| Up-regulation of oligodendrocyte precursor cell alphaV integrin and its extracellular ligands during central nervous system remyelination.
September 10, 2009 at 7:55 am
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| | Up-regulation of oligodendrocyte precursor cell alphaV integrin and its extracellular ligands during central nervous system remyelination. J Neurosci Res. 2009 Sep 8; Authors: Zhao C, Fancy SP, Franklin RJ, Ffrench-Constant C To determine the role of extracellular matrix molecules and their integrin ligands in CNS remyelination, we have examined in experimentally induced focal demyelinated lesions the expression of the two classes of integrins implicated in oligodendrocyte development and myelination: alpha6 laminin-binding integrins and alphaV integrins that bind a range of extracellular matrix proteins containing the -Arg-Gly-Asp- (RGD) recognition sequence. Only alphaV integrins were up-regulated during remyelination, being expressed on oligodendrocyte precursor cells during their recruitment into the lesion. Next, therefore, we examined the expression of extracellular matrix ligands for alphaV integrins and documented increased expression of tenascin-C, tenascin-R, fibronectin, and vitronectin. Taken together with our previous discovery of high levels of expression of another alphaV ligand, osteopontin, during remyelination in these lesions, our findings suggest that alphaV integrins make an important contribution to successful repair in the CNS. (c) 2009 Wiley-Liss, Inc. PMID: 19739252 [PubMed - as supplied by publisher] |
| Strategies for Zonal Cartilage Repair using Hydrogels.
September 10, 2009 at 7:55 am
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| | Strategies for Zonal Cartilage Repair using Hydrogels. Macromol Biosci. 2009 Sep 8; Authors: Klein TJ, Rizzi SC, Reichert JC, Georgi N, Malda J, Schuurman W, Crawford RW, Hutmacher DW Articular cartilage is a highly hydrated tissue with depth-dependent cellular and matrix properties that provide low-friction load bearing in joints. However, the structure and function are frequently lost and there is insufficient repair response to regenerate high-quality cartilage. Several hydrogel-based tissue-engineering strategies have recently been developed to form constructs with biomimetic zonal variations to improve cartilage repair. Modular hydrogel systems allow for systematic control over hydrogel properties, and advanced fabrication techniques allow for control over construct organization. These technologies have great potential to address many unanswered questions involved in prescribing zonal properties to tissue-engineered constructs for cartilage repair. PMID: 19739068 [PubMed - as supplied by publisher] |
| Wild-type FOXP3 is selectively active in CD4+CD25hi regulatory T cells of healthy female carriers of different FOXP3 mutations.
September 10, 2009 at 7:55 am
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| | Wild-type FOXP3 is selectively active in CD4+CD25hi regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood. 2009 Sep 8; Authors: Di Nunzio S, Cecconi M, Passerini L, McMurchy AN, Baron U, Turbachova I, Vignola S, Valencic E, Tommasini A, Junker A, Cazzola G, Olek S, Levings MK, Perroni L, Roncarolo MG, Bacchetta R FOXP3 is constitutively expressed by CD4(+)CD25(hi) regulatory T cells (nTregs). Mutations of FOXP3 cause a severe autoimmune syndrome known as Immune dysregulation Polyendocrinopathy Entheropathy X-linked, in which nTregs are absent or dysfunctional. Whether FOXP3 is essential for both differentiation and function of human nTreg cells remains to be demonstrated. Since FOXP3 is an X-linked gene subject to X-chromosome inactivation (XCI), we studied nine healthy female carriers of FOXP3 mutations to investigate the role of wild-type (WT) versus mutated FOXP3 in different cell subsets. Analysis of active WT versus mut-FOXP3 allele distribution revealed a random pattern of XCI in peripheral blood lymphocytes and in naive and memory CD4(+)T cells, whereas nTregs expressed only the active WT-FOXP3. These data demonstrate that expression of WT-FOXP3 is indispensable for the presence of a normal nTreg compartment and suggest that FOXP3 is not necessary for effector T cell differentiation in humans. PMID: 19738030 [PubMed - as supplied by publisher] |
| Current Tissue Engineering and Novel Therapeutic Approaches to Axonal Regeneration following Spinal Cord Injury using Polymer Scaffolds.
September 10, 2009 at 7:55 am
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| | Current Tissue Engineering and Novel Therapeutic Approaches to Axonal Regeneration following Spinal Cord Injury using Polymer Scaffolds. Respir Physiol Neurobiol. 2009 Sep 5; Authors: Madigan NN, Windebank AJ This review highlights current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury. The concept of developing 3-dimensional polymer scaffolds for placement into a spinal cord transection model has recently been more extensively explored as a solution for restoring neurologic function after injury. Given the patient morbidity associated with respiratory compromise, the discrete tracts in the spinal cord conveying innervation for breathing represent an important and achievable therapeutic target. The aim is to derive new neuronal tissue from the surrounding, healthy cord that will be guided by the polymer implant through the injured area to make functional reconnections. A variety of naturally derived and synthetic biomaterial polymers have been developed for placement in the injured spinal cord. Axonal growth is supported by inherent properties of the selected polymer, the architecture of the scaffold, permissive microstructures such as pores, grooves or polymer fibres, and surface modifications to provide improved adherence and growth directionality. Structural support of axonal regeneration is combined with integrated polymeric and cellular delivery systems for therapeutic drugs and for neurotrophic molecules to regionalize growth of specific nerve populations. PMID: 19737633 [PubMed - as supplied by publisher] |
| Bone marrow stromal cells and bone marrow-derived mononuclear cells: Which are suitable as cell source of transplantation for mice infarct brain?
September 10, 2009 at 7:55 am
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| | Bone marrow stromal cells and bone marrow-derived mononuclear cells: Which are suitable as cell source of transplantation for mice infarct brain? Neuropathology. 2009 Sep 7; Authors: Shichinohe H, Kuroda S, Maruichi K, Osanai T, Sugiyama T, Chiba Y, Yamaguchi A, Iwasaki Y There are few studies that denote whether bone marrow stromal cells (BMSC) and bone marrow-derived mononuclear cells (MNC) show the same therapeutic effects, when directly transplanted into the infarct brain. This study therefore aimed to compare their biological properties and behaviors in the infarct brain. Mouse BMSC were harvested and cultured. Mouse MNC were obtained through centrifugation techniques. Their cell markers were analyzed with FACS analysis. The MNC (10(6) cells; n = 10) or BMSC (2 x 10(5) cells; n = 10) were stereotactically transplanted into the ipsilateral striatum of the mice subjected to permanent middle cerebral artery occlusion at 7 days after the insult. Their survival, migration, and differentiation in the infarct brain were precisely analyzed using immunohistochemistry 4 weeks after transplantation. The MNC were positive for CD34, CD45, CD90, but were negative for Sca-1. The BMSC were positive for CD90 and Sca-1. The transplanted BMSC, but not MNC, extensively migrated into the peri-infarct area. Approximately 20% of the transplanted BMSC expressed a neuronal marker, NeuN in the infarct brain, although only 1.4% of the transplanted MNC expressed NeuN. These findings strongly suggest that there are large, biological differences between MNC and BMSC as cell sources of regenerative medicine for ischemic stroke. PMID: 19737360 [PubMed - as supplied by publisher] |
| Periodontal regeneration.
September 10, 2009 at 7:55 am
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| | Periodontal regeneration. Aust Dent J. 2009 Sep;54(s1):S118-S128 Authors: Ivanovski S The ultimate goal of periodontal therapy is the regeneration of the tissues destroyed as a result of periodontal disease. Currently, two clinical techniques, based on the principles of "guided tissue regeneration" (GTR) or utilization of the biologically active agent "enamel matrix derivative" (EMD), can be used for the regeneration of intrabony and Class II mandibular furcation periodontal defects. In cases where additional support and space-making requirements are necessary, both of these procedures can be combined with a bone replacement graft. There is no evidence that the combined use of GTR and EMD results in superior clinical results compared to the use of each material in isolation. Great variability in clinical outcomes has been reported in relation to the use of both EMD and GTR, and these procedures can be generally considered to be unpredictable. Careful case selection and treatment planning, including consideration of patient, tooth, site and surgical factors, is required in order to optimize the outcomes of treatment. There are limited data available for the clinical effectiveness of other biologically active molecules, such as growth factors and platelet concentrates, and although promising results have been reported, further clinical trials are required in order to confirm their effectiveness. Current active areas of research are centred on tissue engineering and gene therapy strategies which may result in more predictable regenerative outcomes in the future. PMID: 19737264 [PubMed - as supplied by publisher] |
| The Repair of Critical Size Bone Defects using Expedited, Autologous BMP-2 Gene Activated Fat Implants.
September 10, 2009 at 7:55 am
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| | The Repair of Critical Size Bone Defects using Expedited, Autologous BMP-2 Gene Activated Fat Implants. Tissue Eng Part A. 2009 Sep 8; Authors: Betz OB, Betz VM, Abdulazim A, Penzkofer R, Schmitt B, Schröder C, Mayer-Wagner S, Augat P, Jansson V, Müller PE The repair of bone defects can be induced experimentally with Bone Morphogenetic Protein-2 (BMP-2) producing fat derived stem cells, but this ex vivo tissue engineering method requires the isolation and long-term culture of autologous cells. In order to develop an expedited bone repair strategy, we transferred BMP-2 cDNA directly to autologous fat tissue fragments which were held in culture for only 24 hours prior to implantation. We evaluated the ability of such gene activated fat grafts to regenerate large segmental bone defects in rats. Fat tissue was harvested from two of 35 male Fischer 344 rats used for this study. The fat tissue fragments were incubated with an adenoviral vector carrying the cDNA encoding either BMP-2 or Green Flourescent Protein (GFP), or they remained unmodified. According to their group affiliation, the segmental femoral bone defects of 33 rats were filled press fit with either BMP-2 activated fat tissue or GFP transduced fat tissue or unmodified fat tissue. Another control group remained untreated. Femora were evaluated by radiographs, micro-computed tomography (microCT), biomechanical torsional testing and histology. Radiographically and histologically, 100% of the femora treated with BMP-2 activated fat grafts were bridged at 6 weeks after surgery. The femora of this group exceeded the bone volume and the biomechanical stability of intact, contralateral femora. Control defects receiving no treatment, unmodified fat tissue or GFP transduced fat were filled with fibrous or adipose tissue, as evaluated by histology. The use of BMP-2 gene activated fat tissue grafts represents an expedited and effective bone repair strategy that does not require the extraction and expansion of stem cells. PMID: 19737075 [PubMed - as supplied by publisher] |
| The Effects of Wnt Inhibitors on the Chondrogenesis from Human Mesenchymal Stem Cells.
September 10, 2009 at 7:55 am
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| | The Effects of Wnt Inhibitors on the Chondrogenesis from Human Mesenchymal Stem Cells. Tissue Eng Part A. 2009 Sep 8; Authors: Im GI, Quan Z The purpose of this study was to test the hypothesis that the inhibition of the Wnt pathway promotes chondrogenesis from hMSCs. To investigate the effect on early chondrogenesis, in-vitro pellet cultures were carried out using MSCs at passage 3 under 100ng/ml, 200ng/ml and 300ng/ml of either DKK-1 or sFRP-1, and analyzed for chondrogenic gene and protein expression after 3 and 6 days of culture. After that, to study the effects on chondrogenesis at a longer term, 200 ng of sFRP-1 were challenged either in the presence or in the absence of TGF-beta3 to pellets of MSCs at passage 3 for 7 days. Then, the pellets were cultured without sFRP-1 for 14 further days. For early chondrogenesis, both DKK-1 and sFRP-1 increased GAG synthesis as well as the gene and protein expressions of Sox-9 and type II collagen, more prominently by sFRP-1 than by DKK-1. However, after 21 days of in-vitro chondrogenic culture under TGF-beta3, sFRP-1 treatment did not further increase the gene expression of Sox-9 and type II collagen. The overall results of this study suggest that while the inhibitors of Wnt pathway promote early chondrogenesis from MSCs, they do not provide an ultimately enhancing role in the cartilage tissue engineering from MSCs. PMID: 19737074 [PubMed - as supplied by publisher] |
| Stem/progenitor Cell-Mediated De Novo Regeneration of Dental Pulp with Newly Deposited Continuous Layer of Dentin in an In Vivo Model.
September 10, 2009 at 7:55 am
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| | Stem/progenitor Cell-Mediated De Novo Regeneration of Dental Pulp with Newly Deposited Continuous Layer of Dentin in an In Vivo Model. Tissue Eng Part A. 2009 Sep 8; Authors: Huang G, Yamaza T, Shea LD, Djouad F, Kuhn NZ, Tuan R, Shi S The ultimate goal of this study is to regenerate lost dental pulp and dentin via stem/progenitor cell-based approaches and tissue engineering technologies. In the present study, we tested the possibility of regenerating vascularized human dental pulp in emptied root canal space and produceing new dentin on existing dentinal walls using a stem/progenitor cell-mediated approach with a human root fragment and an immunocompromised mouse model. Stem/progenitor cells from apical papilla (SCAP) and dental pulp stem cells (DPSCs) were isolated, characterized, seeded onto synthetic scaffolds consisted of poly-D,L-lactide/glycolide, inserted into the tooth fragments and transplanted into mice. Our results showed that the root canal space was filled entirely by a pulp-like tissue with well-established vascularity. In addition, a continuous layer of dentin-like tissue was deposited onto the canal dentinal wall. This dentin-like structure appeared to be produced by a layer of newly formed odontoblast-like cells expressing dentin sialophosphoprotein, bone sialoprotein, alkaline phosphatase, and CD105. The cells in regenerated pulp-like tissue reacted positively to anti-human mitochondria antibodies, indicating their human origin. This study provides the first evidence showing that pulp-like tissue can be regenerated de novo in emptied root canal space by SCAP and DPSCs which give rise to odontoblast-like cells producing dentin-like tissue on existing dentinal walls. PMID: 19737072 [PubMed - as supplied by publisher] |
| A newly developed chemically crosslinked Dex-PEG hydrogel for cartilage tissue engineering.
September 10, 2009 at 7:55 am
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| | A newly developed chemically crosslinked Dex-PEG hydrogel for cartilage tissue engineering. Tissue Eng Part A. 2009 Sep 8; Authors: Jukes JM, van der Aa H, Hiemstra C, van Veen T, Dijkstra P, Zhong Z, Feijen J, van Blitterswijk CA, De Boer J Cartilage tissue engineering, in which chondrogenic cells are combined with a scaffold, is a cell-based approach to regenerate damaged cartilage. Various scaffold materials have been investigated, amongst which are hydrogels. Previously, we have developed dextran-based hydrogels which form under physiological conditions via a Michael type addition reaction. Hydrogels can be formed in situ by mixing a thiol-functionalized dextran (Dex-SH) with a tetra-acrylated star poly(ethylene-glycol) (PEG-4-Acr) solution. In this manuscript we describe how the degradation time of Dex-PEG hydrogels can be varied from 3 to 7 weeks by changing the degree of substitution of thiol groups on dextran. The degradation times increased slightly after encapsulation of chondrocytes in the gels. The effect of the gelation reaction on cell viability and cartilage formation in the hydrogels was investigated. Chondrocytes or embryonic stem cells (ESCs) were mixed in the aqueous dextran solution and we confirmed that the cells survived gelation. After a 3 week culturing period, chondrocytes and ESC-derived embryoid bodies were still viable and both cell types produced cartilaginous tissue. Our data demonstrate the potential of dextran hydrogels for cartilage tissue engineering strategies. PMID: 19737051 [PubMed - as supplied by publisher] |
| Morphogenesis of polycystic ovaries as assessed by pituitary-ovarian androgenic function.
September 10, 2009 at 7:55 am
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| | Morphogenesis of polycystic ovaries as assessed by pituitary-ovarian androgenic function. Reprod Biomed Online. 2009 May;18(5):635-43 Authors: Mori T, Nonoguchi K, Watanabe H, Ishikawa H, Tamura I, Kinoshita K Despite polycystic ovaries (PCO) being a common morphology in women with polycystic ovary syndrome and regular menstruation, the regulatory principles in the morphogenesis of antral follicles have not yet been elucidated. In recognition of the complementary interaction between androgen-induced expression of the FSH receptor and FSH-augmented expression of the androgen receptor in granulose cells of antral follicles, a possible correlation of antral follicle count (AFC) and pituitary-ovarian androgenic function was investigated in 180 infertile women over days 3-5 of the menstrual cycle. Six discrete types of PCO with decreasing pituitary-ovarian androgenic function were identified: Type I (classical Stein-Leventhal syndrome), Type II (hyperandrogenemism), Type III (singular hyper-LH), Type IV (cryptic hyperandrogenism), Type V (relative LH dominancy) and Type VI (relative FSH dominancy), in parallel to a diminishing number of AFC from Type I to Type VI. Because during the early follicular phase of the cycle until the selection of the dominant follicle, antral follicles are composed of newly emerged healthy follicles plus atretic antral follicles that remain non-ovulated from previous cycles, it is proposed that the six types of PCO may represent the folliculogenetic spectra along which PCO morphogenesis proceeds. PMID: 19549441 [PubMed - indexed for MEDLINE] |
| Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models.
September 10, 2009 at 7:55 am
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| | Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models. Cancer Sci. 2009 Jul;100(7):1351-8 Authors: Kishi Y, Kuba K, Nakamura T, Wen J, Suzuki Y, Mizuno S, Nukiwa T, Matsumoto K, Nakamura T Hepatocyte growth factor (HGF) promotes malignant development of cancer cells by enhancing invasion and metastasis. NK4, a competitive antagonist for HGF, is a bifunctional molecule that acts as a HGF antagonist and angiogenesis inhibitor. Although successful tumor inhibition by NK4 gene expression in tumor models has been demonstrated, the effects of systemic NK4 gene introduction are yet to be addressed. Here we show that systemic administration of a replication-defective adenovirus expressing NK4 (Ad.NK4) inhibits tumor growth and lung metastasis of B16F10 melanoma and Lewis lung carcinoma in syngeneic mice. Single tail-vein injection of Ad.NK4 achieved therapeutic levels of NK4 in the circulation and in multiple organs. Despite NK4 expression that was highest in the liver, toxicity in the liver was minimal. Ad.NK4-mediated growth inhibition was associated with decreased blood vessel density and increased apoptosis in tumor tissues, which suggests that NK4 suppressed tumor growth as an angiogenesis inhibitor. Metastasis of B16F10 melanoma and Lewis lung carcinoma cells to the lung was potently inhibited by systemic Ad.NK4-administration. Our results demonstrated that the adenovirus-mediated induction of high levels of circulating NK4 significantly inhibited in vivo tumor growth and distant metastasis without obvious side effects. NK4 gene therapy is thus a safe and promising strategy for the treatment of cancer patients, and further validation in clinical trials is needed. PMID: 19438869 [PubMed - indexed for MEDLINE] |
| Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration.
September 10, 2009 at 7:55 am
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| | Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15 Authors: Andreas K, Häupl T, Lübke C, Ringe J, Morawietz L, Wachtel A, Sittinger M, Kaps C INTRODUCTION: Rheumatoid arthritis (RA) leads to progressive destruction of articular cartilage. This study aimed to disclose major mechanisms of antirheumatic drug action on human chondrocytes and to reveal marker and pharmacological target genes that are involved in cartilage dysfunction and regeneration. METHODS: An interactive in vitro cultivation system composed of human chondrocyte alginate cultures and conditioned supernatant of SV40 T-antigen immortalised human synovial fibroblasts was used. Chondrocyte alginate cultures were stimulated with supernatant of RA synovial fibroblasts, of healthy donor synovial fibroblasts, and of RA synovial fibroblasts that have been antirheumatically treated with disease-modifying antirheumatic drugs (DMARDs) (azathioprine, gold sodium thiomalate, chloroquine phosphate, and methotrexate), nonsteroidal anti-inflammatory drugs (NSAIDs) (piroxicam and diclofenac), or steroidal anti-inflammatory drugs (SAIDs) (methylprednisolone and prednisolone). Chondrocyte gene expression profile was analysed using microarrays. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed for validation of microarray data. RESULTS: Genome-wide expression analysis revealed 110 RA-related genes in human chondrocytes: expression of catabolic mediators (inflammation, cytokines/chemokines, and matrix degradation) was induced, and expression of anabolic mediators (matrix synthesis and proliferation/differentiation) was repressed. Potential marker genes to define and influence cartilage/chondrocyte integrity and regeneration were determined and include already established genes (COX-2, CXCR-4, IL-1RN, IL-6/8, MMP-10/12, and TLR-2) and novel genes (ADORA2A, BCL2-A1, CTGF, CXCR-7, CYR-61, HSD11B-1, IL-23A, MARCKS, MXRA-5, NDUFA4L2, NR4A3, SMS, STS, TNFAIP-2, and TXNIP). Antirheumatic treatment with SAIDs showed complete and strong reversion of RA-related gene expression in human chondrocytes, whereas treatment with NSAIDs and the DMARD chloroquine phosphate had only moderate to minor effects. Treatment with the DMARDs azathioprine, gold sodium thiomalate, and methotrexate efficiently reverted chondrocyte RA-related gene expression toward the 'healthy' level. Pathways of cytokine-cytokine receptor interaction, transforming growth factor-beta/Toll-like receptor/Jak-STAT (signal transducer and activator of transcription) signalling and extracellular matrix receptor interaction were targeted by antirheumatics. CONCLUSIONS: Our findings indicate that RA-relevant stimuli result in the molecular activation of catabolic and inflammatory processes in human chondrocytes that are reverted by antirheumatic treatment. Candidate genes that evolved in this study for new therapeutic approaches include suppression of specific immune responses (COX-2, IL-23A, and IL-6) and activation of cartilage regeneration (CTGF and CYR-61). PMID: 19192274 [PubMed - indexed for MEDLINE] |
| A Genetic Variant of Aurora Kinase A Promotes Genomic Instability Leading to Highly Malignant Skin Tumors.
September 10, 2009 at 2:55 am
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| | A Genetic Variant of Aurora Kinase A Promotes Genomic Instability Leading to Highly Malignant Skin Tumors. Cancer Res. 2009 Sep 8; Authors: Torchia EC, Chen Y, Sheng H, Katayama H, Fitzpatrick J, Brinkley WR, Caulin C, Sen S, Roop DR Aurora kinase A (Aurora-A) belongs to a highly conserved family of mitotis-regulating serine/threonine kinases implicated in epithelial cancers. Initially we examined Aurora-A expression levels at different stages of human skin cancer. Nuclear Aurora-A was detected in benign lesions and became more diffused but broadly expressed in well and poorly differentiated squamous cell carcinomas (SCC), indicating that Aurora-A deregulation may contribute to SCC development. To mimic the overexpression of Aurora-A observed in human skin cancers, we established a gene-switch mouse model in which the human variant of Aurora-A (Phe31Ile) was expressed in the epidermis upon topical application of the inducer RU486 (Aurora-AGS). Overexpression of Aurora-A alone or in combination with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), did not result in SCC formation in Aurora-AGS mice. Moreover, Aurora-A overexpression in naive keratinocytes resulted in spindle defects in vitro and marked cell death in vivo, suggesting that the failure of Aurora-A to initiate tumorigenesis was due to induction of catastrophic cell death. However, Aurora-A overexpression combined with exposure to TPA and the mutagen 7,12-dimethylbenz(a)anthracene accelerated SCC development with greater metastastic activity than control mice, indicating that Aurora-A cannot initiate skin carcinogenesis but rather promotes the malignant conversion of skin papillomas. Further characterization of SCCs revealed centrosome amplification and genomic alterations by array CGH analysis, indicating that Aurora-A overexpression induces a high level of genomic instability that favors the development of aggressive and metastatic tumors. Our findings strongly implicate Aurora-A overexpression in the malignant progression of skin tumors and suggest that Aurora-A may be an important therapeutic target. [Cancer Res 2009;69(18):7207-15]. PMID: 19738056 [PubMed - as supplied by publisher] | | | 
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