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PubMed2006

Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1.

Myc plays a key role in homeostasis of the skin. We show that Miz1, which mediates Myc repression of gene expression, is expressed in the epidermal basal layer. A large percentage of genes regulated by the Myc-Miz1 complex in keratinocytes encode proteins involved in cell adhesion, and some, including the alpha6 and beta1 integrins, are directly bound by Myc and Miz1 in vivo. Using a Myc mutant deficient in Miz1 binding (MycV394D), we show that Miz1 is required for the effects of Myc on keratinocyte responsiveness to TGF-beta. Myc, but not MycV394D, decreases keratinocyte adhesion and spreading. In reconstituted epidermis, Myc induces differentiation and loss of cell polarization in a Miz1-dependent manner. In vivo, overexpression of beta1 integrins restores basal layer polarity and prevents Myc-induced premature differentiation. Our data show that regulation of cell adhesion is a major function of the Myc-Miz1 complex and suggest that it may contribute to Myc-induced exit from the epidermal stem cell compartment.

Animals↗
PubMed1998

Physical limitations on Salmonella typhi entry into cultured human intestinal epithelial cells.

Kinetic studies of Salmonella typhi invasion of INT407 cells at different multiplicities of infection (MOIs) have revealed a strict physical limitation on S. typhi entry at MOIs of >/=40. Staining of infected monolayers to distinguish intracellular from extracellular bacteria revealed that all monolayer cells are susceptible to infection and that internalized bacteria are typically contained in one to three separate clusters per cell during the first 60 min. Scanning and transmission electron microscopic analyses of time course-infected monolayers showed that at early times postinfection, bacteria bind to shortened, coalesced microvilli in one to three focal aggregate structures per host cell surface. As reported previously for S. typhimurium, focal aggregates progress to conical membrane ruffles that appear to engulf one or a few centrally contained S. typhi cells by a macropinocytic process, which enhanced the entry of simultaneously added Escherichia coli HB101 about 30-fold. Additionally, kinetic studies showed that at an MOI of approximately 400, maximal S. typhi entry is virtually completed within 30 to 35 min. Monolayers pretreated with S. typhi for 30 min to saturate the entry process were severely reduced in the ability to internalize subsequently added kanamycin-resistant strains of S. typhi or S. typhimurium, but E. coli HB101(pRI203) expressing the cloned Yersinia inv gene was not reduced in entry. In invasion inhibition assays, anti-beta1 integrin antibodies markedly reduced E. coli HB101(pRI203) invasion efficiency but did not reduce S. typhi entry. Collectively, these data provide direct physical and visual evidence which indicates that S. typhi organisms are internalized at a limited number (i.e., two to four) of sites on host cells. S. typhi and S. typhimurium likely share INT407 cell entry receptors which do not appear to be members of the beta1 integrin superfamily.

Binding, Competitive↗
PubMed2006

Case report: Avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide.

INTRODUCTION: Recent evidence suggests that blocking inducible nitric oxide (NO) synthase in the penis may exacerbate fibrotic processes and that application of medications known to increase NO in tissues may prevent fibrosis. AIM: To report the use of an antifibrotic regimen consisting of medications known to upregulate NO production in two patients with refractory priapism. METHODS: Two patients presented with priapism of greater than 48-hour duration. After corporal aspiration/irrigation and shunting procedures failed, both were prescribed a daily antifibrotic regimen comprising the phosphodiesterase inhibitors pentoxifylline and sildenafil, and the NO precursor, L-arginine. RESULTS: At 1 year, both patients were found to have supple corpora without evidence of corporal fibrosis. CONCLUSIONS: An antifibrotic regimen consisting of upregulators of NO production may ameliorate the corporal fibrosis associated with recalcitrant priapism.

Arginine↗
PubMed2005

Phenotypic changes induced by expression of beta-galactoside alpha2,6 sialyltransferase I in the human colon cancer cell line SW948.

Beta-galactoside alpha2,6 sialyltransferase (ST6Gal.I), the enzyme which adds sialic acid in alpha2,6-linkage on lactosaminic termini of glycoproteins, is frequently overexpressed in cancer, but its relationship with malignancy remains unclear. In this study, we have investigated the phenotypic changes induced by the expression of alpha2,6-sialylated lactosaminic chains in the human colon cancer cell line SW948 which was originally devoid of ST6Gal.I. Clones derived from transfection with the ST6Gal.I cDNA were compared with untransfected cells and mock transfectants. The ST6Gal.I-expressing clones show (1) increased adherence to fibronectin and collagen IV but not to hyaluronic acid. Treatment with Clostridium perfrigens neuraminidase reduces the binding to fibronectin and collagen IV of ST6Gal.I-expressing cells but not that of ST6Gal.I-negative cells; (2) accumulation and more focal distribution of beta1 integrins on the cell surface; (3) different distribution of actin fibers; (4) flatter morphology and reduced tendency to multilayer growth; (5) improved ability to heal a scratch wound; (6) reduced ability to grow at the subcutaneous site of injection in nude mice. Our data suggest that the presence of alpha2,6-linked sialic acid on membrane glycoconjugates increases the binding to extracellular matrix components, resulting in a membrane stabilization of beta1 integrins, further strengthening the binding. This mechanism can provide a basis for the flatter morphology and the reduced tendency to multilayer growth, resulting in a more ordered tissue organization. These data indicate that in the cell line SW948, the effect of ST6Gal.I expression is consistent with the attenuation of the neoplastic phenotype.

Antigens, CD↗
PubMed2001

Smooth muscle length-dependent PI(4,5)P2 synthesis and paxillin tyrosine phosphorylation.

We studied effects of increasing the length of porcine trachealis muscle on 5.5 microM carbachol (CCh)-evoked phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] synthesis and other parameters of phosphatidylinositol (PI) turnover. PI(4,5)P2 resynthesis rates in muscle held at 1.0 optimal length (L(o)), measured over the first 6 min of CCh stimulation, were 140 +/- 12 and 227 +/- 14% of values found in muscle held at 0.5 L(o) and in free-floating muscle, respectively. Time-dependent changes in cellular masses of PI(4,5)P2, PI, and phosphatidic acid, and PI resynthesis rates, were also altered by the muscle length at which contraction occurred. In free-floating muscle, CCh did not evoke increases in tyrosine-phosphorylated paxillin (PTyr-paxillin), an index of beta1-integrin signaling; however, there were progressive increases in PTyr-paxillin in muscle held at 0.5 and 1.0 L(o) during contraction, which correlated with increases in PI(4,5)P2 synthesis rates. These data indicate that PI(4,5)P2 synthesis rates and other parameters of CCh-stimulated inositol phospholipid turnover are muscle length-dependent and provide evidence that supports the hypothesis that length-dependent beta1-integrin signals may exert control on CCh-activated PI(4,5)P2 synthesis.

Animals↗
PubMed2006

[Regulatory effect of integrin alpha5 and beta1 on proliferation inhibition of K562 cells induced by interferon alpha-2b].

BACKGROUND & OBJECTIVE: Integrin beta1 can inhibit the proliferation of chronic myelocytic leukemia (CML) ph+ cells. The dysfunction of integrin beta1 might accelerate the growth of CML ph+ cells. This study was to explore the effects of integrin alpha5 and beta1 on the proliferation inhibition of K562 cells induced by IFNalpha-2b. METHODS: The expression indexes of integrin alpha5 and beta1 on K562 cells, the binding capability of K562 cells to fibronectin (FN), and K562 cell-FN binding blocking induced by integrin alpha5 and beta1 antibodies were evaluated by flow cytometry (FCM). The viability of K562 cells, treated with IFNalpha-2b (10,000 u/ml), was observed by MTT assay. The mRNA level of focal adhesion kinase (FAK) in K562 cells was detected by reverse transcription-polymerase chain reaction (RT-PCR) 48 h after treatment of interferon alpha-2b (IFNalpha-2b). RESULTS: The positive rates of integrin alpha5 and beta1 were significantly higher on K562 cells than on bone marrow mononuclear cells from healthy donors [(97.59+/-1.04)% vs. (64.05+/-2.38)%, (99.24+/-0.52)% vs. (72.40+/-3.56)%, P<0.05). IFNalpha-2b could not change the expression of integrin alpha5 and beta1 on K562 cells, but improved the binding capability of K562 cells to FN, which could be blocked by anti-alpha5 and/or anti-beta1 antibodies. IFNalpha-2b enhanced the expression of FAK gene, and inhibited the proliferation of K562 cells. The anti-alpha5 and anti-beta1 antibodies improved the inhibitory effect of IFNalpha-2b on the proliferation of K562 cells, and blocked IFNalpha-2b-induced increase of FAK gene expression. CONCLUSION: IFNalpha-2b could inhibit the proliferation of K562 cells through restoring the function of integrin alpha5 and beta1, enhancing binding capability of integrin alpha5 and beta1 to FN, and up-regulating FAK gene expression.

Antibodies↗
PubMed2004

A fibronectin fragment induces tumor necrosis factor production of rat basophilic leukemia cells.

Proteolytic digest of fibronectin (FN), but not intact FN, induced TNF-alpha secretion of rat basophilic leukemia (RBL-2H3) cells. As a result of the identification of FN fragment responsible for TNF-alpha secretion, a 30-kDa fragment derived from the carboxyl-terminal heparin-binding (Hep 2) domain of FN was isolated from the FN digest. The TNF-alpha secretion was abrogated by treatment of RBL-2H3 cells with cycloheximide, indicating the de novo synthesis of TNF-alpha, but not with polymyxin B, excluding the possible TNF-alpha induction by some contaminated lipopolysaccharides. A 22-mer synthetic peptide originated from the Hep 2 domain, termed FNIII14, which has been found to negatively modulate the beta1 integrin activation, had the ability to induce TNF-alpha production, whereas this activity of FNIII14 disappeared by shuffling a YTIYVIAL sequence essential for the integrin-inactivating activity. FNIII14 suppressed the spreading of RBL-2H3 cells on FN substrate, wherein RBL-2H3 cell proliferation was inhibited with FNIII14 in a dose-dependent manner. Thus, it appears that FN fragments containing the YTIYVIAL anti-adhesive site affect the activation status of RBL-2H3 mast cells, characterized by the stimulation of TNF-alpha production and growth suppression, probably due to negative regulation of beta1 integrin activity.

Animals↗
PubMed2006

Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R.

Apoptosis and proliferation are important causes of adverse health effects induced by inhaled ultrafine particles. The molecular mechanisms of particle cell interactions mediating these end points are therefore a major topic of current particle toxicology and molecular preventive medicine. Initial studies revealed that ultrafine particles induce apoptosis and proliferation in parallel in rat lung epithelial cells, dependent on time and dosage. With these end points, two antagonistic reactions seem to be induced by the same extracellular stimulus. It was therefore investigated whether proliferation is induced directly by the particles or as a compensation of particle-caused cell death. Experimental conditions excluding compensatory proliferation demonstrated that both end points are induced independently by specific signaling pathways. Events eliciting signaling cascades leading to apoptosis and proliferation were studied with specific inhibitors of membrane receptors. Epidermal growth factor receptor (EGF-R) kinase activity was identified as essential for apoptosis as well as for proliferation. As ultrafine particle-induced proliferation alone was dependent on the activation of beta1-integrins, these membrane receptors are suggested to mediate the specificity of EGF-R signaling concerning the decision as to whether apoptosis or proliferation is triggered. Accordingly, MAP kinase signaling downstream of EGF-R showed comparable specificity with regard to receptor-dependent induction of apoptosis and proliferation. As key mediators of signaling cascades, the activation of extracellular signal-regulated kinases 1 and 2 proved to be specific for proliferation in a beta1-integrin-dependent manner, whereas phosphorylation of c-Jun NH2-terminal kinases 1 and 2 was correlated with the induction of apoptosis.

Animals↗
PubMed1998

beta1D integrin inhibits cell cycle progression in normal myoblasts and fibroblasts.

Integrins are alphabeta heterodimeric transmembrane receptors involved in the regulation of cell growth and differentiation. The beta1 integrin subunit is widely expressed in vivo and is represented by four alternatively spliced cytoplasmic domain isoforms. beta1D is a muscle-specific variant of beta1 integrin and a predominant beta1 isoform in striated muscles. In the present study we showed that expression of the exogenous beta1D integrin in C2C12 myoblasts and NIH 3T3 or REF 52 fibroblasts inhibited cell proliferation. Unlike the case of the common beta1A isoform, adhesion of beta1D-transfected C2C12 myoblasts specifically via the expressed integrin did not activate mitogen-activated protein kinases. The beta1D-induced growth inhibitory signal was shown to occur late in the G1 phase of the cell cycle, before the G1-S transition. Ha-(12R)Ras, but not (Delta22W)Raf-1 oncogene, was able to overcome completely the beta1D-triggered cell growth arrest in NIH 3T3 fibroblasts. Since perturbation of the beta1D amino acid sequence in beta1A/beta1D chimeric integrins decreased the growth inhibitory signal, the entire cytoplasmic domain of beta1D appeared to be important for this function. However, an interleukin-2 receptor-beta1D chimera containing the cytoplasmic domain of beta1D still efficiently inhibited cell growth, showing that the ectodomain and the ligand-binding site in beta1D were not required for the growth inhibitory signal. Together, our data showed a new specific function for the alternatively spliced beta1D integrin isoform. Since the onset of beta1D expression during myodifferentiation coincides with the timing of myoblast withdrawal from the cell cycle, the growth inhibitory properties of beta1D demonstrated in this study might reflect the major function for this integrin in commitment of differentiating skeletal muscle cells in vivo.

Alternative Splicing↗
PubMed2003

Atomic force microscopy measurement of leukocyte-endothelial interaction.

Leukocyte adhesion to vascular endothelium is a key initiating step in the pathogenesis of many inflammatory diseases. In this study, we present real-time force measurements of the interaction between monocytic human promyelocytic leukemia cells (HL-60) cells and a monolayer of human umbilical vein endothelial cells (HUVECs) by using atomic force microscopy (AFM). The detachment of HL-60-HUVEC conjugates involved a series of rupture events with force transitions of 40-100 pN. The integrated force of these rupture events provided a quantitative measure of the adhesion strength on a whole cell level. The AFM measurements revealed that HL-60 adhesion is heightened in the borders formed by adjacent HUVECs. The average force and mechanical work required to detach a single HL-60 from the borders of a tumor necrosis factor-alpha-activated HUVEC layer were twice as high as those of the HUVEC bodies. HL-60 adhesion to the monolayer was significantly reduced by a monoclonal antibody against beta1-integrins and partially inhibited by antibodies against selectins ICAM-1 and VCAM-1 but was not affected by anti-alphaVbeta3. Interestingly, adhesion was also inhibited in a dose-dependent manner (IC50 approximately 100 nM) by a cyclic arginine-glycine-aspartic acid (cRGD) peptide. This effect was mediated via interfering with the VLA-4-VCAM-1 binding. In parallel measurements, transmigration of HL-60 cells across a confluent HUVEC monolayer was inhibited by the cRGD peptide and by both anti-beta1 and anti-alphaVbeta3 antibodies. In conclusion, these data demonstrate the role played by beta1-integrins in leukocyte-endothelial adhesion and transmigration and the role played by alphaVbeta3 in transmigration, thus underscoring the high efficacy of cRGD peptide in blocking both the adhesion and transmigration of monocytes.

Antibodies↗
PubMed2003

Integrin-mediated suppression of endotoxin-induced DNA damage in lung endothelial cells is sensitive to poly(ADP-ribose) polymerase-1 gene deletion.

Endotoxin (LPS) is a cause of adult respiratory distress syndrome (ARDS), a disease which is preceded by acute lung injury involving the pulmonary endothelium. Experimentally, LPS causes acute DNA strand breakage in mouse lung endothelial cells (MLEC). Engagement of integrin cell adhesion receptors inhibits acute DNA breakage, which could be of use in reducing lung injury. Because integrins presumably inhibit DNA damage or activate repair, we hypothesized that the DNA-damage response protein, poly(ADP-ribose) polymerase-1 (PARP-1), regulates the protective action of integrins, as well as sensitivity to LPS. Therefore, the effect of LPS on MLEC cultured from wild-type and PARP-1 knockout mice was determined. Fluorescence microscopic measures were used to assess plasma membrane integrity, PARP activity, DNA strand breakage and DNA repair in attached cells. LPS caused a concentration-dependent increase in the permeability of wild-type MLEC. Engagement of beta1 integrins with an antibody protected wild-type MLEC from this LPS-induced injury. Wild-type cells treated with the PARP-inhibitor, 3-aminobenzamide, and PARP-1 knockout MLEC were also resistant. LPS caused acute DNA breakage in both wild-type and knockout MLEC, but PARP was activated only in wild-type cells. LPS-induced DNA breakage was inhibited by 3-aminobenzamide, but not by knockout. Anti-beta1 integrin antibody also inhibited the DNA breakage and PARP activation caused by LPS in wild-type MLEC. However, integrin engagement did not prevent DNA breakage in PARP-1 knockout cells, despite a similar level of beta1 integrin in wild-type and knockout cells. Thus, integrin engagement, 3-aminobenzamide, and PARP-1 deletion protected MLEC from increases in membrane permeability caused by LPS. PARP-1 deletion also impaired the ability of integrin engagement to inhibit LPS-induced DNA breakage, suggesting that knockout may affect nuclear factors necessary for integrin-mediated suppression of LPS-induced DNA breakage.

Animals↗
PubMed2000

Tetraspanins are localized at motility-related structures and involved in normal human keratinocyte wound healing migration.

We have described previously that beta1 integrins, which mediate keratinocyte cell adhesion and migration, are in ligand-occupied conformation at the basal surface but not at the lateral and apical surfaces of keratinocytes. This led us to study the cellular localization and function of tetraspanin molecules, which have been postulated to modulate integrin activity. We found that CD9 and CD81 are highly expressed by keratinocytes clearly delineating filopodia at lateral and apical surfaces. CD63 and CD151 are largely expressed in the intracellular compartment, although some membrane expression is observed. We found accumulation of CD9, CD81, and CD151 together with alpha3 and beta1 integrins at intercellular junctions. In low calcium medium, this intercellular space is crossed by a zipper of filopodia enriched in alpha3beta1 and tetraspanin proteins. Interestingly, the expression of CD9, CD81, and beta1 and alpha3 integrins was detected in the footprints and rippings of motile keratinocytes, suggesting their role in both adhesion to extracellular matrix and keratinocyte motility. beta1 integrins were only partially activated in the rips, whereas cytoskeleton-linking proteins such as talin were completely absent. On the other hand, antitetraspanin antibodies did not stain focal adhesions, which contain talin. The involvement of tetraspanins in keratinocyte motility was assessed in a wound healing migration assay. Inhibition of cell migration was observed with antibodies to CD9, CD81, beta1, and alpha3, and, to a lesser extent, to CD151. Together these results indicate that tetraspanin-integrin complexes might be involved in transient adhesion and integrin recycling during keratinocyte migration, as well as in intercellular recognition.

Antigens, CD↗
PubMed2003

[In vitro culture of murine fetal epidermal stem cell and its relationship with the regeneration of follicle].

OBJECTIVE: To isolate and culture the murine fetal epidermal stem cells (ESCs) and folliculus pili cells (FPCs) in vitro, and to observe the regeneration of hair follicle and epidermis after cografting of ESCs and FPCs. METHODS: The ESCs were isolated by adhering to murine type IV collagen and were cultured in conditional medium. The expression level of beta1-integrin and keratin 15 in ESCs was detected. At the same time, the cell cycle and clony forming eficiency (CFE) in ESCs were also determined. The FPCs were isolated and cultured and inoculated in fibrin-gel to form FPCs-gel. A full skin equivalent was prepared by combining ESCs with FPCs-gel and was grafted onto total skin loss wounds on the back of BALB/C nude mice. The histological changes of the wounds and the hair follicles were observed at 8 - 10 weeks after the grafting. RESULTS: There were high level expressions of beta1-integrin and keratin 15 in murine fetal ESCs. It was indicated by cell cycle analysis that cells in G1 stage accounted for 94.9% of the cells, while that in S stage, 3.5%, suggesting slow cell cycle. Nevertheless, the keratinocytes in G1 stage accounted for 74.1% and that in S stage, 17.5% of cells in control group. The CFE of ESCs was 15.3%, and it was much higher than that in control group (6.7%). The newly formed hair follicles could be found in the grafted rats but not in the control group 8 - 10 weeks after the wound healing in nude rats. CONCLUSION: The ESCs could be successfully isolated and cultured in vitro and might participate in the formation of hair follicle structure under the induction of FPCs.

Animals↗
PubMed2002

Extracellular matrix regulation of drug resistance in small-cell lung cancer.

Tumour recurrence following chemotherapy remains a major obstacle to the cure of many cancers. This is exemplified by small-cell lung cancer (SCLC). Host-tumour interactions are central to tumour survival and proliferation. We hypothesized that a factor(s) within the local environment of SCLC cells could provide a survival signal or block a death signal, thereby accounting for the protection of SCLC cells from chemotherapy-induced apoptosis. Here we review recent work undertaken in our laboratory addressing this issue. We have shown that, in vivo, SCLC cells are surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites which contains, among other proteins, fibronectin, laminin and collagen IV. Furthermore, adhesion of SCLC cells to fibronectin, laminin and collagen IV through beta1 integrins enhances tumorigenicity and confers resistance to apoptosis induced by standard chemotherapeutic agents, including etoposide, cis-platinum and adriamycin. Adhesion to ECM proteins stimulated protein tyrosine kinase (PTK) activity in both untreated and etoposide-treated cells. This effect could be completely blocked by a selective PTK inhibitor or by a function-blocking beta1 integrin antibody. PTK activation was found to block chemotherapy-induced activation of the death protease caspase-3 and, hence, apoptosis. Adhesion to ECM or treatment with a PTK inhibitor did not affect etoposide inhibition of topoisomerase II. Thus adhesion to ECM through beta1 integrins protects SCLC cells from chemotherapy-induced caspase-3 activation and apoptosis by activating PTK signalling downstream of DNA damage. Survival of tumour cells attached to ECM within this microenvironment could explain the local recurrence of SCLC and other tumours that is often seen clinically after chemotherapy.

Antineoplastic Agents↗
PubMed2003

A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells.

We have reported previously that levels of lysophosphatidic acid (LPA) are elevated in the blood and ascites from patients with ovarian cancer. LPA stimulates proliferation of ovarian cancer cells and has been proposed as an autocrine growth factor. Here, we show that a novel autocrine loop of LPA promotes the migration of ovarian cancer cells, which is a critical step of tumor metastasis. We report that laminin, but not other extracellular matrix proteins, induces LPA production in ovarian cancer cells. A neutralizing antibody against beta1 integrin and a calcium-independent phospholipase A2-specific inhibitor, HELSS, block both LPA production and the haptotactic activity of laminin. Exogenously added LPA restores the migratory ability of HEY ovarian cancer cells to laminin. These data suggest that laminin-induced cell migration is mediated by LPA. We further show that a specific receptor for LPA, LPA3, is required for mediating the chemotactic activity of LPA. In addition, we show that cytosolic PLA2 is required for cell migration and its activation is phosphatidylinositol-3 kinase-dependent. These findings have revealed a new mechanism of crosstalk between a beta1 integrin receptor and a G protein-coupled receptor.

Autocrine Communication↗
PubMed1998

Influence of extracellular matrix proteins on the development of cultured human dendritic cells.

The development of dendritic cells (DC) is still only partly understood. Recently established culture systems using CD34+ cells or monocytes as precursor cells for the generation of DC indicate the necessity of pro-inflammatory cytokines for their development. In vivo the contact to other cells or to the proteins of the extracellular matrix might also be essential for their development. In our experiments we used granulocyte-macrophage colony-stimulating factor- and IL-4-treated human monocytes as precursor cells to investigate the interaction of DC at different maturation stages with the matrix proteins fibronectin, collagen type I and collagen type IV. We demonstrate a strong beta1-integrin-mediated adherence of immature DC to fibronectin that is lost completely during maturation. The binding to collagen type I was less strong but induced a maturation of the precursor cells. After 3 days of culture on this protein, the cells showed all features of fully matured DC such as expression of CD83 and an excellent allostimulatory capacity. The reason for this effect was shown to be the induction of TNF-alpha production by the DC themselves. In contrast to the adhesion to fibronectin, the maturation and the cytokine production of DC induced by collagen type I could not be inhibited by blocking of beta1-integrins. These results indicate that proteins of the extracellular matrix play an important role in the development and function of human DC.

Antigens, Surface↗
PubMed2002

[Study on the relationship between epidermal stem cells and the developing process of sweat gland in human fetal skin].

OBJECTIVE: To explore the relationship between epidermal stem cells and the developing process of sweat gland in human fetal skin, so as to obtain a hint for future induction of epidermal stem cells to differentiate into sweat gland cells. METHODS: Total layer of human skin from the back of fetus at gestational ages from 11 to 31 weeks, obtained from spontaneous abortion was routinely examined. The expressions of beta1 integrin and keratin 19 in sweat gland cords or buds and mature sweat gland cells were dynamically observed with SP immunohistochemical technique. The development and maturation of sweat gland were identified by the positive staining of keratin 8 with immunohistochemistry. RESULTS: It was revealed by histologic observation that basal layer cells of the primary epidermal ridge exhibited focal aggregation and formed hillocks at 16 gestational weeks. The hillocks of cells then migrated downward as cords into the dermis during 18 - 20 gestational weeks. Then, the end part of the cell cord developed into a round lump of twining cords assuming the mature sweat gland. The expressions of beta1 integrin and keratin 19 were found not only in sweat gland cords and buds but also in the mature cells and lasted throughout the total period of sweat gland development. The expression of keratin 8 in sweat gland buds started since 14 - 16 gestational weeks and maintained thereafter. CONCLUSION: The sweat gland started to develop during 14 - 16 gestational weeks and matured at 24 weeks. During the development process of sweat gland, epidermal stem cells were considered to be the key source.

Aborted Fetus↗
PubMed1998

Disruption of the talin gene compromises focal adhesion assembly in undifferentiated but not differentiated embryonic stem cells.

We have used gene disruption to isolate two talin (-/-) ES cell mutants that contain no intact talin. The undifferentiated cells (a) were unable to spread on gelatin or laminin and grew as rounded colonies, although they were able to spread on fibronectin (b) showed reduced adhesion to laminin, but not fibronectin (c) expressed much reduced levels of beta1 integrin, although levels of alpha5 and alphaV were wild-type (d) were less polarized with increased membrane protrusions compared with a vinculin (-/-) ES cell mutant (e) were unable to assemble vinculin or paxillin-containing focal adhesions or actin stress fibers on fibronectin, whereas vinculin (-/-) ES cells were able to assemble talin-containing focal adhesions. Both talin (-/-) ES cell mutants formed embryoid bodies, but differentiation was restricted to two morphologically distinct cell types. Interestingly, these differentiated talin (-/-) ES cells were able to spread and form focal adhesion-like structures containing vinculin and paxillin on fibronectin. Moreover, the levels of the beta1 integrin subunit were comparable to those in wild-type ES cells. We conclude that talin is essential for beta1 integrin expression and focal adhesion assembly in undifferentiated ES cells, but that a subset of differentiated cells are talin independent for both characteristics.

Actins↗