells in the BM niche, are located in the vicinity of BM sinusoids and interfere with different cells, including, MSCs, OCs and HSCs. Mks play an important role in the induction of HSC quiescence by secreting different chemokines, especially CXCL4. The mechanism of HSC quiescence by CXCL4 is still unknown but may be mediated by binding with cell surface heparin and increasing HSC adhesion to stromal cells, which results in cell cycle arrest and induction of quiescence [34,36,73]. Additionally, this factor performs several functions in coagulation, angiogenesis control, immune system modulation and spread of cancer through megakaryopoiesis inhibition [23]. Despite various studies on the role of Mks and their secreted factors in the HSC niche, there are still unanswered questions about their importance in the vascular niche in both physiologic and pathologic conditions. In addition, the association between Mks and the vascular niche as well as pathways promoting the megakaryocyte-induced effects have not been clearly defined. Therefore, the importance of Mks in determining HSC fate and the idea of a megakaryocytic niche are concepts demanding further comprehensive studies to validate. Conflict of interest All authors declare no conflict of interest. Acknowledgement This paper is issued from the thesis of Fatemeh Norozi, MSc. student of hematology and blood banking. This work was financially
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supported by Grant IR. AJUMS. REC. TH94/8 from vice chancellor for Research Affairs of Ahvaz Jundishapur, University of Medical Sciences.
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Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Review
Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche Fatemeh Norozi a , Saeid Shahrabi b , Avital Mendelson c , Saeideh Hajizamani d , Najmaldin Saki a,∗ a
Health Research Institute, Thalassemia and Hemoglobinopathies Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Department of biochemistry and hematology, faculty of medicine, Semnan University of medical sciences, Semnan, Iran c Albert Einstein College of Medicine, Bronx, NY, USA d Diagnostic Laboratory, Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran b
a r t i c l e
a b s t r a c t
i n f o
Article history: Available online xxx Keywords: Megakaryocyte CXCL4 Hematopoietic stem cell Quiescence
Platelet factor-4 (CXCL4/PF-4) is a member of CXC-chemokine family produced by megakaryocytic lineage and stored in platelet ␣-granules. Platelet stimulation by aggregating agents such as thrombin and ADP leads to CXCL4 secretion. CXCL4 plays several roles in coagulation, angiogenesis control, immune system modulation and spread of cancer. Megakaryocytes (Mks) are associated with the vascular niche in the bone marrow (BM) and are located in vicinity of BM sinusoids. Mk-derived CXCL4 is involved in several hematopoietic processes, including inhibition of megakaryopoiesis and maintenance of hematopoietic stem cell (HSC) quiescence. The major aim of this review article was to evaluate the role of CXCL4 in hematological malignancies, promotion of HSC quiescence as well as BM niche cells. © 2015 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Characteristics of CXCL4/PF-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Interaction of megakaryocytes and BM cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 CXCL4 and hematologic malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author. Fax: +98 611 3738330. E-mail address: [email protected] (N. Saki). http://dx.doi.org/10.1016/j.leukres.2015.12.012 0145-2126/© 2015 Elsevier Ltd. All rights reserved.
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2
1. Introduction Megakaryocytes (Mks) are derived from hematopoietic stem cells (HSCs) and are recognized by their large size and specific morphological characteristics [1,2]. These cells are located in the vicinity of bone marrow (BM) sinusoids and are associated with the vascular niche [3–6]. Several studies indicate that MKs, which produce platelets, are involved in the regulation and protection of BM niches by production of cytokines and growth factors. Platelet-derived factors play important roles in many biological processes such as hematopoiesis, inflammatory and immune responses, angiogenesis and hemostasis [7]. CXCL4 (platelet factor 4/PF4) and CXCL7 are the most frequently released platelet-derived chemokines, which have been recognized as important markers of the megakaryocytic lineage [8,9]. Furthermore, they have been demonstrated to downregulate normal and abnormal megakaryopoiesis in vitro [10]. Mks are also the major source of proangiogenic and antiangiogenic factors such as VEGF in the BM, which cause survival and proliferation of BM-derived sinusoidal endothelial cells in vitro [11]. In vivo studies in mouse models showed that angiogenic processes in BM are regulated by secreted factors from Mks and platelets, including thrombospondins 1 and 2 [12,13]. In addition to the aforementioned factors, other chemokines including C–C motif ligand 5 (CCL5), macrophage migration inhibitory factor (MIF), CXCL12 (stromal cell derived factor 1/SDF-1), and CXCL5 (epithelial neutrophil-activating peptide/ENA-78) are produced and released by platelets in high levels [8,14,15]. Specific cytokines, including GM-CSF, IL-3, IL-6, IL-11, IL-12 and erythropoietin (EPO), stimulate the proliferation of Mk progenitors [16]. IL-1␣ and leukemia inhibitory factor (LIF) play a role in Mk maturation and platelet release [16,17]. Moreover, thrombopoietin (TPO) is the most potent stimulator of hematopoietic progenitor cell (HPC) differentiation to the Mk lineage, which is involved in the maintenance of HSCs quiescence [18]. TPO has synergistic functions with other hematopoietic cytokines (including SCF, IL-11 and EPO) to enhance the proliferation of progenitor cells in vitro [19,20]. CXCL12 by itself and in combination with TPO increases the formation of megakaryocytes [21]. As a chemotactic factor, it also acts through endothelial cells of BM to increase the migration of Mks via CXCR4 [22]. The major aim of this review article was to evaluate the function of CXCL4 in hematological malignancies as well as its impact on BM niche cells and promotion of HSC quiescence.
important feature of CXCL4. Nearly all chemokines are able to bind heparin and heparin-sulfates (HS) but the ability of CXCL4 to bind GAGs is about 100-1000 times higher than other CXC family members. CXCL4 is the only chemokine directly related to other GAGs such as chondroitin sulfates [32,33]. Therefore, CXCL4 may take advantage of this characteristic to induce quiescence in HSCs by binding heparin or other HSC surface GAGs, enhancing HSC adhesion to stromal cells. This in turn could result in cell cycle arrest and entrance into the quiescence phase [34–36]. In addition to CXCL4, expression of the non-allelic gene variant known as PF4alt (CXCL4L1) by platelets has been indicated [23,37]. Unlike the CXCL4 stored in granules and released by platelet activation, CXCL4L1 seems to be continuously produced and released [23]. Both variants affect the same target cells with different biological efficacy, half-life and affinity for glycosaminoglycans [32,38]. During the innate immune response, CXCL4 and CXCL4L1 increase monocyte differentiation to macrophages or antigen-presenting cells (APC) in presence of IL-4 [39]. CXCL4 is also able to inhibit the development and maturation of Mk progenitor cells and colony-forming unit-Mks (CFU-Mks) [35,40]. Therefore, CXCL4 intervention to reduce the colony-forming units and percentage of colonies containing mature cells raises CXCL4 as a negative regulator of megakaryopoiesis [40,41]. The ability of CXCL4 (>2.5 g/mL) to inhibit Mk progenitors, CFU-Mk (colony forming unit-megakaryocyte), mCFU-Mk (mixed CFUMk) and BFU-Mk (burst FU-Mk) has also been reported. CXCL4 (>5 g/mL in vitro) inhibits colony formation by human BM multipotential CFU-GEMM (CFU-granulocyte, erythrocyte, monocyte and megakaryocyte), BFU-E (BFU-erythroid) and CFU-GM (CFUgranulocyte/macrophage). CXCL4 (1 g/ml) plays an important role in hematopoiesis by binding to human CD34+ hematopoietic progenitor cells via chondroitin sulfate [24,42]. Moreover, CXCL4 plays a key role in hematopoiesis through regulation of hematopoiesis by increasing progenitor cell adhesion. It is also involved in quiescence via interaction between HPCs and the chondroitin sulfate-containing moiety [36]. CXCL4 may indirectly bind and interfere with IL-8. Therefore, IL-8-dependent signaling is abrogated in hematopoietic progenitor cells [36]. Several other biological function of CXCL4 have also been recognized and the most important functions are summarized in Table 1. Understanding the precise mechanisms involved in each of these processes can reveal the influence of CXCL4 on HSCs as well as other BM cells.
3. Interaction of megakaryocytes and BM cells 2. Characteristics of CXCL4/PF-4 CXCL4 is a member of CXC chemokine family produced by Mks, which plays several roles in coagulation, angiogenesis control, immune system modulation and spread of cancer (Fig. 1) [23]. The genes encoding human CXCL4 and other members of the CXC chemokine family, including interleukin-8 (CXCL8/IL8), granulocyte chemotactic protein-2 (CXCL6/GCP-2), growthrelated oncogene (CXCL1/GRO-␣), CXCL2/GRO-, CXCL3/GRO-␥, neutrophil-activating peptide-2 (CXCL7/NAP-2) and epithelial cell-derived neutrophil-activating peptide (CXCL5/ENA-78) are localized to q13.1 locus in the global run-on (GRO) region of chromosome 4 [24,25]. Unlike the majority of CXC chemokine genes, which usually consist of four exons and three introns, CXCL4 gene includes three exons and two introns similar to CC chemokine genes [26]. CXCL4 is produced by Mks, is internalized in vesicles and is then packed in platelet ␣-granules [27,28]. CXCL4 is released from granules after platelet activation by platelet aggregating agents such as thrombin, adenosine 5-diphosphate (ADP) or arachidonic acid [29–31]. The ability to bind glycosaminoglycans (GAGs) is an
The HSC niche is a specific anatomical location providing essential factors for survival, regulation and proliferation of hematopoietic stem cells. In addition to HSCs, mesenchymal stem cells (MSCs) are located in this site [43]. Overall, the BM consists of two supportive HSC niches: osteoblastic/endosteal and vascular/endothelial niches. Osteoblastic niche maintains HSCs in quiescence phase and provides a microenvironment for long-term HSCs involved in hematopoiesis [44,45]. In contrast, vascular niche, which is composed of sinusoidal endothelial cells, promotes the differentiation and proliferation of short-term HSCs [45–47]. The non-hematopoietic microenvironment surrounding HSCs plays an important role in regulating the function and fate of HSCs through the production of paracrine factors [34,48]. Most HSCs are in the G0 phase of the cell cycle in the adult BM, a phenomenon known as quiescence. Several factors such as stem cell factor (SCF), transforming growth factor beta-1 (TGF-1), angiopoietin (ANGPT1) and TPO are involved in HSC quiescence. Furthermore, CXCL12 and its receptor (CXCR4), adhesion molecules such as vascular cell adhesion protein 1 (VCAM-1), different selectins and extracellular matrix (ECM) proteins including fibronectin or
Please cite this article in press as: F. Norozi, et al., Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche, Leuk Res (2016), http://dx.doi.org/10.1016/j.leukres.2015.12.012
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Fig. 1. Overview of biological functions of CXCL4. CXCL4/PF-4 has been reported to be involved in different biological processes, including hematopoiesis and angiogenesis inhibition, platelet coagulation interference, and host inflammatory response promotion. In addition, numerous studies have indicated the angiostatic and anti-tumor effects of CXCL4. Table 1 Biological role of CXCL4. Systems
Functions
Hematopoiesis • CXCL4 inhibites the maturation of Mks progenitor cells and CFU-Mks • Increased progenitor adhesion and quiescence through interaction between HPC and chonroitin sulphate-containing moiety, and indirectly through binding or interfer with other signalings of hematopoietically active chemokines such as IL-8 Coagulation
References [36,43]
• CXCL4 prevents heparin-anti thrombin [44,45] complex formation and decrease heparin-dependent accelaration of thrombin inactivation through heparin inhibition. • Prevents factor XII activation • Activates protein C
Immune system • Activates granulocyte (releasing lysosomal [39,43,46–52] enzymes) • Has an ability to differentiate monocytes to special macrophage subtypes and APCs • Inhibits CD4+ CD25− T-cells proliferation and stimulates CD4+ CD25+ T-cells proliferation • Affects cytokines production by Th1 cells, Th2 cells, CD4+ CD25− T-cells and CD4+ CD25+ T-cells • Decreases IFN-␥ production by Th1 cells and increases IL-4, IL-5 and IL-13 in Th2 cells • Induces intracellular signaling in T lymphocyte Angiogenesis
• CXCL4 is able to bind FGFs and VEGF directly [23,53] and inhibits their binding to cell surface receptors
Abbreviations: Mks: megakaryocytes; CFU-Mks: colony-forming unit-Mks; HPC: hematopoietic progenitor cells; APC: antigene-presenting cells; FGFs: fibroblast growth factors; VEGF: vascular endothelial growth factor.
hyaluronic acid are required for HSC homing, regulation and anchoring in the niche [49,50]. In addition, cell-bound molecules
like notch ligands, IL-7 and Epo are important in regulation of HSC proliferation and differentiation [50,51]. Studies have shown that Mks are located near BM sinusoids and are associated with MSCs as well as vascular BM niche. MSCs play a role in the regulation of Mk function by producing cytokines and soluble factors (Table 2). In particular, IL-6, IL-11, SCF and LIF are considered as modulators of Mk development and maturation [19,52–54]. In addition to cytokine secretion, MSCs can directly interact with HSCs via expression of adhesion molecules such as intracellular adhesion molecule-1/2 (ICAM-1/2), VCAM1 and E-selectin [55]. Therefore, direct cell/cell interaction and paracrine-secreted cytokines may be involved in Mk differentiation and platelet production in the BM niche. Moreover, the effect of Mks on different BM niche cells such as osteoblasts (OBs) and osteoclasts (OCs) has been demonstrated (Table 2). In vitro studies have demonstrated that Mks inhibit OCs development through the production of different factors, including Osteoprotegerin (OPG), receptor activator of nuclear factor-B ligand (RANKL), TGF-1, GM-CSF, IL-10 and IL-3 [56–58]. On the other hand, the factors produced by megakaryocytes play a role in the proliferation and differentiation of OBs and bone formation [52]. Therefore, since the osteoblastic niche has been shown to play an important role in HSC maintenance and quiescence [44] as well as production of hematopoietic growth factors enhancing HSCs survival [59], Mks may be indirectly involved in the induction of HSC quiescence by increasing differentiation toward the osteoblastic cell lineage. Reduced number of Mks may be associated with increased proliferation and differentiation of HSCs in some hematological malignancies, which is a topic for further study. The majority of previous studies have focused on the role of OBs, reticular stromal cells, endothelial cells and nerve cells in HSC niche regulation. However, recent studies have indicated the direct contact between HSCs and Mks in BM, leading to the hypothesis that HSCs are regulated by Mks (Table 2). This concept has been confirmed by several studies [60,61]. For example, Zhao et al. [60] demonstrated that Mks are the major source of TGF-1 in BM and are able to maintain HSC quiescence through the TGF- signaling pathway. In addition to the above factors, Mks are able to secrete other quiescence-promoting factors such as CXCL4. CXCL4 leads to
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4 Table 2 Megakaryocyte and BM cells interaction. Cell type
Mediators
Final result
References
HSCs
Mks produce TGF-1 Mks produce TPO Mks produce CXCL4
[8,71]
MSCs
MSCs produce and secrete IL-6, IL-11, SCF, LIF MSCs express ICAM-1/2, VCAM and E-selectin Mks produce OPG, RANKL, TGF-1, GM-CSF, IL-10 and IL-13
Maintain HSCs quiescence due to TGF- signaling pathway Cause increased the Mks maturation and HSC quiescence maintenance Lead to cell cycle arrest and quiescence induction in HSCs via increasing HPCs and stromal cells binding Mks development, maturation and differentiation
OCs development inhibition, OBs proliferation and bone formation
[63,67–69]
OBs & OCs
[19,63–66]
Abbreviations: HSC: hematopoietic stem cells; TPO: thrombopoietin; HPCs: hematopoietic progenitor cells BM: bone marrow; Mks: megakaryocutes; MSCs: mesenchymal stem cells; SCF: stem cell factor; LIF: leukemia inhibitory factor; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion protein; OCs:osteoclasts; OBs: osteoblasts; OPG: osteoprotegrin; RANKL: receptor activator of nuclear factor-B ligand; GM-CSF: granulocyte monocyte-colony stimulating factor.
cell cycle arrest and quiescence in HSCs via increased binding of HPCs to stromal cells [18,36,61]. Several mechanisms inhibiting cell growth by CXCL4 have been demonstrated, including CXCL4 binding to growth factors such as fibroblast growth factors (FGFs) and vascular endothelial growth factor as well as inhibition of their binding to receptors [23,62]. This chemokine can also block growth factor receptors and inhibit cell growth and dimerization of the factor (Fig. 2). Recently, CXCR3B receptor for CXCL4 has been detected on endothelial cells, which mediates the antiangiogenic effects of CXCL4 as well as cell cycle-dependent manner [23,63]. This binding induces signaling pathways such as cAMP-dependent signaling, which may be responsible for phenotypic modifications of endothelial cells in CXCR3B expression. p38 (MAPK) seems to be the downstream effector induced by CXCL4 binding CXCR3B [64,65]. CXCL4 binding to CXCR3B increases the intracellular level of cAMP, cyclin-dependent kinase inhibitor (CKI) and p21CIP1/WAF . Activation of CXCR3B causes reduced DNA synthesis and increased apoptotic death of human micro-vascular endothelial cell line-1 (HMEC-1) through the activation of different signaling pathways (Fig. 2) [63]. Therefore,
CXCL4 effectively arrests cell cycle progression during S phase by inhibiting DNA synthesis in S phase as well as progress from G1 phase into S phase [66]. Molecular mechanisms of CXCL4 interference with cell cycle include maintenance of p21Cip1/WAF1 , increased binding of p21Cip1/WAF1 to E-cyclin-dependent kinase 2 (E-cdk2), decreased activity of E-cdk2 and reduced phosphorylation of retinoblastoma protein (pRb), which inhibit the EGF-induced proliferation of endothelial cells that can be effective in inhibition of angiogenesis [67]. Based on the above, CXCL4 might take advantage of this cell cycle arrest mechanism to induce HSCS quiescence, and further studies are needed to prove this hypothesis. Mks support HSC quiescence through CXCL4 production in a feedback loop. However, the mechanisms of CXCL4 involvement in this process have not been elucidated. Therefore, recognition of the characteristics and functions of CXCL4 may be helpful for better understanding of its involvement in HSCs quiescence. Furthermore, according to the role of Mks in HSC fate, the likelihood of a megakaryocytic niche is raised, which needs further comprehensive studies to prove.
Fig. 2. Mechanisms of cell cycle arrest by CXCL4. CXCL4 is able to directly bind some growth factors such as b-FGFs and VEGF or block the binding of b-FGF and VEGF to their receptors, which inhibits the cell proliferation pathways. Also, binding of CXCL4 to CXCR3B leads to increased intracellular cAMP, CKI and p21CIP1/WAF . These events reduce DNA synthesis and lead to cell cycle arrest. Abbreviation: bFGF: basic fibroblast growth factor; VEGF: vascular endothelial growth factor; cAMP: cyclic adenosine monophosphate; CKI: cyclin-dependent kinase inhibitor.
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4. CXCL4 and hematologic malignancies Altered CXCL4 level has been shown in a number of hematological malignancies but there are limited studies on its role in severity and prognosis of disease. For example, a low level of CXCL4 has been shown in BM of myelodysplastic syndrome (MDS) patients, which may be a reason for hypercellularity in patients according to its inhibitory role in hematopoiesis [24]; however, further studies are required to demonstrate its role. In addition, some studies demonstrated that CXCL4 and its variant have an anti-tumor role. It has been shown that the level of CXCL4 and CXCL7 chemokines is significantly decreased in serum of MDS patients progressing towards acute myeloid leukemia (AML) [68]. In addition to MDS patients, some studies have shown that the breakpoint in 4q21 involves CXCL4 gene in acute lymphoblastic leukemia (ALL) harboring translocation (4q21; 11q23) [69,70]. In addition to the above, a number of studies indicated the tumor suppressor role of CXCL4 gene. For example, Cheng et al. [71] studied chromosomal imbalances in multiple myeloma cell lines, BM CD138+ plasma cells from monoclonal gammopathy patients and different stages of multiple myeloma patients. They observed that the CXCL4 gene was frequently silenced by a common deletion region on 4q13.3, promoter hypermethylation in multiple myeloma cell lines as well as multiple myeloma patients. In this regard, they concluded a likely tumor suppressor role for CXCL4. In addition to the role of CXCL4 in malignancies, some studies have shown anti-tumor effects of CXCL4, CXCL4 variants and CXCL4-derived peptides [29]. Intravenous or subcutaneous injection of CXCL4 also been shown to significantly inhibit experimental lung metastases in animal models of B16-F10 melanoma [72]. Based on these findings, we can conclude that CXCL4 inhibits the metastasis of tumor cells as well as their growth and may be used as a factor to prevent metastasis of malignant cells in future. 5. Conclusions and future directions Mks are important cells in the BM niche, are located in the vicinity of BM sinusoids and interfere with different cells, including, MSCs, OCs and HSCs. Mks play an important role in the induction of HSC quiescence by secreting different chemokines, especially CXCL4. The mechanism of HSC quiescence by CXCL4 is still unknown but may be mediated by binding with cell surface heparin and increasing HSC adhesion to stromal cells, which results in cell cycle arrest and induction of quiescence [34,36,73]. Additionally, this factor performs several functions in coagulation, angiogenesis control, immune system modulation and spread of cancer through megakaryopoiesis inhibition [23]. Despite various studies on the role of Mks and their secreted factors in the HSC niche, there are still unanswered questions about their importance in the vascular niche in both physiologic and pathologic conditions. In addition, the association between Mks and the vascular niche as well as pathways promoting the megakaryocyte-induced effects have not been clearly defined. Therefore, the importance of Mks in determining HSC fate and the idea of a megakaryocytic niche are concepts demanding further comprehensive studies to validate. Conflict of interest All authors declare no conflict of interest. Acknowledgement This paper is issued from the thesis of Fatemeh Norozi, MSc. student of hematology and blood banking. This work was financially
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supported by Grant IR. AJUMS. REC. TH94/8 from vice chancellor for Research Affairs of Ahvaz Jundishapur, University of Medical Sciences.
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Please cite this article in press as: F. Norozi, et al., Regulatory role of Megakaryocytes on Hematopoietic Stem Cells Quiescence by CXCL4/PF4 in Bone Marrow Niche, Leuk Res (2016), http://dx.doi.org/10.1016/j.leukres.2015.12.012
