EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation

Arthur, Agnieszka; Zannettino, Andrew C.W.; Panagopoulos, Romana; Koblar, Simon; Sims, Natalie A.; Stylianou, Con; Matsuo, Koichi; Gronthos, Stan

doi:10.1016/j.bone.2010.10.180

Cited by 81 publications

(129 citation statements)

References 62 publications

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“…In non-neuronal tissues, ephrins are required for such diverse processes as T-cell maturation and function (Stimamiglio et al, 2010), vascular growth and patterning (reviewed in Kuijper et al, 2007), bone homeostasis (reviewed by Edwards and Mundy, 2008), glucose metabolism and insulin secretion (Konstantinova et al, 2007;Kulkarni and Kahn, 2007). In the context of adult stem cells, ephrins mediate key activities in stem/progenitor cells of bone (Arthur et al, 2010), intestine (reviewed by Pitulescu and Adams, 2010), dental pulp (Stokowski et al, 2007) and hair follicles (Genander et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Other changes downstream of ephrin signaling, such as adhesion receptor clustering and changes in substrate affinity, are required for cell sorting during rhombomere and somite segmentation (Cooke et al, 2001;Tanaka et al, 2003;Glazier et al, 2008;Kemp et al, 2009;Julich et al, 2009). Finally, in the case of interactions between stem cells and their niche, Eph/ephrin signaling has been shown to direct both homing to and activities within the niche via modifications in adhesion receptor activity and modulation of downstream signaling pathways (Stokowski et al, 2007;Arthur et al, 2010;Ting et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, roles for these proteins in regenerative and homeostatic processes in neurons (Goldshmit et al, 2006;Bolsover et al, 2008;Lai and Ip, 2009), vasculature (Wang et al, 2010), bone (Edwards and Mundy, 2008;Irie et al, 2009;Arthur et al, 2010), and stem cell niches (Stokowski et al, 2007;Arthur et al, 2010;Genander et al, 2010;Murai and Pasquale, 2010) have been established. Eph/ephrin involvement in tumor progression (Castano et al, 2008;Merlos-Suarez and Batlle, 2008;Noberini and Pasquale, 2009) has also been described in several organ systems.…”

Section: Introductionmentioning

confidence: 99%

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Eph/ephrin interactions modulate muscle satellite cell motility and patterning

et al. 2011

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SUMMARYDuring development and regeneration, directed migration of cells, including neural crest cells, endothelial cells, axonal growth cones and many types of adult stem cells, to specific areas distant from their origin is necessary for their function. We have recently shown that adult skeletal muscle stem cells (satellite cells), once activated by isolation or injury, are a highly motile population with the potential to respond to multiple guidance cues, based on their expression of classical guidance receptors. We show here that, in vivo, differentiated and regenerating myofibers dynamically express a subset of ephrin guidance ligands, as well as Eph receptors. This expression has previously only been examined in the context of muscle-nerve interactions; however, we propose that it might also play a role in satellite cell-mediated muscle repair. Therefore, we investigated whether Eph-ephrin signaling would produce changes in satellite cell directional motility. Using a classical ephrin 'stripe' assay, we found that satellite cells respond to a subset of ephrins with repulsive behavior in vitro; patterning of differentiating myotubes is also parallel to ephrin stripes. This behavior can be replicated in a heterologous in vivo system, the hindbrain of the developing quail, in which neural crest cells are directed in streams to the branchial arches and to the forelimb of the developing quail, where presumptive limb myoblasts emigrate from the somite. We hypothesize that guidance signaling might impact multiple steps in muscle regeneration, including escape from the niche, directed migration to sites of injury, cell-cell interactions among satellite cell progeny, and differentiation and patterning of regenerated muscle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Eph/ephrin interactions modulate muscle satellite cell motility and patterning

et al. 2011

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“…RT-PCRs were performed using SyberGreen PCR Master Mix (SABiosciences) and Rotorgene 3000 series (Corbett Life Sciences). EphB, ephrin-B, INFg, IDO, HGF, and TGF-b1 primer sets were used as previously described [14,37]. Other primer sequences (0.05 mM; Geneworks) are indicated in Table 1.…”

Section: Real-time-polymerase Chain Reactionmentioning

confidence: 99%

EphB and ephrin-B interactions mediate human mesenchymal stem cell suppression of activated T-cells

Nguyen

Gronthos

Arthur

et al. 2013

Experimental Hematology

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Mesenchymal stromal/stem cells (MSC) express the contact-dependent erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinase family and their cognate ephrin ligands, which are known to regulate thymocyte maturation and selection, T-cell transendothelial migration, activation, co-stimulation, and proliferation. However, the contribution of Eph/ephrin molecules in mediating human MSC suppression of activated T-cells remains to be determined. In the present study, we showed that EphB2 and ephrin-B2 are expressed by ex vivo expanded MSC, while the corresponding ligands, ephrin-B1 and EphB4, respectively, are highly expressed by T-cells. Initial studies demonstrated that EphB2-Fc and ephrin-B2-Fc molecules suppressed T-cell proliferation in allogeneic mixed lymphocyte reaction (MLR) assays compared with human IgG-treated controls. While the addition of a third-party MSC population demonstrated dramatic suppression of T-cell proliferation responses in the MLR, blocking the function of EphB2 or EphB4 receptors using inhibitor binding peptides significantly increased T-cell proliferation. Consistent with these observations, shRNA EphB2 or ephrin-B2 knockdown expression in MSC reduced their ability to inhibit T-cell proliferation. Importantly, the expression of immunosuppressive factors, indoleamine 2, 3-dioxygenase, transforming growth factor-b1, and inducible nitric oxide synthase expressed by MSC, was up-regulated after stimulation with EphB4 and ephrin-B1 in the presence of interferon (IFN)-g, compared with untreated controls. Conversely, key factors involved in T-cell activation and proliferation, such as interleukin (IL)-2, IFN-g, tumor necrosis factor-a, and IL-17, were down-regulated by T-cells treated with EphB2 or ephrin-B2 compared with untreated controls. Studies utilizing signaling inhibitors revealed that inhibition of T-cell proliferation is partly mediated through EphB2-induced ephrin-B1 reverse signaling or ephrin-B2-mediated EphB4 forward signaling by activating Src, PI3Kinase, Abl, and JNK kinase pathways, activated by tyrosine phosphorylation. Taken together, these observations suggest that EphB/ephrin-B interactions play an important role in mediating human MSC inhibition of activated T cells.

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“…The importance of Eph/ephrin has also been shown in various stem cell niches, including: neural, dental and intestinal stem cell compartments 140,141 …”

Section: Expression and Function Of The Eph And Ephrin Genesmentioning

confidence: 99%

The role of Eph proteins in haematopoiesis and leukaemia

Charmsaz¹

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When HSCs from wild type mice were transduced with the MLL-AF9 retrovirus and engrafted into recipient mice, the subsequent leukaemias showed significant expression of EphA2 on leukemic blast cells. However when EphA2 null HSCs were engrafted, the absence of EphA2 appeared to have no effect on the leukemic process, demonstrating that EphA2 is not essential for leukaemia progression. Analysis showing increased expression of EphA7 and other Eph proteins demonstrate a possible compensatory role for the lack EphA2 expression, if Eph signalling was required for leukemic evolution in this model. Following these observations, the role iii of EphA2 as a therapeutic target for MLL-AF9 leukaemia was evaluated. Results showed that radiolabelled (beta particle-emitting lutetium) EphA2 was an effective therapeutic approach by significantly delaying the progression of MLL-AF9 leukaemia. Given the poor prognosis of MLL-driven paediatric acute lymphoblastic leukaemia (ALL) this data raises the prospect of effective EphA2-targeted therapy for this disease.EphA3 is another member of the Eph/ephrin family of RTKs, which was originally described in leukaemia and has subsequently been described in many other different cancers including sarcomas, lung cancer, melanoma and glioblastoma. The EphA3-specific monoclonal antibody, IIIA4, binds and activates both human and mouse

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EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation

Cited by 81 publications

References 62 publications

Eph/ephrin interactions modulate muscle satellite cell motility and patterning

Eph/ephrin interactions modulate muscle satellite cell motility and patterning

EphB and ephrin-B interactions mediate human mesenchymal stem cell suppression of activated T-cells

The role of Eph proteins in haematopoiesis and leukaemia

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