Browsing by Subject "Cell adhesion molecules"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Cadherin-7 function in zebrafish development
    (Springer, 2008-10) Liu, Qin; Marrs, James A.; Londraville, Richard L.; Wilson, Amy L.; Department of Medicine, IU School of Medicine
    Cadherin cell adhesion molecules play crucial roles in vertebrate development. Most studies have focused on examining the functions of classical type I cadherins (e.g., cadherin-2) in the development of vertebrates. Little information is available concerning the function of classical type II cadherins (e.g., cadherin-7) in vertebrate development. We have previously shown that cadherin-7 mRNA exhibits a dynamic expression pattern in the central nervous system and notochord in embryonic zebrafish. To gain insight into the role of cadherin-7 in the formation of these structures, we analyzed their formation in zebrafish embryos injected with cadherin-7-specific antisense morpholino oligonucleotides (MO). Notochord development was severely disrupted in MO-injected embryos, whereas gross defects in the development of the central nervous system were not detected in MO-injected embryos. Our results thus demonstrate that cadherin-7 plays an important role in the normal development of the zebrafish notochord.
  • Thumbnail Image
    Item
    Heat shock protein 90, a potential biomarker for type I diabetes: mechanisms of release from pancreatic beta cells
    (2016-05-23) Ocaña, Gail Jean; Blum, Janice Sherry, 1957-; Kaplan, Mark H.; Serezani, C. Henrique; Sun, Jie
    Heat shock protein (HSP) 90 is a molecular chaperone that regulates diverse cellular processes by facilitating activities of various protein clients. Recent studies have shown serum levels of the alpha cytoplasmic HSP90 isoform are elevated in newly diagnosed type I diabetic patients, thus distinguishing this protein as a potential biomarker for pre-clinical type I diabetes mellitus (TIDM). This phase of disease is known to be associated with various forms of beta cell stress, including endoplasmic reticulum stress, insulitis, and hyperglycemia. Therefore, to test the hypothesis that HSP90 is released by these cells in response to stress, human pancreatic beta cells were subjected to various forms of stress in vitro. Beta cells released HSP90 in response to stimulation with a combination of cytokines that included IL-1β, TNF-α, and IFN-γ, as well as an agonist of toll-like receptor 3. HSP90 release was not found to result from cellular increases in HSP90AA1 gene or HSP90 protein expression levels. Rather, cell stress and ensuing cytotoxicity mediated by c-Jun N-terminal kinase (JNK) appeared to play a role in HSP90 release. Beta cell HSP90 release was attenuated by pre-treatment with tauroursodeoxycholic acid (TUDCA), which has been shown previously to protect beta cells against JNK-mediated, cytokine-induced apoptosis. Experiments here confirmed TUDCA reduced beta cell JNK phosphorylation in response to cytokine stress. Furthermore pharmacological inhibition and siRNA-mediated knockdown of JNK in beta cells also attenuated HSP90 release in response to cytokine stress. Pharmacological inhibition of HSP90 chaperone function exacerbated islet cell stress during the development of TIDM in vivo; however, it did not affect the overall incidence of disease. Together, these data suggest extracellular HSP90 could serve as a biomarker for preclinical TIDM. This knowledge may be clinically relevant in optimizing treatments aimed at restoring beta cell mass. The goal of such treatments would be to halt the progression of at-risk patients to insulin dependence and lifelong TIDM.
  • Thumbnail Image
    Item
    Impact of ALCAM (CD166) on homing of hematopoietic stem and progenitor cells
    (2012-12-18) Aleksandrova, Mariya Aleksandrova; Goebl, Mark G.; Srour, Edward F.; Hurley, Thomas D., 1961-
    The potential of hematopoietic stem cells (HSC) to home and to anchor within the bone marrow (BM) microenvironment controls the ability of transplanted HSCs to establish normal hematopoiesis. Activated Leukocyte Cell Adhesion Molecule (ALCAM; also identified as CD166), which participates in homophilic interactions, is expressed on a group of osteoblasts in the hematopoietic niche capable of sustaining functional HSC in vitro. Since we could also detect ALCAM expression on HSC, we suspect that ALCAM may play a role in anchoring primitive hematopoietic cells to ALCAM expressing components of the hematopoietic niche via dimerization. We investigated the role of ALCAM on the homing abilities of hematopoietic stem and progenitor cells (HSPC) by calculating recovery frequency of Sca-1+ALCAM+ cells in an in vivo murine bone marrow transplantation model. Our data supports the notion that ALCAM promotes improved homing potential of hematopoietic Sca-1+ cells. Recovery of BM-homed Sca-1+ cells from the endosteal region was 1.8-fold higher than that of total donor cells. However, a 3.0-fold higher number of Sca-1+ALCAM+ cells homed to the endosteal region compared to total donor cells. Similarly, homed Sca-1+ALCAM+ cells were recovered from the vascular region at 2.1-fold greater frequency than total homed donor cells from that region, compared to only a 1.3-fold increase in the recovery frequency of Sca-1+ cells. In vitro quantitation of clonogenic BM-homed hematopoietic progenitors corroborate the results from the homing assay. The frequency of in vitro clonogenic progenitors was significantly higher among endosteal-homed Sca-1+ALCAM+ cells compared to other fractions of donor cells. Collectively, these data demonstrate that engrafting HSC expressing ALCAM home more efficiently to the BM and within the BM microenvironment, these cells preferentially seed the endosteal niche.
  • Thumbnail Image
    Item
    Mechanisms of alcohol-induced damage to the developing nervous system
    (The National Institute on Alcohol Abuse and Alcoholism, 2001) Goodlett, Charles R.; Horn, Kristin H.; Psychology, School of Science
    Numerous mechanisms likely contribute to the damaging effects of prenatal alcohol exposure on the developing fetus and particularly the developing central nervous system (CNS). The coexistence of a multitude of mechanisms that may act simultaneously or consecutively and differ among various cell types poses particular challenges to researchers. To study alcohol’s effects on the fetus more easily, investigators have used animal models and tissue-culture experiments. Such approaches have identified numerous potential mechanisms through which alcohol acts on the fetus, many of which result in cell death by necrosis or apoptosis. Among these mechanisms are increased oxidative stress, damage to the mitochondria, interference with the activity of growth factors, effects on glia cells, impaired development and function of chemical messenger systems involved in neuronal communication, changes in the transport and uptake of the sugar glucose, effects on cell adhesion, and changes in the regulation of gene activity during development.
  • Thumbnail Image
    Item
    Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin
    (Nature Publishing Group, 2018-02-22) Duchamp de Lageneste, Oriane; Julien, Anaïs; Abou-Khalil, Rana; Frangi, Giulia; Carvalho, Caroline; Cagnard, Nicolas; Cordier, Corinne; Conway, Simon J.; Colnot, Céline; Pediatrics, School of Medicine
    Bone regeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized. Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bone marrow stromal cells/skeletal stem cells (BMSCs) in mice. Although periosteal cells (PCs) and BMSCs are derived from a common embryonic mesenchymal lineage, postnatally PCs exhibit greater clonogenicity, growth and differentiation capacity than BMSCs. During bone repair, PCs can efficiently contribute to cartilage and bone, and integrate long-term after transplantation. Molecular profiling uncovers genes encoding Periostin and other extracellular matrix molecules associated with the enhanced response to injury of PCs. Periostin gene deletion impairs PC functions and fracture consolidation. Periostin-deficient periosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs within periosteum and the requirement of Periostin in maintaining this pool. Overall our results highlight the importance of analyzing periosteum and PCs to understand bone phenotypes
  • Thumbnail Image
    Item
    Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease
    (American Society for Clinical Investigation, 2016-05-05) Li, Wei; Liu, Liangyi; Gomez, Aurelie; Zhang, Jilu; Ramadan, Abdulraouf; Zhang, Qing; Choi, Sung W.; Zhang, Peng; Greenson, Joel K.; Liu, Chen; Jiang, Di; Virts, Elizabeth; Kelich, Stephanie L.; Chu, Hong Wei; Flynn, Ryan; Blazar, Bruce R.; Hanenberg, Helmut; Hanash, Samir; Paczesny, Sophie; Department of Microbiology & Immunology, IU School of Medicine
    Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA-transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA- transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.