Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion.

Mohamadzadeh, Mansour; DeGrendele, Heather; Arizpe, H. M.; Estess, Pila; Siegelman, Mark H.

doi:10.1172/jci1604

Cited by 287 publications

(259 citation statements)

References 67 publications

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“…[7][8][9]. Hyaluronic acid (HA) (10) is the principal ligand of CD44 that mediates extravasation of CD44 ϩ/ϩ white cells (11) and is expressed by activated endothelial cells of small blood vessels (12).…”

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confidence: 99%

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

Nedvetzki

Gonen

Assayag

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

182

175

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We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined

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mentioning

confidence: 99%

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

Nedvetzki

Gonen

Assayag

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

182

175

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“…Notably, prior studies have indicated that MSCs can localize to sites of inflammation in a CD44-dependent manner (50). Such recruitment may be mediated by CD44 binding to vascular deposits of HA triggering VLA-4 adhesiveness, as vascular lumen and perivascular HA deposition is characteristic of inflammation (51,52). However, owing to prominent display of E-selectin on vascular endothelium at sites of inflammation, the capability to specifically enforce expression of the step 1 effector HCELL to engage E-selectin would markedly amplify trafficking of hMSCs to injury sites.…”

Section: Discussionmentioning

confidence: 99%

Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells

Thankamony

Sackstein

2011

Proc. Natl. Acad. Sci. U.S.A.

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According to the multistep model of cell migration, chemokine receptor engagement (step 2) triggers conversion of rolling interactions (step 1) into firm adhesion (step 3), yielding transendothelial migration. We recently reported that glycosyltransferaseprogrammed stereosubstitution (GPS) of CD44 on human mesenchymal stem cells (hMSCs) creates the E-selectin ligand HCELL (hematopoietic cell E-selectin/L-selectin ligand) and, despite absence of CXCR4, systemically administered HCELL + hMSCs display robust osteotropism visualized by intravital microscopy. Here we performed studies to define the molecular effectors of this process. We observed that engagement of hMSC HCELL with E-selectin triggers VLA-4 adhesiveness, resulting in shear-resistant adhesion to ligand VCAM-1. This VLA-4 activation is mediated via a Rac1/Rap1 GTPase signaling pathway, resulting in transendothelial migration on stimulated human umbilical vein endothelial cells without chemokine input. These findings indicate that hMSCs coordinately integrate CD44 ligation and integrin activation, circumventing chemokinemediated signaling, yielding a step 2-bypass pathway of the canonical multistep paradigm of cell migration.T he successful application of adoptive cellular therapies, including stem cell-based regenerative medicine, critically depends on delivering relevant cells to target sites (1). Four distinct steps have been described in the process of cell migration: tethering and rolling mediated principally by the selectin group of adhesion molecules (step 1), chemokine receptor engagement and resultant G-protein-coupled "inside-out" activation of integrins (step 2), firm adhesion by integrins (step 3), culminating in transendothelial migration (TEM) (step 4) (2, 3). The conventional multistep paradigm holds that step 2 is critical for TEM, with engagement of discrete chemokine receptors on the cell surface triggering subsequent integrin-dependent steps. For recruitment of circulating cells to bone marrow, the CXCL12/CXCR4 chemokine axis plays a central role (4). Notably, specialized sinusoidal vessels constitutively express CXCL12 and E-selectin at sites where cells extravasate into the marrow parenchyma (5). Hematopoietic stem cells express multiple E-selectin ligands and abundant CXCR4 (1), and are thus equipped with relevant effectors of step 1 and step 2 events mediating osteotropism.Mesenchymal stem cells (MSCs) can differentiate into a variety of tissues (6, 7) and display potent immunomodulatory effects (8, 9). Although MSCs have shown therapeutic potential in skeletal diseases (10), myocardial injury, and immunologic disorders (11, 12), a critical limitation to the therapeutic use of MSCs is their modest tissue colonization upon systemic administration (13-15). Importantly, human MSCs (hMSCs) lack expression of various adhesion receptors that mediate step 1 interactions, particularly E-selectin ligands (16). Moreover, in contrast to hematopoietic cells, hMSCs display a rather limited repertoire of chemokine receptors, with variable eviden...

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“…Because the expression/synthesis of HA and TSG-6 are up-regulated in blood vessels during inflammation (1-3, 18, 19, 51, 52), the inflammatory environment may provide the proper conditions for activation of "dormant" CD44 by creating a ligand consisting of HA modified by TSG-6. Indeed, CD44-mediated, HA-dependent rolling of T lymphocytes on an endothelial substrate was enhanced when the endothelial cells were stimulated with pro-inflammatory cytokines, which increased the retention of HA on the endothelial monolayer (53). Cytokine treatment could also induce TSG-6 expression in endothelial cells (52).…”

Section: Discussionmentioning

confidence: 99%

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44

Lesley

Gál

Mahoney

et al. 2004

Journal of Biological Chemistry

161

203

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Interactions between CD44 and hyaluronan are implicated in the primary adhesion of lymphocytes to endothelium at inflammatory locations. Here we show that preincubation of hyaluronan with full-length recombinant TSG-6 or its Link module domain (Link_TSG6) enhances or induces the binding of hyaluronan to cell surface CD44 on constitutive and inducible cell backgrounds, respectively. These effects are blocked by CD44-specific antibodies and are absent in CD44-negative cells. Enhancement of CD44-mediated interactions of lymphoid cells with hyaluronan by TSG-6 proteins was seen under conditions of flow at shear forces that occur in post-capillary venules. Increases in the number of rolling cells were observed on substrates comprising TSG-6-hyaluronan complexes as compared with a substrate containing hyaluronan alone. In ligand competition experiments, cell surface-bound TSG-6-hyaluronan complexes were more potent than hyaluronan alone in inhibiting cell adhesion to immobilized hyaluronan. Link_TSG6 mutants with impaired hyaluronan binding function had a reduced ability to modulate ligand binding by cell surface CD44. However, some mutants that exhibited close to wild-type hyaluronan binding were found to have either reduced or increased activity, suggesting that some amino acid residues outside of the hyaluronan binding site might be involved in protein self-association, potentially leading to the formation of cross-linked hyaluronan fibers. In turn, cross-linked hyaluronan could increase the binding avidity of CD44 by inducing receptor clustering. The ability of TSG-6 to modulate the interaction of hyaluronan with CD44 has important implications for CD44-mediated cell activity at sites of inflammation, where TSG-6 is expressed.

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Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion.

Cited by 287 publications

References 67 publications

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44

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