Receptor tyrosine kinase, EphB4 (HTK), accelerates differentiation of select human hematopoietic cells

Abstract

EphB4 (HTK) and its ligand, ephrinB2, are critical for angiogenesis and result in fatal abnormalities of capillary formation in null mice. EphB4 was originally identified in human bone marrow CD34 ؉ cells by us and has since been reported to be expressed in erythroid progenitors, whereas the ligand ephrinB2 is expressed in bone marrow stromal cells. Reasoning that the developmental relationship between angiogenesis and hematopoiesis implies common regulatory molecules, we assessed whether EphB4 signaling influences the function and phenotype of primitive human hematopoietic cells. IntroductionHematopoietic stem cells (HSCs) have the capacity to self-renew and to differentiate along a number of pathways, thereby generating all blood cells. Understanding the molecular mechanisms that regulate the formation, growth, and differentiation of HSCs has become increasingly complex. 1 The bone marrow (BM) is a diverse environment that contains a variety of different cell types and extracellular matrix molecules. The BM microenvironment produces a wide range of stimuli to different hematopoietic cells, providing combinatorial relationships that result in the finely tuned hematopoietic system. How factors (in either membrane-bound or soluble form) produced by BM stromal cells regulate the balance of self-renewal and differentiation of specific blood cell lineages remains a major question.Eph receptor tyrosine kinases and their ligands, ephrins, play important roles in various processes during embryonic development, including the targeting behavior of migratory neurons, vascular cell assembly, and angiogenesis. 2 Fourteen Eph receptors have been catalogued into EphA or EphB subclasses based on their affinity for ligands. Eight ephrins have been identified to date. They are membrane proteins of either glycerophosphatidylinsitol (GPI)-linked (ephrinA) or transmembrane (ephrinB). 3 Rather than longrange communication, signaling from Eph receptors and their ligands is restricted to sites of direct cell-cell contact and is capable of inducing reciprocal bidirectional events between interacting cells. 4 Some Eph and ephrin molecules have been found to be expressed in the hematopoietic system. EphA3 (Hek) was originally cloned from a pre-B-cell leukemia and is expressed in some T-cell lines. 5 EphA1 (Esk), EphA2 (Eck), and EphB2 (Hek5) were reported to be expressed in thymus. 6-8 EphA4 (Hek8) and EphA7 (Hek11) appear to be expressed in human fetal bone marrow pro-B cells. 9 The receptor tyrosine kinase EphB4 (HTK) and its cognate ligand, ephrinB2 (HTKL) are widely expressed in fetal and adult tissues. 10,11 Unlike most of the Eph subfamily members, EphB4 does not appear to be expressed in the central nervous system. Recent studies have shown that EphB4 is specifically expressed at the venous endothelium, whereas ephrinB2 is specifically and reciprocally expressed on arterial endothelial cells at the earliest stages of vascular development. 12 Mice lacking either EphB4 or ephrinB2 display identical defects in angiogenesis by arteri...

Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels

“…We previously noted that overexpression (activation) of EphB4 led to accelerated exit of primitive adult hematopoietic cells from a functional stem cell population. 29 In the setting of the EphB4-deficient ES model used here, inhibition of differentiation and preservation of a primitive cell type was observed. Therefore the relative gradient of ligand/receptor expression and interaction may dictate the relative abundance of cells from specific differentiation stages.…”

“…Our previous studies indicated that EphB4 participates in adult hematopoiesis with primitive human CD34 ϩ hematopoietic cells undergoing accelerated differentiation in the context of activated EphB4. 29 We therefore examined EphB4 effects on the hemangioblast, where the processes of hematopoiesis and vasculogenesis intersect.…”

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

“…EPHB4 is expressed in hematopoietic progenitor cells and is downregulated during differentiation to mature erythroid cells upon removal of its ligand. 34 Active EphB4 enforces preferentially megakaryocytic and erythroid differentiation. It was described that the ephrinB2/EphB4 axis is dysregulated in multiple myeloma.…”

`Eph'ective signaling: forward, reverse and crosstalk

“…These findings have important implications for understanding and treating cancer because Eph proteins probably regulate angiogenic processes associated with tumor growth (Brantley et al, 2002;Dodelet and Pasquale, 2000;Ogawa et al, 2000;Pandey et al, 1995). Interestingly, EphB4 and ephrin-B2 also play a role in erythropoiesis by influencing hematopoietic cell lineages that share a common ancestry with endothelial cells (Suenobu et al, 2002;Wang et al, 2002b). Furthermore, Eph proteins play a role in platelet clustering and hence may be important for blood clotting at sites of vascular injury (Prevost et al, 2002).…”