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PubMed2001

Cross-talk between alpha(4)beta(1)/alpha(5)beta(1) and c-Kit results in opposing effect on growth and survival of hematopoietic cells via the activation of focal adhesion kinase, mitogen-activated protein kinase, and Akt signaling pathways.

Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or beta(1)-integrins. In nonhematopoietic cells, integrins and receptor tyrosine kinases can collaborate to modulate cellular functions, providing evidence for cross-talk between signals emerging from these cell surface molecules. Using specific recombinant fibronectin peptides that contain the binding site for the integrin alpha(4)beta(1) (FN-H296) or alpha(5)beta(1) (FN-CH271) or both alpha(4)beta(1) and alpha(5)beta(1) (FN-CH296), this study investigated the effect of adhesion alone, or in combination with activation of c-Kit, on functional and biochemical outcomes in an EPC line, G1E-ER2, and primary EPCs. G1E-ER2 cells and primary EPCs cultured on FN-CH271 in the presence of c-Kit activation led to a significant increase in proliferation in comparison with cells grown on FN-H296 or FN-CH296. G1E-ER2 cells cultured on FN-H296 or FN-CH296 resulted in significant cell death in comparison to cells grown on FN-CH271. Activation of c-Kit enhanced the survival of G1E-ER2 cells grown on FN-H296 or FN-CH296; however, the rescue was only partial. The reduced survival of G1E-ER2 cells on FN-H296 correlated with reduced activation of Akt and expression of Bcl-2 and Bcl-x(L), whereas increase in proliferation on FN-CH271 correlated with significantly enhanced and sustained activation of focal adhesion kinase (FAK) and extracellular-regulated kinase (ERK) pathways. These data demonstrate that adhesion-induced signals emanating from ligation of alpha(4)beta(1) and alpha(5)beta(1) result in distinct biologic outcomes, including death via alpha(4)beta(1) and survival/proliferation via alpha(5)beta(1). (Blood. 2001;97:1975-1981)

Animals↗
PubMed2001

Intercellular adhesion molecule-4 binds alpha(4)beta(1) and alpha(V)-family integrins through novel integrin-binding mechanisms.

The LW blood group glycoprotein, ICAM-4, is a member of the intercellular adhesion molecule (ICAM) family expressed in erythroid cells. To begin to address the function of this molecule, ligands for ICAM-4 on hemopoietic and nonhemopoietic cell lines were identified. Peptide inhibition studies suggest that adhesion of cell lines to an ICAM-4-Fc construct is mediated by an LDV-inhibitable integrin on hemopoietic cells and an RGD-inhibitable integrin on nonhemopoietic cells. Antibody inhibition studies identified the hemopoietic integrin as alpha(4)beta(1.) Antibody inhibition studies on alpha(4)beta(1)-negative, nonhemopoietic cell lines suggested that adhesion of these cells is mediated by alpha(V) integrins (notably alpha(V)beta(1) and alpha(V)beta(5)). The structure of ICAM-4 modeled on the crystal structure of ICAM-2 was used to identify surface-exposed amino acid residues for site-directed mutagenesis. Neither an unusual LETS nor an LDV motif in the first domain of ICAM-4 was critical for integrin binding. ICAM-4 is the first ICAM family member shown to be a ligand for integrins other than those of the beta(2) family, and the data suggest that ICAM-4 has a novel integrin-binding site(s). These findings suggest a role for ICAM-4 in normal erythropoiesis and may also be relevant to the adhesive interactions of sickle cells.

Amino Acid Sequence↗
PubMed2001

Molecular pathways in bone marrow homing: dominant role of alpha(4)beta(1) over beta(2)-integrins and selectins.

The specific retention of intravenously administered hemopoietic cells within bone marrow is a complex multistep process. Despite recent insights, the molecular mechanics governing this process remain largely undefined. This study explored the influence of beta(2)-integrins on the homing to bone marrow and repopulation kinetics of progenitor cells. Both antifunctional antibodies and genetically deficient cells were used. In addition, triple selectin-deficient mice were used as recipients of either deficient (selectin or beta(2)) or normal cells in homing experiments. The homing patterns of either beta(2) null or selectin null cells into normal or selectin-deficient recipients were similar to those of normal cells given to normal recipients. Furthermore, spleen colony-forming units and the early bone marrow repopulating activity for the first 2 weeks after transplantation were not significantly different from those of control cells. These data are in contrast to the importance of beta(2)-integrin and selectins in the adhesion/migration cascade of mature leukocytes. The special bone marrow flow hemodynamics may account for these differences. Although early deaths after transplantation can be seen in recipients deficient in CD18 and selectin, these are attributed to septic complications rather than homing defects. However, when beta(2)- or selectin-null donor cells are treated with anti-alpha(4) antibodies before their transplantation to normal or selectin-deficient recipients, a dramatic inhibition of homing (>90%) was found. The data suggest that the alpha(4)beta(1)/vascular cell adhesion molecule-1 pathway alone is capable of providing effective capture of cells within the bone marrow, but if its function is compromised, the synergistic contribution of other pathways, that is, beta(2)-integrins or selectins, is uncovered.

Animals↗
PubMed1996

The expression of adhesion molecules in cigarette smoke-induced airways obstruction.

Cigarette smoking produces peripheral airway inflammation in all smokers, and chronic airways obstruction in approximately 20% of heavy smokers. The present study was designed to test the hypothesis that airways obstruction is related to changes in the expression of adhesion molecules involved in the recruitment of cells to sites of inflammation in the lung. Freshly resected lungs from heavy smokers with airways obstruction (n = 10) and from heavy smokers with normal lung function (n = 10) were collected in the operating room, inflated with optimal cutting temperature (OCT) medium and frozen over liquid nitrogen. Six micrometres thick cryostat sections cut from random samples of this tissue were stained, using immunohistochemistry, with monoclonal antibodies to the adhesion molecules on leucocytes: L-selectin, very late activation antigen-4 (VLA-4), CD11a/CD18, CD11b/CD18, CD11c/CD18; and on endothelial and epithelial surfaces: E-selectin, P-selectin, vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM)-1 and ICAM-2 using the alkaline phosphatase anti-alkaline phosphatase (APAAP) technique. The slides were coded and the expression of each molecule scored by three observers using a semiquantitative grading system. Two inducible adhesion molecules, E-selectin on endothelium and CD11b on leucocytes, were also evaluated using quantitative morphometric analysis. The results showed a distribution of adhesion molecules that was consistent with the inflammatory response in the airways and parenchyma of all subjects but failed to show any differences between those with or without airways obstruction. We conclude that development of airways obstruction in heavy smokers cannot be explained by differences in the expression of adhesion molecules known to be involved in the control of cell traffic in the lung.

Aged↗
PubMed1996

Expression of CD44 and integrins in bronchial mucosa of normal and mildly asthmatic subjects.

We have investigated the expression of cell surface markers and leucocyte cell adhesion molecules by immunohistochemistry in bronchial biopsies from 10 mild atopic asthmatics and 8 normal, nonatopic subjects. Significantly increased numbers of eosinophils (p<0.01) were evident in the bronchial submucosa of asthmatic subjects. In epithelium there were more CD44+ (p<0.02) and lymphocyte function-associated antigen-1 (LFA-1)+ (p<0.06) leucocytes in asthmatics than in normal subjects. Bronchial epithelial cells stained positively with anti-CD44 monoclonal antibodies (moAb) in both groups; however, when the staining was expressed as percentage of the total basement membrane, a considerable and highly significant increase was observed in the asthmatics (median 80 vs 22%, p=0.003). Few leucocytes were positive for very late activation antigen (VLA)-1, VLA-2 and VLA-4. The moAb for VLA-6 stained the basement membrane of the bronchial epithelium; while intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were constitutively expressed in endothelium. A positive correlation was found between LFA-1+ cells and activated eosinophils (EG2+) in the submucosa (p<0.005; r(s)=0.80). We conclude that even in mild asthma there is evidence of increased expression of cell surface ligands, and suggest that adhesive mechanisms play a role both in cell recruitment and disease activity.

Adult↗
PubMed1998

LFA-1 expression by blood eosinophils is increased in atopic asthmatic children and is involved in eosinophil locomotion.

Allergic asthma is characterized by eosinophil migration in the airways, which is strictly dependent on the expression of adhesion molecules. This study investigated whether the expression of adhesion molecules on eosinophils is increased and associated with disease activity in allergic asthma. Twenty atopic asthmatic (AA) subjects and nine controls were studied and the expression of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18), Mac-1 (CD11b/CD18) and very late antigen-4 (VLA-4; CD49d/CD29) on blood eosinophils was evaluated by specific monoclonal antibody (Mab) staining and flow-cytometric analysis. Compared with controls, eosinophils from AA showed increased expression of LFA-1 (p<0.005), but not of Mac-1 or VLA-4 (p>0.1). In addition, LFA-1 expression correlated positively with blood eosinophil number (r=0.792, p<0.05), while no correlations were observed between Mac-1 or VLA-4 expression and blood eosinophil number. The migration of eosinophils through human umbilical vein endothelial cells with or without anti-LFA-1, Mac-1 and VLA-4-blocking Mab was studied. Compared with controls, eosinophils from AA showed increased migration toward C5a (p<0.01). Cell migration was totally inhibited by preincubating eosinophils with anti-LFA-1 (p<0.05), while anti-Mac-1 had no effect (p>0.1). Thus, the expression of lymphocyte function-associated antigen-1 by blood eosinophils is increased in atopic asthmatics and seems to modulate the enhanced eosinophil migration observed in allergic asthma.

Asthma↗
PubMed2002

VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine production by synovial nurse-like cells from rheumatoid arthritis patients.

Nurse-like stromal cell lines from the synovial tissue of patients with rheumatoid arthritis (RA-SNC) produce, on coculture with lymphocytes, large amounts of proinflammatory cytokines. In the present paper, we analyze the molecular events necessary for the induction of cytokine release from RA-SNC cells, and particularly the roles played by cell adhesion and the transmigration (also known as pseudoemperipolesis) of lymphocytes. For this purpose, the effects of various mAbs on the binding and transmigration of a human B-cell line, MC/car, were examined using a cloned RA-SNC line, RA-SNC77. To analyze the role of lymphocyte binding and transmigration on upregulated cytokine production by the RA-SNC77 cells, we used C3 exoenzyme-treated MC/car cells, which could bind to RA-SNC77 cells but could not transmigrate. Treatment with anti-CD29 or anti-CD49d mAb significantly reduced binding and transmigration of the MC/car cells. In contrast, the neutralizing anti-CD106/vascular cell adhesion molecule 1 mAb did not show any inhibitory effect. Likewise, none of the neutralizing mAbs against CD11a, CD18, CD44, CD49e, or CD54 showed significant effects. Binding of C3-treated or untreated MC/car cells to RA-SNC77 cells induced comparable levels of IL-6 and IL-8 production. In addition, the enhanced cytokine production by RA-SNC77 cells required direct lymphocyte contact via a very late antigen-4 (VLA-4)-independent adhesion pathway. These results indicate that, although both the VLA-4-dependent/vascular cell adhesion molecule 1-independent and the VLA4-independent adhesion pathways are involved in MC/car binding and subsequent transmigration, only the VLA4-independent adhesion pathway is necessary and sufficient for the enhanced proinflammatory cytokine production by RA-SNC77 cells. The transmigration process, which is dependent on Rho-GTPase, is not a prerequisite for this phenomenon.

Antibodies, Monoclonal↗
PubMed1997

VLA-4 expression on peripheral blood lymphocytes is downregulated after treatment of multiple sclerosis with interferon beta.

Adhesion molecules are likely to play a critical role in the immunopathogenesis of multiple sclerosis (MS). The interaction of vascular cell adhesion molecule-1 (VCAM-1) with its lymphocyte ligand very late antigen-4 (VLA-4) may mediate migration of lymphocytes into the CNS. We have previously demonstrated that MS patients treated with interferon beta (IFN-beta) have a significant increase in soluble VCAM-1 (sVCAM-1) soon after the initiation of treatment, and this effect correlated with the resolution of contrast-enhancing MRI lesions. We studied the cell surface expression of VLA-4 by flow cytometry in 10 MS patients before and during IFN-beta treatment. We found a significant decrease in mean VLA-4 fluorescence of MS patients' lymphocytes on treatment and no change in untreated controls. In vitro treatment of lymphocytes with IFN-beta did not reproduce this effect, but the addition of sVCAM-1 did result in a decrease in VLA-4 expression. These data indicate that the previously identified increase in sVCAM-1 may lead to a decrease in VLA-4 expression and that this effect may partially explain the mechanism of action of IFN-beta.

Adjuvants, Immunologic↗
PubMed1998

Methylprednisolone reduces adhesion molecules in blood and cerebrospinal fluid in patients with MS.

OBJECTIVE: To analyze the expression of adhesion molecules on mononuclear cells from blood and CSF of patients with exacerbations of MS before and after megadose IV methylprednisolone (MP). BACKGROUND: Adhesion molecules regulate transmigration of lymphocytes and monocytes/macrophages to the CNS and have an important role in the pathogenesis of MS. METHODS: The expression of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1, lymphocyte function-associated antigen 1 (LFA-1), and intercellular adhesion molecule 1 (ICAM-1) was analyzed immunocytologically on lymphocytes and monocytes from blood and CSF of 23 patients and 11 healthy control subjects. The results were correlated with the Expanded Disability Status Scale and in half of the patients with the number of T2-weighted MS plaques and brain atrophy analyzed by MRI. RESULTS: After treatment, the mean proportions of VLA-4, LFA-1, and ICAM-1 on blood lymphocytes (p < 0.0003, p < 0.00001, p < 0.01) and monocytes (p < 0.0001, p < 0.0002, p < 0.007) of 23 patients decreased. The expression of these adhesion proteins was also diminished on CSF leukocytes. However, even after treatment, the levels of VLA-4 and LFA-1 on lymphocytes from blood of MS patients remained higher than in the control subjects. The level of VLA-4 and LFA-1 on blood lymphocytes (r=0.67, p=0.023) and VLA-4 on monocytes (r=0.61, p=0.047) correlated with the number of T2-weighted lesions. CONCLUSIONS: Megadose MP may suppress brain inflammation by reducing the expression of adhesion molecules on mononuclear cells from blood and CSF of MS patients. The inhibition of cellular trafficking in MS by MP offers an important means of altering the autoimmune response in MS.

Adult↗
PubMed2001

IFN-beta decreases adhesion and transmigration capacities of lymphocytes in Guillain-Barré syndrome.

The adhesion capacities, transmigration capacities, and integrin expression of lymphocytes from patients with Guillain-Barré syndrome incubated with interferon-beta were studied. Interferon-beta induced a dose-dependent inhibition of lymphocyte adhesion to recombinant vascular adhesion molecule-1 (p < 0.0001) and recombinant intercellular adhesion molecule-1 (rICAM-1) (p < 0.01) without modulation of very late activation molecule-4 and lymphocyte function-associated antigen-1 expressions and a dose-dependent decrease of lymphocyte transmigration across fibronectin (p < 0.0001). Inhibition of adhesion to rICAM-1 was similar after long (18 hours) or short (5 minutes) incubation time. These results support the potential therapeutic benefit of interferon-beta in Guillain-Barré syndrome.

Adjuvants, Immunologic↗
PubMed1993

Lymphocyte migration across high endothelium is associated with increases in alpha 4 beta 1 integrin (VLA-4) affinity.

The constitutive recirculation of lymphocytes between the widely distributed organs of the immune system is essential for host defence. We have developed an in vitro model of lymphocyte migration from the blood into lymph nodes which employs primary cultures of high endothelial cells (HEC). HEC-adherent lymphocytes adopt one of two distinct morphologies which correlates with their position in the endothelial layer; type I cells are bound to the surface of HEC and type II cells are underneath the endothelial layer. In a previous study we reported that the numbers of type I and type II cells are independently regulated, however the relationship between these two lymphocyte populations was not determined. In this study we have carried out detailed kinetic, phenotypic and functional analyses of type I and type II lymphocytes and determined their relationship. Using allotype marked lymphocytes from the PVG.RT7a and PVG.RT7b rat strains in a pulse-chase analysis, type I and type II lymphocytes were found to represent the same population of lymphocytes at different stages of interaction with the endothelial layer, rather than representing two independent lymphocyte populations. Migration was an irreversible event and the efficiency of migration (i.e. transition from type I to type II) was related to the concentration of lymphocytes plated on to the HEC layer. Following transmigration lymphocytes showed an increased ability to migrate across HEC layers and to bind to immobilised CS1 peptide. The increased binding to CS1 peptide was transient and fell to control levels over a 3 hour time period. The expression of alpha 4 integrin subunit on lymphocytes was unchanged following migration which suggests that the affinity of the CS1 receptor, alpha 4 beta 1, is upregulated by interaction with HEC. Together these results suggest that transendothelial migration is regulated by increases in the affinity of alpha 4 beta 1 integrin on lymphocytes following contact with HEC.

Animals↗
PubMed1994

Identification of a key integrin-binding sequence in VCAM-1 homologous to the LDV active site in fibronectin.

The integrin adhesion receptor alpha 4 beta 1 binds two ligands, the extracellular matrix glycoprotein fibronectin and the immunoglobulin superfamily member VCAM-1. Ligand-binding sites are contained with the HepII/IIICS domain of fibronectin, and within the homologous immunoglobulin domains 1 and 4 of VCAM-1. Previous studies have shown that the binding of each ligand to alpha 4 beta 1 is mutually exclusive, suggesting that they may employ similar mechanisms to bind receptor. Fibronectin contains at least three distinct peptide sequences that are active sites for alpha 4 beta 1 binding, two homologous sequences Leu-Asp-Val-Pro (LDVP) and Ile-Asp-Ala-Pro (IDAP), and a third related to Arg-Gly-Asp (RGD). Using a combination of site-directed mutagenesis and synthetic peptide approaches in conjunction with VCAM-1-dependent cell adhesion assays, we now report the identification of a key alpha 4 beta 1-binding sequence in both domains 1 and 4 of VCAM-1 as the tetrapeptide Ile-Asp-Ser-Pro (IDSP). Mutagenesis studies also suggest that an additional sequence in domain 1, KLEK, participates in receptor binding. Since IDSP is homologous to the LDVP and IDAP fibronectin peptides, this therefore provides a molecular explanation for the promiscuity of ligand binding by alpha 4 beta 1 and has implications for the design of synthetic VCAM-1 antagonists. The extrapolation of these findings to other integrin-binding immunoglobulin ligands is also discussed.

Amino Acid Sequence↗
PubMed1995

The role of alpha 4 beta 1 integrin in cell motility and fibronectin matrix assembly.

The alpha 4 beta 1 integrin has been suggested to play important roles in embryogenesis and pathogenesis of many diseases which involve both cell adhesion and cell migration. Previous studies using anti-alpha 4 beta 1 antibodies and fibronectin (Fn) fragments have suggested that alpha 4 beta 1 integrins may be involved in cell motility on Fn and vascular cell adhesion molecule-1 (VCAM-1). However, the cells used in these studies also express other Fn integrin receptors including alpha 5 beta 1 integrin, which is known to function in cell motility on Fn. To test whether alpha 4 beta 1 integrins mediate cell motility on Fn and VCAM-1 in the absence of alpha 5 beta 1 integrin, we expressed human alpha 4 integrin in a Chinese hamster ovary (CHO) cell line that is deficient in alpha 5 beta 1 integrin (CHO B2). The parental alpha 5 deficient CHO B2 cells were unable to adhere, spread or migrate on Fn, nor could they assemble a fibrillar Fn matrix. Expression of alpha 4 beta 1 integrin in the CHO B2 cells enabled the cells to adhere, spread and migrate on Fn and on VCAM-1 but not to assemble a fibrillar Fn matrix. The cellular processes mediated by the interaction of alpha 4 beta 1 with Fn or VCAM-1 were inhibited by the CS1 peptide derived from the major alpha 4 beta 1 binding site on Fn. These findings demonstrate that alpha 4 beta 1 integrins not only function as cell adhesion receptors but also as cell motility receptors for Fn and VCAM-1 independent of alpha 5 beta 1. Moreover, they reveal important functional differences between Fn binding integrins. The alpha 4-positive, alpha 5-negative CHO cells described in this report will be useful tools in studying the mechanism of molecular signalling during integrin mediated cellular processes.

Amino Acid Sequence↗
PubMed2001

Recovery of purification-associated reduction in antigen-induced histamine release from rat peritoneal mast cells.

Immunoglobulin E (IgE)-dependent histamine release from purified rat peritoneal mast cells (PMC) is very low in comparison to that from a non-purified preparation (PEC). The reduced histamine release from PMC is recovered or potentiated by reconstitution with separated non-mast cells (NMC). In the present study, further characterization was undertaken to elucidate the mechanisms involved. Sensitized mast cells were recovered from peritoneal cavities of rats, and purified by density gradient centrifugation with Percoll. Effects of NMC reconstitution, membrane fraction of NMC, NMC incubation supernatant, adhesion molecules and extracellular matrix proteins on IgE-dependent histamine release from PMC were examined. IgE-dependent histamine release was significantly potentiated by NMC reconstitution to PMC. The potentiation was dependent on the concentration of NMC reconstituted and reached a plateau after 30 min incubation. Increasing concentration of PMC did not affect the histamine release. Membrane fraction prepared from NMC also potentiated PMC histamine release in a dose-dependent manner. The potentiation reached a plateau in 5 min. Furthermore, incubation supernatant of NMC potentiated PMC histamine release. Antibodies against intercellular adhesion molecule (ICAM)-1, lymphocyte function-associated antigen (LFA)-1, very late activation antigen (VLA)-1, VLA-4 and VLA-6, and fibronectin did not affect the potentiation of PMC histamine release by NMC reconstitution. Fibronectin, laminin and collagen failed to potentiate PMC histamine release. These results indicate that the membrane component(s) of NMC in the rat peritoneal cavity seems to modulate IgE-dependent histamine release from peritoneal mast cells of rats, and that the active molecule(s) may be released from NMC. Adhesion molecules such as ICAM-1, LFA-1 and VLA are not involved.

Animals↗
PubMed1997

Modulation of anti-glomerular basement membrane nephritis in rats by ONO-1301, a non-prostanoid prostaglandin I2 mimetic compound with inhibitory activity against thromboxane A2 synthase.

The antinephritic effects of ONO-1301 ([7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]-aminooxy]ethyl]-1 -naphtyloxy]acetic acid) on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats were investigated. ONO-1301 was orally given to crescentic-type anti-GBM nephritic rats for 40 days after the induction of nephritis. ONO-1301 (30 mg/kg) suppressed the elevation of protein excretion into urine. In the ONO-1301-treated rats, cholesterol and urea nitrogen content in the plasma was lower than that of the nephritic control rats. Histological observation demonstrated that ONO-1301 suppressed the incidence of crescent formation and adhesion of capillary wall to Bowman's capsule. However, ONO-1301 failed to inhibit the antibody production against rabbit IgG and the rat-IgG deposition on the GBM. The increase in very late antigen-4 (CD49b, VLA-4)-positive cells in nephritic glomeruli was significantly reduced by ONO-1301 treatment on day 5. cAMP-elevating agents inhibited the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression on the surface of human umbilical vein endothelial cells (HUVECs) mediated by tumor necrosis factor (TNF)-alpha. These findings suggest that the antinephritic action of ONO-1301 is due to, at least in part, inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of VCAM-1.

Animals↗
PubMed2001

Expression of adhesion molecules on CD34(+) cells in peripheral blood of non-hodgkin's lymphoma patients mobilized with different growth factors.

Adhesion molecules on CD34(+) cells were implicated in the process of peripheral blood stem cell (PBSC) mobilization and homing. We studied the mobilization of CD34(+)Thy1(+) cells, CD34(+) very late-acting antigen (VLA)4(+) cells, and CD34(+)L-selectin(+) cells in non-Hodgkin's lymphoma patients mobilized with cyclophosphamide plus G-CSF, GM-CSF, or GM-CSF followed by G-CSF. The mean percentage of CD34(+) cells in the bone marrow (BM) expressing Thy1 was 23.6% +/- 11% and 17.8% +/- 8% in the PB before mobilization, and was markedly decreased to 4.5% +/- 3.3% in the apheresis collections. Similarly, the mean percentage of CD34(+) cells expressing L-selectin was 35.8% +/- 4.3% in the BM, 21.6% +/- 4.1% in the PB before mobilization and was markedly decreased to 9.1% +/- 2.5% in the apheresis collections. Patients in the three arms of the study had a similar pattern of CD34(+)Thy1(+) and CD34(+)L-selectin(+) cell mobilization. Also, a similar pattern of coexpression of CD34(+)Thy1(+) and CD34(+)L-selectin(+) cells was observed when the patients were regrouped as "good mobilizers" (> or =2 x 10(6) CD34(+)CD45(dim) cells/kg, in four collections) and "poor mobilizers" (<0.4 x 10(6) CD34(+)CD45(dim) cells/kg, in two collections). The mean percentage of CD34(+) cells expressing VLA-4 in the BM and PB was relatively high (73.4% +/- 12% and 65.4% +/- 6.6%, respectively) and dropped considerably in the PBSC collections to 43.5% +/- 7.1% with a similar pattern observed for patients in arms A, B, and C. However, when the patients were regrouped as "good mobilizers" and "poor mobilizers," a higher percentage of CD34(+) cells expressing VLA-4 was observed in the PBSC of the pooled "good mobilizers" (50.5% +/- 9% versus 36.3% +/- 6.4%; p = 0.01). We conclude that release of CD34(+) cells to the PB involves a general downregulation of Thy1, L-selectin and VLA-4 on CD34(+) cells, irrespective of the growth factor used for mobilization. However, good mobilizers had a relatively higher percentage of CD34(+) cells expressing the VLA-4 antigen.

Adult↗
PubMed2002

Ex vivo expansion of stem cells from umbilical cord blood: expression of cell adhesion molecules.

Expansion of stem cells from cord blood has been demonstrated to increase the numbers of CD34+ cells, CD34+ subsets, long-term culture-initiating cells, and severe combined immunodeficient mouse, repopulating cells. However, reports suggest that the ex vivo expanded population behaves differently than freshly isolated cells and shows a delayed or diminished engraftment. In this study, we investigated the effects of the cytokines flt3 ligand, stem cell factor, and thrombopoietin on expansion of CD34+ and CD34+/CD38- cells. In addition, we studied the expression of adhesion molecules, very late activation antigen-4 (VLA-4) and leukocyte function antigen-1 (LFA-1), on CD34+ cells from cord blood by flow cytometry. We also looked at the expression of an adhesion receptor, namely, vascular cell adhesion molecule-1 (VCAM-1) on bone marrow stromal cells by Western blot analysis after exposure to low dose gamma irradiation. After culturing for 7 days, increases in the absolute numbers of CD34+, CD34+/CD38-, CD34+/VLA-4+, and CD34+/LFA-1+ cells were 5.67 +/- 2.91 (mean +/- standard deviation) fold, 7.21 +/- 4.38 fold, 99.56 +/- 101.5 fold, and 101.39 +/- 83.25 fold, respectively. There was a transient upregulation in the expression levels of VCAM-1 on stromal cells, which peaked at 4 hours. Though there was an increase in the absolute numbers of CD34+ cells expressing the adhesion molecules, the expression levels (antigen density) of the adhesion molecules on the CD34+ cells remained unaffected.

ADP-ribosyl Cyclase↗