Experimental Hematology
Volume 38, Issue 7 , Pages 557-563, July 2010

Derivation of multipotent progenitors from human circulating CD14+ monocytes

  • Noriyuki Seta
    • ,
  • Masataka Kuwana

      Affiliations

    • Corresponding Author InformationOffprint requests to: Masataka Kuwana, M.D., Ph.D., Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Received 28 February 2010; received in revised form 28 February 2010; accepted 24 March 2010. published online 01 April 2010.

Article Outline

Circulating CD14+ monocytes are originated from hematopoietic stem cells in the bone marrow and believed to be committed precursors for phagocytes, such as macrophages. Recently, we have reported a primitive cell population termed monocyte-derived multipotential cells (MOMCs), which has a fibroblast-like morphology in culture and a unique phenotype positive for CD14, CD45, CD34, and type I collagen. MOMCs are derived from circulating CD14+ monocytes, but circulating precursors for MOMCs still remain undetermined. Comparative analysis of gene expression profiles of MOMCs and other monocyte-derived cells has revealed that embryonic stem cell markers, Nanog and Oct-4, are specifically expressed by MOMCs. In vitro generation of MOMCs requires binding to fibronectin and exposure to soluble factors derived from activated platelets. MOMCs contain progenitors with capacity to differentiate into a variety of nonphagocytes, including bone, cartilage, fat, skeletal and cardiac muscle, neuron, and endothelium, indicating that circulating monocytes are more multipotent than previously thought. In addition, MOMCs are capable of promoting ex vivo expansion of human hematopoietic progenitor cells through direct cell-to-cell contact and secretion of a variety of hematopoietic growth factors. These findings obtained from the research on MOMCs indicate that CD14+ monocytes in circulation are involved in a variety of physiologic functions other than innate and acquired immune responses, such as repair and regeneration of the damaged tissue.

 

Hematopoietic stem cells (HSCs) are defined as a cell population with extensive self-renewal and proliferation capacity, as well as the capacity to differentiate into progenitors of a variety of blood cells, including erythrocytes, granulocytes, monocytes, platelets, and all subtypes of lymphocytes. It has long been thought that HSCs function solely to maintain hematopoietic lineages, but a series of recent reports have challenged this concept [1]. Bone marrow (BM) cells enriched by various methods for HSCs contribute to multiple nonhematopoietic cells within the skin, lung, intestine, liver, pancreas, skeletal muscle, vessels, heart, and brain in a transplanted mouse model, as well as in patients undergoing allogeneic HSC transplantation [1]. Recent sophisticated studies utilizing clonal HSC transplantation approaches have confirmed the differentiation of HSCs into various types of mesenchymal cells, such as fibroblasts and adipocytes, in many organs and tissues 2, 3, 4. However, it remains uncertain which cell type of HSC origin in circulation gives rise to cells in the mesenchymal lineage in adults.

Circulating CD14+ monocytes are originated from HSCs in the BM and consist of 5% to 10% of circulating white blood cells in adult humans. They are heterogeneous population in terms of surface markers, phagocytic capacity, and differentiation potentials, but are committed precursors in transit from the BM to ultimate sites of activity. Circulating monocytes have the capacity to differentiate into a variety of phagocytes, including macrophages, dendritic cells, osteoclasts, microglia, and Kupffer cells 5, 6, 7. Until recently, it was believed that the differentiation potential of monocytes is restricted to cells possessing phagocytic capacity, which function as phagocytes and/or specialized antigen-presenting cells. However, recent accumulating evidence indicates that circulating monocytes have potential to differentiate into a variety of cell types other than phagocytes 8, 9. Our recent discovery of a primitive cell population termed monocyte-derived multipotential cells (MOMCs) supports a concept of the multipotential nature of human circulating monocytes [10].

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Identification of MOMCs 

MOMCs, previously called monocyte-derived mesenchymal progenitors, are a human cultured cell population with a fibroblast-like morphology, and have a unique phenotype positive for CD14, CD45, CD34, and type I collagen [10]. We accidentally discovered this cell population in cultures of human peripheral blood mononuclear cells (PBMCs), which were aimed at assessing T-cell responses to various foreign and self-antigens. These fibroblast-like cells made their appearance in cultures of PBMCs for 7 to 10 days on fibronectin-coated plastic plates in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum as the only source of growth factors. Their unique shape was apparently different from the morphology of macrophages and dendritic cells, which are adherent cells also generated from cultures of CD14+ monocytes (Fig. 1). We were interested in the phenotype and origin of these cultured cells and performed the following analyses.

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  • Figure 1 

    Morphology of monocyte-derived multipotential cells (MOMCs), macrophages, and dendritic cells, which are obtained by culturing peripheral blood CD14+ monocytes. Original magnification: ×80.

By electron microscopic examination, MOMCs represented mixed features of phagocytes (primary lysosomes and cell surface projections like pseudopodia), mesenchymal cells (prominent bundles of intermediate filaments and small lipid droplets), and endothelial cells (rod-shaped microtubulated bodies). MOMCs expressed hematopoietic and monocyte lineage markers, including CD45, CD11b, CD14, and CD68. MOMCs also showed expression of several stem cell markers, such as CD34 and CD105, but lacked expression of c-kit or CD133. Endothelial markers vascular endothelial−cadherin and vascular endothelial growth factor receptor type 1 (VEGFR1) were present on the surface of MOMCs. In addition, MOMCs are positive for type I and III collagens, fibronectin, and vimentin, which are typically produced by cells of mesenchymal origin. These findings clearly showed that MOMCs have mixed morphologic and phenotypic features of phagocytes, mesenchymal cells, and endothelial cells. These characteristics are unique, and are not consistent with any other previously described cells derived from human peripheral blood.

MOMCs appeared to be originated from circulating monocytes because they are positive for monocytic markers and appearance of MOMCs in PBMC cultures was completely inhibited by depletion of CD14+ monocytes. To further confirm the monocytic origin of MOMCs, highly enriched CD14+ monocytes were prelabeled with a green fluorescent dye and cultured with unlabeled CD14− PBMCs on fibronectin-coated plates. As expected, fluorescence-labeled cells exclusively showed a fibroblast-like morphology and expressed CD34, indicating that precursors for MOMCs are present within circulating CD14+ monocytes.

The number of MOMCs increased during culture on fibronectin, but cell expansion became slower after the passage and cell proliferation finally stopped beyond the fifth passage, indicating that MOMCs have the ability to self-replicate, but their lifespan is limited [10]. This feature is apparently different from stem cells. We tried to establish MOMC lines by introducing human catalytic subunit of telomerase gene in combination with or without human papillomavirus E6 and E7 oncogenes using lentivirus vector system into MOMCs, but immortalization of MOMCs has never succeeded, although this method was shown to prolong the lifespan of human mesenchymal stem cells [11]. Recently, we have successfully generated a potential rat counterpart of MOMCs using the method used for generation of human MOMCs. The adherent cells obtained in these cultures were comparable to human MOMCs in terms of their morphology and expression of CD45, CD34, and type I collagen.

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Differentiation potentials of MOMCs 

MOMCs have capacity to differentiate into a variety of mesenchymal cell types in specific permissive culture conditions principally developed for mesenchymal stem cells [12]. The induction treatment of MOMCs in vitro resulted in the expression of genes and proteins specific for bone, cartilage, fat, and skeletal muscle. The differentiation of MOMCs into individual mesenchymal cells followed the steps observed in mesenchymal stem cell differentiation in terms of the timing of lineage-specific transcription factor expression. For example, expression of the myogenic transcription factor MyoD preceded the expression of skeletal muscle actin and myosin. In vitro differentiation of MOMCs along the cardiomyogenic lineage required a coculture with cardiomyocytes prepared from the embryonic rat heart [13]. During the first 10 days of coculture, the morphology of MOMCs changed from spindle-shaped to round and spread out, and the majority of MOMCs expressed the cardiomyocyte-specific transcription factors, such as Nkx2.5, GATA-4, and eHAND. After 2 weeks of coculture with rat cardiomyocytes, MOMCs gradually displayed a marked increase in surface area and became multiangular morphology. Spontaneously beating MOMCs were observed after 3 weeks of coculture, albeit at relatively low efficiency (<5% of total MOMCs). These cells made contact with the surrounding rat cardiomyocytes and contracted in synchrony. At this stage, MOMCs expressed cardiomyocyte-specific structural proteins, such as α-sarcomeric actinin and troponin I, with typical staining patterns of the sarcomeric structures. In addition, MOMCs expressed connexin43, a protein consisting of gap junctions, and ultimately formed cell-to-cell contacts with the surrounding rat cardiomyocytes. Microinjection of the fluorescent dye into MOMCs revealed coupling as determined by direct dye transfer to neighboring rat cardiomyocytes. Cytoplasmic staining of atrial natriuretic peptide, which is almost exclusively secreted by atrial cardiomyocytes, was observed in the perinuclear regions. Expression of CD45 and CD14 was gradually downregulated during cardiomyogenic differentiation and was finally lost when they started spontaneous beating. An electrophysiological study revealed that contracting MOMCs showed spontaneous periodic action potentials typical of cardiac myocytes. These observations clearly indicate that a very minor subset of MOMCs is able to differentiate into cardiomyocytes of a mature phenotype with typical electrophysiological characteristics in vitro.

Subsequently, we demonstrated that human MOMCs were able to differentiate in vitro into the neuronal lineage using the similar coculture assay using primary cultures of neuronal cells prepared from the embryonic rat brain [14]. Within 3 days of cocultivation, the vast majority of MOMCs showed nuclear expression of early neuroectodermal transcription factors, including Ngn2 and NeuroD. These transcription factor−positive MOMCs coexpressed nestin, an intermediate filament protein expressed during neurogenesis. During the next 2 weeks of the culture with rat neurons, a small population of MOMCs displayed a multipolar neuron-like morphology. MOMCs expressing neurofilament had numerous axon-like processes projecting long distances and formed complex neural networks on the cocultivated rat neurons. MOMCs expressed β3-tubulin and MAP2, which are known to be preferentially expressed by axonal processes in both shaft and spine synapses. In addition, these neuron-like MOMCs also exhibited nuclear expression of the neuron-specific RNA-binding protein Hu and the postmitotic neuron-specific nuclear protein NeuN. At this stage, MOMC-derived neuron-like cells lost the expression of CD45 and CD14. Again, the differentiation of MOMCs into neurons followed the steps observed in normal differentiation; i.e., expression of proneuronal transcription factors preceded the expression of mature neuron-specific nuclear and structural proteins. Taken together, a subset of MOMCs is capable of differentiating along the neuronal lineage when placed into an appropriate environment, although their differentiation efficiency into mature neurons with typical morphologic and molecular features was very low (<5% of the total MOMCs). In the coculture system, we could not exclude the possibility that cell fusion was partly responsible for the phenotypic change of MOMCs.

We recently reported that MOMCs are able to differentiate into endothelium of a mature phenotype with typical morphologic, phenotypic, and functional characteristics [15]. MOMCs treated with a combination of angiogenic growth factors for 7 days changed their morphology from spindle-shaped to caudate, and these cells had numerous rod-shaped microtubulated structures resembling Weibel-Palade bodies. Almost every MOMC expressed endothelial markers, such as CD31, vascular endothelial−cadherin, VEGFR1, VEGFR2, Tie-2, von Willebrand factor, endothelial nitric oxide synthase, and CD146, but expression of CD14 and CD45 was markedly downregulated. Functional characteristics, including von Willebrand factor release upon histamine stimulation and upregulated expression of VEGF and VEGFR1 in response to hypoxia, were indistinguishable between the MOMC-derived endothelial-like cells and cultured human umbilical vein endothelial cells. In contrast to low differentiation efficiency to bone, fat, skeletal, and cardiac muscle, and neural lineages, morphologic and molecular features typical of mature endothelial cells were observed in nearly all adherent MOMCs in cultures. MOMCs responded to angiogenic stimuli and promoted the formation of mature endothelial cell tubules in Matrigel cultures. Finally, in xenogenic transplantation studies using a severe combined immunodeficient mouse model in which syngeneic colon carcinoma cells were injected subcutaneously with or without human MOMCs, cotransplantation of MOMCs significantly promoted the formation of blood vessels, and >40% of the tumor vessel sections incorporated human endothelial cells derived from MOMCs. These findings together indicate that human MOMCs can differentiate along the endothelial lineage in a specific permissive environment in vitro and in vivo. However, in the tumor neovascularization model, only 10% of transplanted MOMCs differentiated in vivo into mature endothelial cells incorporating into the vessel wall, and the majority of transplanted MOMCs remained CD45+CD34+type I collagen+ fibroblastic cells. This suggests an idea that MOMCs promote blood vessel formation not only through vasculogenesis, but also through angiogenesis. In fact, MOMCs were capable of producing a large amount of angiogenic factors, including VEGF, basic fibroblast growth factor, hepatocyte-growth factor, and stromal cell-derived factor−1.

Interestingly, MOMCs still retain potentials to differentiate into phagocytes. Upon exposure to macrophage colony-stimulating factor (CSF), MOMCs displayed a marked increase in surface area, and represented phagocytic capacity and ability to induce antigen-dependent T-cell proliferation. These features are compatible with those of macrophages. In addition, MOMCs cultured on fibronectin at high density resulted in the appearance of tartrate-resistant acid phosphatase-positive giant multinucleated cells forming actin-ring [16]. A subset of these cells showed bone resorption capacity on dentine slices and expression of genes for cathepsin K and calcitonin receptor, characteristic of functional osteoclasts. MOMCs expressed receptor activator of nuclear factor-kB ligand (RANKL), which is required for osteoclast formation from mononuclear precursors. These results indicate that human MOMCs can express RANKL and differentiate into functional osteoclasts without RANKL-expressing accessory cells.

Circulating CD14+ monocytes are long believed to be committed precursors specific for phagocytes, but our recent findings on MOMCs indicate that circulating monocytes contain a cell population that has the capacity to differentiate into several distinct mesodermal and neuroectodermal lineages through differentiation into MOMCs. However, it is not known whether MOMCs contain multipotent precursors or a group of monopotent precursors for several distinct lineages. Efficiencies of differentiation in in vitro cultures are greatly variable among cell lineages, i.e., high efficiency for endothelial differentiation, but low efficiency for differentiation into skeletal and cardiac myogenic lineages and neuronal lineage. We are currently examining in vivo differentiation potentials of MOMCs by delivering rat MOMCs directly into the damaged tissue of syngeneic rats. In a rat model of cerebral ischemia, transplantation of MOMCs into the ischemic core resulted in a significant improvement in neurologic function, but transplantation of macrophages did not. Despite multipotent differentiation potentials of human MOMCs in vitro, only a small number of transferred MOMCs differentiated into mature endothelial cells and contribute to the blood vessel formation. There was no NeuN+ neuronal cell derived from MOMCs, and the majority of transplanted MOMCs remained CD45+CD34+type I collagen+ fibroblastic cells. It is possible that in vivo differentiation from MOMCs to nonphagocytic cells other than endothelial cells may not be a common event even in case of massive tissue injury, but further analyses using different animal models are necessary to draw a conclusion.

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Molecular factors required for MOMC generation 

Generation of MOMCs was not observed when CD14+ monocytes were cultured alone on fibronectin. On the other hand, MOMCs were not generated in cultures of PBMCs on plastic plates without fibronectin coating. This clearly indicates that CD14− cells and binding to fibronectin are both required for the MOMC generation from precursors within the CD14+ monocytes [10]. MOMCs were efficiently generated when CD14+ monocytes were cultured alone in the conditioned medium generated by culture of CD14− cells on fibronectin, suggesting an important role of soluble factor(s) produced by CD14− cells, rather than a cell-to-cell contact. In this regard, we have recently found that soluble factors and microparticles released from activated platelets promote the MOMC generation. Adherent cells with spindle-shaped morphology were also obtained when we set up MOMC cultures on type I collagen, instead of fibronectin. Interestingly, these cells lacked expression of CD34 and did not have the ability to differentiate in vitro into bone, cartilage, fat, or endothelium.

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CD14+ MOMC precursors in circulation 

It is obvious that precursors for MOMCs reside within circulating CD14+ monocytes, but we still have not identified specific markers for the MOMC precursors. Until now, several distinct human cell populations that are originated from circulating CD14+ monocytes and have capacity to differentiate into nonphagocytes have been described. Zhao and colleagues demonstrated that pluripotent stem cells were generated from a subset of peripheral blood monocytes by repeated stimulation with a high concentration of macrophage-CSF and phorbol myristate acetate [8]. These spindle-shaped CD34+ cells termed pluripotent stem cells had the capacity to differentiate along several distinct cell lineages, including macrophages, T cells, epithelial cells, endothelial cells, neuronal cells, and hepatocytes. On the other hand, monocyte-derived endothelial progenitor cells resided within the CD14+CD34low cell population were shown to have ability to differentiate not only into endothelial cells, but also into osteoblasts, adipocytes, or neuronal cells [9]. Finally, fibrocytes were reported as a circulating cell population with fibroblast properties that plays an important role both in normal wound repair and in pathological fibrotic responses [17]. Fibrocytes were characterized by their distinctive phenotype positive for CD45, CD34, and type I collagen [17], and a characteristic chemokine receptor expression pattern CCR3+CCR5+CCR7+CXCR4+ was shown to be useful in identifying fibrocytes in circulation [18]. Although fibrocytes lacked the expression of CD14 [17], recent studies have shown that fibrocytes derive from circulating CD14+ monocytes [19].

These monocyte-derived cells commonly have spindle-shaped morphology and express both CD45 and CD34, but have several distinct characteristics. For example, pluripotent stem cells and fibrocytes are able to self-replicate and expand in long-term cultures, whereas MOMCs have a limited lifespan, like monocytic endothelial progenitor cells. Because cellular origins of these cell types have not been fully identified yet, circulating precursors within circulating CD14+ monocytes may be different. Alternatively, distinct differentiation potentials of these primitive cells might be due to different culture conditions of the same precursors.

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Gene expression profiling of MOMCs 

To understand the molecular characteristics underlying functional differences between CD14+ monocytes and cultured cells originated from CD14+ monocytes, we performed DNA microarray analyses using Affymetrix gene chips, containing 12,600 genes. Comparative analysis of gene expression profiles resulted in identification of several genes specifically expressed by MOMCs, but not by circulating monocytes, macrophages, or dendritic cells. These included embryonic stem cell markers, Nanog and Oct-4 20, 21. Other genes of interest were DLG3 and myosin-X (Myo10). The DLG3 is a human homolog of the Drosophila discs large tumor suppressor protein, and a member of the membrane-associated guanylate kinase protein family, which is important regulators of epithelial polarity and plays a major role in the organization of receptors [22]. This protein tended to be expressed in nonproliferating cells, such as neurons and cardiac myocytes, but is largely downregulated in proliferative cells, including various cultured cancer cell lines, suggesting that DLG3 negatively regulates cell proliferation. This may be one of the reasons why MOMCs were highly resistant to the immortalization treatment by introducing human papillomavirus E6 and E7 oncogenes. Myo10 is a molecular motor with capacity to bind actin, microtubules, and β-integrins, and localizes to the tips of filopodia and functions in filopodia formation [23]. A recent study showed that Myo10-mediated relocalization of integrins serves to form adhesive structures and thereby promote filopodial extension [24]. In this regard, cell surface filopodia-like structure was prominent in MOMCs by electron microscopy [10]. Upregulated gene expression of Myo 10 in MOMCs may contribute to their enhanced migration capacity.

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Ex vivo expansion of hematopoietic progenitors by MOMCs 

MOMCs have several features that are typical of BM stromal cells: adherent cells with fibroblast-like morphology, and the potential to differentiate into various mesenchymal lineages. Because BM stromal cells are known to support sustained growth and preservation of hematopoietic progenitor cells [25], we assessed the potential of MOMCs to support hematopoiesis using a coculture system with human cord blood CD34+ cells. Specifically, cord blood CD34+ cells were plated on a monolayer of MOMCs, BM stromal cells, or macrophages without any exogenous growth factors and cultured for up to 2 weeks (Fig. 2). In this culture, 5% fetal bovine serum was the only source of growth factors. The total number of nucleated cells was increased in a time-dependent manner in cultures with MOMCs or stromal cells, but not in the culture with macrophages. The numbers of CD34+ cells and their immature population CD34+CD38− cells were similarly expanded in the cultures with MOMCs and stromal cells. When harvested cells were assayed for the formation of erythroid (burst-forming unit erythroid), granulocyte-macrophage (colony-forming unit granulocyte-macrophage), and mixed colonies (colony-forming unit granulocyte-erythrocyte-macrophage-megakaryocyte), coculture of cord blood CD34+ cells with MOMCs greatly increased all colony-forming units. Compared with stromal cells, MOMCs were observed to be similarly efficient to enhance the generation of colonies. A noncontact culture of MOMCs and cord blood CD34+ cells using the Transwell inserts resulted in loss of capacity to expand hematopoietic progenitor cells, indicating an essential role of a cell-to-cell contact. Analysis of gene expression showed that MOMCs expressed interleukin (IL)-3, IL-6, IL-7, stem cell factor, leukemia inhibitory factor, granulocyte-macrophage CSF, macrophage-CSF, fms-like tyrosine kinase 3 ligand, and erythropoietin, but not granulocyte CSF or thrombopoietin. These findings indicate that MOMCs could support hematopoiesis through a direct cell-to-cell interaction and secretion of various hematopoietic growth factors. MOMCs may be of value for developing strategies for ex vivo expansion of human hematopoietic progenitor cells as the autologous feeder.

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  • Figure 2 

    Effect of monocyte-derived multipotential cells (MOMCs) on ex vivo expansion of cord blood CD34+ cells. One-thousand human cord blood CD34+ cells were plated on a monolayer of MOMCs, bone marrow stroma cells, or macrophages without any exogenous growth factors. (A) After 1 and 2 weeks of cultures, cells were harvested and the number of total nucleated cells was counted. Results shown are the mean and standard deviation of eight independent experiments. (B) Recovered cells were subjected to colony-forming cell assay for evaluating burst-forming unit erythroid (BFU-E), colony-forming unit granulocyte-macrophage (CFU-GM), and CFU granulocyte-erythrocyte-macrophage-megakaryocyte (CFU-GEMM). Results shown are the mean of four independent experiments.

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Roles of MOMCs in health and disease 

There are several lines of convincing evidence showing that circulating CD14+ monocytes have the potential to differentiate into various nonphagocytes, including mesodermal and neuroectodermal lineages. These observations challenge the traditional view of the biology of the monocyte/phagocyte system. A series of researches on MOMCs will lead to further progress in the understanding of the differentiation potential of CD14+ monocytes and the roles they play in the physiology of health and disease.

Differentiation from monocytes to nonphagocytic cells may not be induced during normal development, but may be readily induced in the presence of cues, such as massive tissue injury. Because the differentiation of monocytes into MOMCs requires binding to fibronectin and soluble factor(s) from activated platelets, circulating monocytes may encounter these signals at the site of tissue injury and inflammation. MOMCs subsequently differentiate into tissue-specific cells in response to organ-specific cues provided by the surrounding cells. In addition, MOMCs are able to release various soluble mediators, including angiogenic factors and ckemokines, thereby promoting angiogenesis and tissue regeneration. Therefore, strategies to recruit MOMCs to the site of injury may be a useful approach for repairing the damaged tissue.

On the other hand, there are several pathologic conditions with tissue accumulation of CD45+CD34+ fibroblast-like cells that actively synthesize extracellular matrix components, such as collagens [26]. These conditions include scleromyxedema and nephrogenic systemic fibrosis, a severe fibrotic disorder described in patients with renal disease in association with gadolinium-based contrast agents [27]. The origin of CD45+CD34+ fibroblast-like cells is currently undetermined, but CD14+ monocytes could be a source of these pathogenic cells. In addition, similar cells were also shown to participate in the stromal reaction to tumor development [28]. Prevention of harmful tissue remodeling in fibrotic diseases and tumors may be achieved by inhibiting accumulation of monocyte-derived fibroblastic cells.

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Acknowledgments 

This work was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture (Tokyo, Japan), and New Energy and Industrial Technology Development Organization of Japan (Kawasaki, Japan). We thank Aya Komori, Yuka Okazaki, Akihiro Koreki, Masahiro Toriumi, Jun Kikuchi, Dai Kusumoto, Mitsuhiro Nishida, Naofumi Sumitomo, and Yoshikazu Kishino for their expert technical assistance, Tohru Kiyono for providing lentivirus vectors, and Hidetoshi Inoko for instructing us in the gene chip analysis.

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Conflict of Interest Disclosure 

No financial interest/relationships with financial interest related to the topic of this article have been declared.

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PII: S0301-472X(10)00106-2

doi:10.1016/j.exphem.2010.03.015

Experimental Hematology
Volume 38, Issue 7 , Pages 557-563, July 2010

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