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PubMed2001

Differential tissue expression of epitopes of the tetraspanin CD151 recognised by monoclonal antibodies.

CD151, a member of the tetraspanin family of cell membrane proteins, is widely expressed in epithelial, endothelial and muscle cells as well as platelets and megakaryocytes. Several monoclonal antibodies recognising CD151 in transfected cells and immunoprecipitating typical bands of 28 and 32 kDa from cell lysates have been produced. Surprisingly, these antibodies show different patterns of staining on tissue sections and on haemopoietic cells. Here we show that these differences are at least in part due to masking of certain epitopes in integrin/CD151 complexes. These data have important implications for the use of monoclonal antibodies in studies of the distribution and function of CD151. Of six monoclonal antibodies from four laboratories, 11B1 was found to be the most reliable for detection of CD151 in different cell and tissue contexts.

Animals↗
PubMed2003

Evidence of a limited contribution of feto-maternal interactions to trophoblast differentiation along the invasive pathway.

Trophoblast differentiation is a key event in human placental development. During extravillous trophoblast (EVT) differentiation, stem cells from the anchoring villi detach from their basement membrane and proliferate to form aggregates called trophoblast cell columns (TCCs). They subsequently invade the decidua and differentiate into interstitial and endovascular trophoblasts. The influence of the decidua on EVT differentiation is controversial. We therefore compared the pattern of trophoblast differentiation marker expression in viable intrauterine and tubal pregnancies, as decidual cell markers (prolactin [PRL] and insulin-like growth factor binding Protein-1 [IGFBP1]) were only expressed in endometrial implantation sites. Extravillous trophoblast differentiation in anchoring villi from uterine and ectopic pregnancies exhibited a comparable phenotypical switch: alpha6 integrin subunit, E-cadherin, EGF receptor, Ki 67 and connexin 40 were localized in the proximal part of the TCC, while alpha5beta1 and alpha1 integrins, c-erb B2, hPL and HLA-G were expressed by invasive cytotrophoblasts. The cyclin-dependent kinase inhibitors p16 and p57 were mainly detected in invasive cytotrophoblasts some distance from the columns. However, the TCC was markedly longer in tubal pregnancy than in intrauterine pregnancy. These findings suggest that the decidua is not necessary to trigger EVT invasion, but that it is likely to limit the extent of the TCC and to accelerate the onset of EVT migration.

Biomarkers↗
PubMed2000

Melanocytes in nevi and melanomas synthesize basement membrane and basement membrane-like material. An immunohistochemical and electron microscopic study including immunoelectron microscopy.

Light microscopic studies have shown that nevus cell nests and melanoma nests are surrounded by basement membrane (BM) material containing type IV collagen and laminin. This study confirms this by electron microscopy and relates it to proteins which interact with the basement membrane. Nevi except for dysplastic and Spitz nevi, malignant melanomas, and melanoma metastases were studied by immunohistopathology, routine electron microscopy (EM), and immunoelectron microscopy. The lesions were incubated with monoclonal antibody (moAb) against type IV collagen, laminin, and the integrin alpha6 and studied by light microscopy. In addition, melanomas were studied by immuno-EM after incubation with a moAb against matrix metalloproteinase-2 (MMP-2). Nevus cell nests and melanoma nests are surrounded by BM material containing type IV collagen and laminin by immuno-EM. The BM material various in thickness and is amorphous. Type IV collagen, laminin, and MMP-2 are synthesized by melanoma cells as well as adjacent fibroblasts. Destruction or loss of the BM is not mandatory for melanoma invasion or even metastasis. Possibly the BM material is a protective wall for melanoma cells. Interactions between melanocytes and the extracellular matrix of which the BM is a part, can be traced back to the migration of melanocytes from the neural crest.

Antibodies, Monoclonal↗
PubMed2002

Organotypic keratinocyte coculture using normal human serum: an immunomorphological study at light and electron microscopic levels.

Organotypic human skin equivalents of keratinocytes and fibroblasts embedded in collagen matrix have been the subject of studies dealing with various culture conditions. Development of standardized living skin equivalents using defined culture media containing respective supplements can provide important instruments of investigation in skin biology. In addition, tissue engineering has created human skin substitutes for treatment of acute and chronic wounds. In our study, we generate a modified organotypic human skin equivalent using normal human serum instead of fetal calf serum (FCS). This living skin equivalent shows regular stratification of the epidermis and the dermal-epidermal junction zone at the light and electron microscopic level after 1 and 3 weeks of coculture. Indirect immunofluorescence reveals regular expression of differentiation antigens and the major structural proteins collagen IV, laminin 5 and the integrin chains alpha 6 and beta 4 at the dermo-epidermal junction zone. Immunoelectron microscopy demonstrates expression of collagen IV, alpha 6 and beta 4 integrin after 1 and 3 weeks of coculture. This organotypic skin model could be the basis for autologous skin grafting for acute or chronic wounds using autologous serum as well as patients' keratinocytes and fibroblasts, thus minimizing the risk of transmitting infectious agents.

Animals↗
PubMed1997

Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains beta 1, alpha 1 to 6 and alpha V.

Accumulation of extracellular matrix is important in the progression of glomerulonephritis. Since adherent cell types utilize integrins to bind and organize extracellular matrix proteins, we have assessed expression of the beta 1 integrins in sequential sections from 85 human renal biopsies and 4 normal kidneys by immunohistochemical staining. Our results demonstrate strong correlations between expression of the alpha 5 chain within the interstitium, the alpha V chain on proximal and distal tubular epithelium and the presence of chronic histological damage. Moreover, staining for interstitial alpha 5 and proximal and distal tubular alpha V were also strongly associated with expression of certain adhesion molecules (ICAM-1, VCAM-1, E-selectin and L-selectin) and the presence of macrophages within the interstitium, which have been linked, in an earlier study, with the degree of chronic histological damage and disease progression. However, in contrast to our earlier study of adhesion molecules, there were also associations between expression of integrin chains within the glomerulus and tubulointerstitium. For example, there were strong positive associations between staining for alpha 5 on glomerular endothelium and its expression on extraglomerular vascular endothelium and between both mesangial alpha 1 and podocyte alpha 3 and tubular staining for the common beta 1 subunit. While the functional significance of these associations is obscure, they suggest some kind of communication between cells in different sites in the kidney. There were also positive associations between staining for different integrins within the glomerulus, notably mesangial cell staining for alpha 2, glomerular endothelial cells staining for alpha 5 and glomerular epithelial cell alpha 3. These results suggest that there is a coordinated upregulation of integrin expression both within the tubulointerstitium and the glomerulus and that at least some of these integrins (interstitial alpha 5 and distal tubular alpha V) are associated with the expression of other adhesion molecules, macrophage infiltration and the presence of markers of disease progression (interstitial fibrosis and tubular atrophy).

Antigens, CD↗
PubMed2006

Derivation of male germ cells from bone marrow stem cells.

Recent studies have demonstrated that somatic stem cells have a more flexible potential than expected, whether put into tissue or cultured under different conditions. Bone marrow (BM)-derived stem cells can transdifferentiate into multilineage cells, such as muscle of mesoderm, lung and liver of endoderm, and brain and skin of ectoderm origin. Here we show that BM stem cells are able to transdifferentiate into male germ cells. For derivation of male germ cells from adult BM stem (BMS) cells, we used the Stra8-enhanced green fluoresence protein (EGFP) transgenic mouse line expressing EGFP specifically in male germ cells. BMS cell-derived germ cells expressed the known molecular markers of primordial germ cells, such as fragilis, stella, Rnf17, Mvh and Oct4; as well as molecular markers of spermatogonial stem cells and spermatogonia including Rbm, c-Kit, Tex18, Stra8, Piwil2, Dazl, Hsp90alpha, beta1- and alpha6-integrins. Our ability to derive male germ cells from BMS cells reveals novel aspects of germ cell development and opens the possibilities for use of these cells in reproductive medicine.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Feeder-free growth of undifferentiated human embryonic stem cells.

Previous studies have shown that maintenance of undifferentiated human embryonic stem (hES) cells requires culture on mouse embryonic fibroblast (MEF) feeders. Here we demonstrate a successful feeder-free hES culture system in which undifferentiated cells can be maintained for at least 130 population doublings. In this system, hES cells are cultured on Matrigel or laminin in medium conditioned by MEF. The hES cells maintained on feeders or off feeders express integrin alpha6 and beta1, which may form a laminin-specific receptor. The hES cell populations in feeder-free conditions maintained a normal karyotype, stable proliferation rate, and high telomerase activity. Similar to cells cultured on feeders, hES cells maintained under feeder-free conditions expressed OCT-4, hTERT, alkaline phosphatase, and surface markers including SSEA-4, Tra 1-60, and Tra 1-81. In addition, hES cells maintained without direct feeder contact formed teratomas in SCID/beige mice and differentiated in vitro into cells from all three germ layers. Thus, the cells retain fundamental characteristics of hES cells in this culture system and are suitable for scaleup production.

Cell Culture Techniques↗
PubMed2002

CNS integrins switch growth factor signalling to promote target-dependent survival.

Depending on the stage of development, a growth factor can mediate cell proliferation, survival or differentiation. The interaction of cell-surface integrins with extracellular matrix ligands can regulate growth factor responses and thus may influence the effect mediated by the growth factor. Here we show, by using mice lacking the alpha(6) integrin receptor for laminins, that myelin-forming oligodendrocytes activate an integrin-regulated switch in survival signalling when they contact axonal laminins. This switch alters survival signalling mediated by neuregulin from dependence on the phosphatidylinositol-3-OH kinase (PI(3)K) pathway to dependence on the mitogen-activated kinase pathway. The consequent enhanced survival provides a mechanism for target-dependent selection during development of the central nervous system. This integrin-regulated switch reverses the capacity of neuregulin to inhibit the differentiation of precursors, thereby explaining how neuregulin subsequently promotes differentiation and survival in myelinating oligodendrocytes. Our results provide a general mechanism by which growth factors can exert apparently contradictory effects at different stages of development in individual cell lineages.

Animals↗
PubMed1995

Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia.

Pyloric atresia associated with junctional epidermolysis bullosa (PA-JEB), is a rare inherited disorder characterized by pyloric stenosis and blistering of the skin as primary manifestations. We demonstrate that in one PA-JEB patient the disease resulted from two distinct mutations in the beta 4 integrin gene alleles. The paternal mutation consists of a one base pair deletion causing a shift in the open reading frame, and a downstream premature termination codon. The maternal mutation occurs in a donor splice site, and results in in-frame exon skipping involving the cytoplasmic domain of the polypeptide. Our results implicate mutations in the beta 4 integrin gene in some forms of PA-JEB.

Alleles↗
PubMed2004

Epidermal and hair follicle progenitor cells express melanoma-associated chondroitin sulfate proteoglycan core protein.

Basal keratinocytes in the epidermis and hair follicle are biologically heterogeneous but must include a stable subpopulation of epidermal stem cells. In animal models these can be identified by their retention of radioactive label due to their slow cycle (label-retaining cells) but human studies largely depend on in vitro characterization of colony forming efficiency and clonogenicity. Differential integrin expression has been used to detect cells of increased proliferative potential but further stem cell markers are urgently required for in vivo and in vitro characterization. Using LHM2, a monoclonal antibody reacting with a high molecular weight melanoma-associated proteoglycan core protein, a subset of basal keratinocytes in both the interfollicular epidermis and the hair follicle has been identified. Coexpression of melanoma-associated chondroitin sulfate proteoglycan with keratins 15 and 19 as well as beta 1 and alpha 6 integrins has been examined in adult and fetal human skin from hair bearing, nonhair bearing, and palmoplantar regions. Although melanoma-associated chondroitin sulfate proteoglycan coexpression with a subset of beta 1 integrin bright basal keratinocytes within the epidermis suggests that melanoma-associated chondroitin sulfate proteoglycan colocalizes with epidermal stem cells, melanoma-associated chondroitin sulfate proteoglycan expression within the hair follicle was more complex and multiple subpopulations of basal outer root sheath keratinocytes are described. These data suggest that epithelial compartmentalization of the outer root sheath is more complex than interfollicular epidermis and further supports the hypothesis that more than one hair follicle stem cell compartment may exist.

Animals↗
PubMed1998

Protein kinase C mediates the signal for interferon-gamma mRNA expression in cytotoxic T cells after their adhesion to laminin.

A cytotoxic T-cell line, CTLL-2 cells, showed spreading after adhering to extracellular matrix proteins such as fibronectin (FN), laminin (LN) and hyarulonic acid (HA). The adhesion of CTLL-2 cells to LN was mediated by very late activation antigen-6 (VLA-6). Expression of interferon-gamma (IFN-gamma) mRNA was enhanced in CTLL-2 cells, also when they adhered to extracellular matrix proteins; and the enhanced IFN-gamma mRNA expression by adhering to LN was blocked by anti-alpha 6 antibody. Calphostin C, a protein kinase C (PKC) inhibitor, markedly inhibited the enhancement of IFN-gamma mRNA expression in a dose-dependent manner, which suggested that PKC acted as a second messenger in the IFN-gamma mRNA expression mediated by the interaction of VLA-6 with LN in CTLL-2 cells. Furthermore, confocal laser-microscopic analysis and Western blot analysis revealed that PKC-alpha was activated after CTLL-2 cells adhered to LN. PKC activity translocated from the cytosol fraction to the particulate fraction, after CTLL-2 cells adhered to LN. Altogether, we suggest that PKC plays an important role in the signal transduction for IFN-gamma mRNA expression after cytotoxic T cells adhere to LN.

Animals↗
PubMed2001

Expression of beta 1 integrins in human dental pulp in vivo: a comparative immunohistochemical study on healthy and chronic marginal periodontitis samples.

AIM: The objective of this study was to determine the tissue distribution of beta 1 integrin chains in sound human dental pulps and to compare the findings with connective tissue compartments of other organs and to pulp tissue in teeth extracted due to periodontal disease. METHODOLOGY: Freshly frozen pulp tissue samples from teeth extracted for orthodontic reasons were examined and compared to samples from teeth extracted due to chronic (marginal) periodontitis. beta 1 integrin chains were determined using an indirect-immunoperoxidase technique. Seven monoclonal antibodies recognizing alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, alpha 6 and beta 1 chains of Very Late Activation Antigen (VLA) integrins were used for this purpose. RESULTS: VLA-1, VLA-2, VLA-3 and VLA-5 were expressed by vascular endothelium and vascular smooth muscle in varying intensities in both groups. VLA-6 reactivity was observed in the basal surfaces of arterial, venous and capillary endothelia. Our results indicate that there was no significant difference in the expression of VLA integrins in sound pulp tissue when compared to the samples from chronic (marginal) periodontitis and the connective tissue compartments of other viscera. CONCLUSION: The present findings suggest that human dental pulp tissue is not different from other connective tissue compartments in the body with respect to VLA integrin expression, and chronic marginal periodontitis does not affect pulp tissue to a histopathologically detectable extent.

Antibodies, Monoclonal↗
PubMed1999

Expression of the integrin subunits alpha 5, alpha 6 and beta 1 in the testes of the common marmoset.

Integrin subunits alpha 5, alpha 6 and beta 1 were localized in the testis of pre-pubertal or adult non-human primates (Callithrix jacchus) by immunofluorescence staining and in situ hybridization. In animals of all ages subunits alpha 5 and beta 1 were localized in cells of the lamina propria of the seminiferous epithelium. In prepubertal animals, the integrin subunits alpha 5, alpha 6, as well as beta 1, were distributed all over the plasma membrane of Sertoli cells. In adult animals the integrin subunits were confined to those plasma membrane regions of Sertoli cells which are assigned to the basal compartment, including the basement membrane of the seminiferous tubules. Protein expression of integrin subunits alpha 6 and beta 1 was most pronounced in tubular stages in which elongated spermatids were not yet present in the adluminal compartment of the epithelium, suggesting that these integrin subunits are particularly essential at certain developmental stages of spermatogenesis. Non-radioactive in situ hybridization revealed that the mRNA for integrin subunits alpha 5, alpha 6 and beta 1 was expressed by Sertoli cells. In situ hybridization, together with immunofluorescence data, shows that these integrin subunits were exclusively synthesized in Sertoli cells. As to functional aspects, it is concluded that during primate spermatogenesis. Sertoli cell integrins may be involved in both cell matrix as well as cell-cell interactions, particularly during early spermatogenesis.

Animals↗
PubMed2001

Segmentation of nuclei and cells using membrane related protein markers.

Segmenting individual cell nuclei from microscope images normally involves volume labelling of the nuclei with a DNA stain. However, this method often fails when the nuclei are tightly clustered in the tissue, because there is little evidence from the images on where the borders of the nuclei are. In this paper we present a method which solves this limitation and furthermore enables segmentation of whole cells. Instead of using volume stains, we used stains that specifically label the surface of nuclei or cells: lamins for the nuclear envelope and alpha-6 or beta-1 integrins for the cellular surface. The segmentation is performed by identifying unique seeds for each nucleus/cell and expanding the boundaries of the seeds until they reach the limits of the nucleus/cell, as delimited by the lamin or integrin staining, using gradient-curvature flow techniques. We tested the algorithm using computer-generated objects to evaluate its robustness against noise and applied it to cells in culture and to tissue specimens. In all the cases that we present the algorithm gave accurate results.

Algorithms↗
PubMed1997

Expression of integrins during axolotl limb regeneration.

Limb regeneration in urodeles is achieved through the dedifferentiation of tissues at the amputation plane and through the production of the blastema. This tissue breakdown is possible by extensive alterations in molecules of the extracellular matrix. In this respect we describe the regulation of several integrins during such events. It was found that alpha 1 and beta 1 integrins were down-regulated as blastema formation proceeded. In contrast, the expression of alpha 3, alpha 6 and alpha v integrins were upregulated in the blastema. These data are consistent with the roles of integrins in developmental phenomena and are discussed in light of the mechanisms of dedifferentiation.

Ambystoma↗
PubMed2003

Interleukin-6 enhances whereas tumor necrosis factor alpha and interferons inhibit integrin expression and adhesion of human mast cells to extracellular matrix proteins.

Integrins are expressed on mast cells and constitute an essential prerequisite for the accumulation of the cells at sites of inflammation. In order to clarify a potential contribution of inflammatory cytokines to this process, we have studied the modulation of integrin expression and adhesion of immature human mast cells (HMC-1) to extracellular matrix proteins by interleukin-6, tumor necrosis factor alpha, interferon-alpha and interferon-gamma. Corticosteroids were used for comparison. On fluorescence-activated cell sorter analysis, preincubation of cells for 48 h with different concentrations of interleukin-6 induced a significant, up to 40%, increase of alpha v alpha 5, CD49b (alpha 2), CD49e (alpha 5), CD49f (alpha 6), and CD51 (alpha v). In contrast, different concentrations of tumor necrosis factor alpha, interferon-alpha, interferon-gamma, and dexamethasone (10-8-10-10 M) inhibited expression of adhesion receptors by up to 60%, reaching significance for some but not all integrins. On semiquantitative polymerase chain reaction analysis, interleukin-6, the other cytokines, and corticosteroids significantly modulated expression of alpha1, alpha v and alpha 5 integrin chains at mRNA level. Functional significance of these findings was proven in adhesion assays using fibronectin, laminin, and vitronectin, with interleukin-6 causing significant enhancement of adhesion in all cases, tumor necrosis factor alpha and dexamethasone inducing significant reduction of adhesion to fibronectin and laminin, and interferon-gamma significantly inhibiting adhesion to fibronectin only. Specificity of interleukin-6-induced changes was demonstrated using antibodies against alpha1 and alpha 5 integrins in unstimulated and interleukin-6-prestimulated cells. These data show that interleukin-6 stimulates mast cell adhesion to extracellular matrix and thus allows for the accumulation of the cells at tissue sites by enhancing integrin expression, whereas tumor necrosis factor alpha, interferon-alpha, interferon-gamma, and dexamethasone downmodulate this process.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Mesenchymal-epithelial interactions regulate gene expression of type VII collagen and kalinin in keratinocytes and dermal-epidermal junction formation in a skin equivalent model.

Anchoring fibrils constituted primarily of type VII collagen and anchoring filaments composed of kalinin are essential structural elements of the dermal-epidermal junction and critical for its stability. The role of fibroblasts in the production of these structural elements and the formation of the dermal-epidermal junction was studied by using a living skin equivalent model. This model had been modified such that keratinocytes and fibroblasts were allowed direct contact. After 2 weeks, immunohistochemical studies showed the linear deposition of type VII collagen and kalinin, as well as type IV collagen and alpha6 integrin at the dermal-epidermal junction. By electron microscopy, anchoring fibrils, a continuous lamina densa, and numerous hemidesmosomes were noted. Reverse transcriptase-polymerase chain reaction analysis showed an increased expression of both type VII collagen and kalinin genes in keratinocytes when they were in direct contact with fibroblasts. These results suggest that fibroblasts synthesize an extracellular matrix which favors keratinocyte adhesion and the formation of a dermal-epidermal junction by increasing the production and the further arrangement of dermal-epidermal junction components.

Journal Article↗
PubMedDate not supplied

Fibroblast subpopulations in intra-oral wound healing.

The objective of this study was to characterize fibroblasts at sequential time points during intra-oral wound healing in the rat. Experimental wounds were made at several time points in the mucoperiosteum of the palate of 35-day-old Wistar rats. Fibroblasts were cultured from the biopsies under standard conditions for the same number of passages. The expression of the integrin subunits alpha 1, alpha 6, and beta 1; and the intermediate filaments alpha-smooth muscle actin and vimentin were analyzed by flow cytometry. Western blot analysis was performed at 0, 8, and 60 days postwounding to confirm the expression of both intermediate filaments. The phenotypic profiles of fibroblasts cultured from subsequent stages in the wound healing process differed considerably. We conclude that distinct fibroblast phenotypes can be isolated from different stages in wound healing. These phenotypes remained stable during in vitro culturing. In addition, cryosections of the wound areas were made at identical time points and were immunohistochemically stained for the same antigens. The immunohistochemical staining correlated well to the flow-cytometric data. These results suggest the occurrence of multiple subpopulations of fibroblasts with a specialized function during wound healing. We hypothesize that undesirable consequences of wound healing might be prevented through the modulation of specific fibroblast subpopulations.

Animals↗