| Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma.
January 28, 2010 at 6:58 AM
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| | Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma. Int J Cancer. 2010 Jan 26; Authors: Suzuki Y, Sakai K, Ueki J, Xu Q, Nakamura T, Shimada H, Nakamura T, Matsumoto K NK4 exhibits two distinct biological actions: antagonistic inhibition of hepatocyte growth factor (HGF) through binding to the Met/HGF receptor, and anti-angiogenic action through binding to perlecan. Here, the anti-tumor effect of NK4 on malignant pleural mesothelioma was investigated. Of seven human malignant mesothelioma cell lines (ACC-Meso-1, ACC-Meso-4, EHMES-1, EHMES-10, H28, H2052, JMN-1B), only EHMES-10 cells formed subcutaneous tumors when implanted into mice. For EHMES-10 cells, HGF facilitated invasion of the cells in collagen gel, whereas NK4 and neutralizing anti-HGF antibody suppressed the HGF-induced invasion. In addition, NK4 but not anti-HGF antibody suppressed proliferation of EHMES-10 cells in collagen, suggesting that the suppression by NK4 was independent of the HGF-Met pathway. In the subcutaneous tumor model, recombinant adenovirus-mediated intratumoral expression of NK4 inhibited tumor growth, while the invasive characteristic of tumor cel! ls was not observed. Analysis of Met receptor tyrosine phosphorylation, proliferation, apoptosis, and blood vessels in the tumor tissues indicated that the inhibitory effect of NK4 expression might be primarily caused by the inhibition of tumor angiogenesis. In all seven mesothelioma lines, HGF stimulated Met tyrosine phosphorylation, and this was associated with enhanced cell migration. HGF-dependent Met activation and migration were inhibited by NK4. Since malignant pleural mesothelioma represents an aggressive neoplasm characterized by extensive invasive growth, suppression of invasive growth has therapeutic value. Thus, the simultaneous inhibition of the HGF-Met pathway and angiogenesis by NK4 for treatment of malignant pleural mesothelioma is significant, particularly to attenuate migration and invasive growth. (c) 2010 UICC. PMID: 20104519 [PubMed - as supplied by publisher] | | |
| Bone marrow-derived stem cells in liver repair: 10 years down the line.
January 28, 2010 at 6:58 AM
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| | Bone marrow-derived stem cells in liver repair: 10 years down the line. Liver Transpl. 2010 Jan 26;16(2):118-129 Authors: Gilchrist ES, Plevris JN Hematopoietic stem cells have potential in the field of regenerative medicine because of their capacity to form cells of different lineages. Bone marrow stem cells have been shown to contribute to parenchymal liver cell populations, and although this may not be functionally significant, it has sparked interest in the field of autologous stem cell infusion as a possible treatment for cirrhosis. In this review, we will examine the evidence for the contribution of bone marrow-derived cells to populations of liver cells and for the functional contribution of bone marrow-derived cells to both liver fibrosis and repair. The mechanisms by which cells are trafficked from the bone marrow to the liver are complex; the stromal derived factor-1/CXC receptor 4 axis is central to this process. There are limited data in liver injury, but we will examine findings from the bone marrow transplantation literature and discuss their relevance to liver disease. Stromal derived factor-1! also has a role in endogenous liver stem cell accumulation. Some groups have already started infusing autologous bone marrow cells into patients with cirrhosis. We will review these trials in the context of the basic science that we have discussed, and we will consider targets for investigation in the future. Liver Transpl 16:118-129, 2010. (c) 2010 AASLD. PMID: 20104479 [PubMed - as supplied by publisher] | | |
| Hypoxia inducible factors in cancer stem cells.
January 28, 2010 at 6:58 AM
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| | Hypoxia inducible factors in cancer stem cells. Br J Cancer. 2010 Jan 26; Authors: Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB, Rich JN Oxygen is an essential regulator of cellular metabolism, survival, and proliferation. Cellular responses to oxygen levels are monitored, in part, by the transcriptional activity of the hypoxia inducible factors (HIFs). Under hypoxia, HIFs regulate a variety of pro-angiogenic and pro-glycolysis pathways. In solid cancers, regions of hypoxia are commonly present throughout the tissue because of the chaotic vascular architecture and regions of necrosis. In these regions, the hypoxic state fluctuates in a spatial and temporal manner. Transient hypoxic cycling causes an increase in the activity of the HIF proteins above what is typical for non-pathologic tissue. The extent of hypoxia strongly correlates to poor patient survival, therapeutic resistance and an aggressive tumour phenotype, but the full contribution of hypoxia and the HIFs to tumour biology is an area of active investigation. Recent reports link resistance to conventional therapies and the metastatic poten! tial to a stem-like tumour population, termed cancer stem cells (CSCs). We and others have shown that within brain tumours CSCs reside in two niches, a perivascular location and the surrounding necrotic tissue. Restricted oxygen conditions increase the CSC fraction and promote acquisition of a stem-like state. Cancer stem cells are critically dependant on the HIFs for survival, self-renewal, and tumour growth. These observations and those from normal stem cell biology provide a new mechanistic explanation for the contribution of hypoxia to malignancy. Further, the presence of hypoxia in tumours may present challenges for therapy because of the promotion of CSC phenotypes even upon successful killing of CSCs. The current experimental evidence suggests that CSCs are plastic cell states governed by microenvironmental conditions, such as hypoxia, that may be critical for the development of new therapies targeted to disrupt the microenvironment.British Journal of Cancer advance ! online publication, 26 January 2010; doi:10.1038/sj.bjc.660555! 1 www.bj cancer.com. PMID: 20104230 [PubMed - as supplied by publisher] | | |
| Application of low-pressure cell seeding system in tissue engineering.
January 28, 2010 at 6:58 AM
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| | Application of low-pressure cell seeding system in tissue engineering. Biosci Trends. 2009 Dec;3(6):216-9 Authors: Dai W, Dong J, Chen G, Uemura T Tissue engineering has been one of the most promising strategies for the regeneration of impaired tissue. Application of three-dimensional porous scaffolds has greatly improved the outcome of tissue engineering in many categories. Cell seeding is one of the key issues in tissue regeneration. It depends not only on the biocompatibility and affinity of the scaffold, but also on the seeding techniques. Current seeding techniques such as centrifugation and perfusion have enhanced better cell seeding, but still have their limitations. How to seed cells more efficiently and uniformly, especially in the inner parts of the scaffolds, and with no impairment to the cells, has been one of the major challenges in using porous scaffolds for tissue engineering. Low pressure seeding meets the above requirements and can easily be integrated into other seeding systems. Here we review, based on the literature, and discuss the feasibility and application of this low pressure system ! to promote tissue regeneration. PMID: 20103850 [PubMed - in process] | | |
| Immunobiological Characterization of Cancer Stem Cells Isolated from Glioblastoma Patients.
January 28, 2010 at 6:58 AM
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| | Immunobiological Characterization of Cancer Stem Cells Isolated from Glioblastoma Patients. Clin Cancer Res. 2010 Jan 26; Authors: Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, Mortini P, Ferrone S, Doglioni C, Marincola FM, Galli R, Parmiani G, Maccalli C PURPOSE: Cancer stem cells (CSC) have been isolated from human tumors, including glioblastoma multiforme (GBM). The aims of this study were the immunobiological characterization of GBM CSCs and the assessment of whether these cells represent suitable targets for immunotherapy. EXPERIMENTAL DESIGN: GBM CSC lines and their fetal bovine serum (FBS)-cultured non-CSC pair lines were generated and examined by flow cytometry for expression of known tumor antigens, MHC-I and MHC-II molecules, antigen-processing machinery components, and NKG2D ligands. In addition, immunogenicity and immunosuppression of such cell lines for autologous or allogeneic T lymphocytes were tested by cytokine secretion (ELISPOT) or proliferation (carboxyfluorescein diacetate succinimidyl ester) assays, respectively. RESULTS: Both GBM CSC and FBS lines were weakly positive and negative for MHC-I, MHC-II, and NKG2D ligand molecules, respectively. Antigen-processing machinery molecules were also def! ective in both cell types. Upregulation of most molecules was induced by IFNs or 5-Aza deoxycytidine, although more efficiently in FBS than in CSCs. Patient T-cell responses, mediated by both TH1 and the TH2 subsets, against autologous CSC could be induced in vitro. In addition, CSC but not their paired FBS tumor lines inhibited T-cell proliferation of healthy donors. Notably, a differential gene signature that was confirmed at the protein levels for some immunologic-related molecules was also found between CSC and FBS lines. CONCLUSIONS: These results indicate lower immunogenicity and higher suppressive activity of GBM CSC compared with FBS lines. The immunogenicity, however, could be rescued by immune modulation leading to anti-GBM T cell-mediated immune response. Clin Cancer Res; 16(3); 800-13. PMID: 20103663 [PubMed - as supplied by publisher] | | |
| Percutaneous Tissue-Engineered Pulmonary Valved Stent Implantation.
January 28, 2010 at 6:58 AM
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| | Percutaneous Tissue-Engineered Pulmonary Valved Stent Implantation. Ann Thorac Surg. 2010 Jan;89(1):259-263 Authors: Lutter G, Metzner A, Jahnke T, Bombien R, Boldt J, Iino K, Cremer J, Stock UA PURPOSE: The purpose of this study was to evaluate the feasibility of percutaneously implanted tissue-engineered valved stents in the ovine pulmonary valve position. DESCRIPTION: Porcine pulmonary heart valves and small intestinal submucosa were obtained from a slaughterhouse, and the intestinal submucosa used to cover the inside of the porcine pulmonary valved stents. Endothelial cells and autologous myofibroblasts were obtained from carotid artery segments of juvenile sheep. After myofibroblast seeding, constructs were placed in a dynamic bioreactor system and were cultured for 16 days. After Endothelial cell seeding, the tissue-engineered valved stents were deployed into the pulmonary valve annular site. Angiography was performed at implantation and explantation (4 weeks). Constructs were analyzed macroscopically and microscopically. EVALUATION: Orthotopic positioning of the stents (n = 3) at the time of implantation and explantation, as well as normal valve fu! nction, was observed through angiography. Gross morphology confirmed excellent opening and closing of all leaflets. Strong expression of alpha-smooth muscle actin in neointerstitial cells and of von-Willebrand-Factor in endothelial cells was revealed by immunocytochemistry. CONCLUSIONS: This study demonstrates successful merging of two novel technologies: (1) percutaneous valved stent implantation and (2) tissue engineering of autologous heart valves. PMID: 20103248 [PubMed - as supplied by publisher] | | |
| Engineered Dermal Equivalent Tissue in Vitro by Micro Tissue Precursors Assembly.
January 28, 2010 at 6:58 AM
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| | Engineered Dermal Equivalent Tissue in Vitro by Micro Tissue Precursors Assembly. Acta Biomater. 2010 Jan 23; Authors: Palmiero C, Imparato G, Urciuolo F, Netti P Tissue engineered constructs can be fabricated by the assembly of smaller building blocks in order to mimic much of the native biology that is often made from repeating functional units. Our aim was to realize a 3D tissue-like construct in vitro by means of functional Micrometric Tissue Precursors (muTPs) induced-assembly. muTPs were obtained by dynamic cell seeding of bovine fibroblasts on porous gelatine microcarriers by using spinner flask bioreactor. During the dynamic seeding cells adhered, proliferated and synthesized a thin layer of extracellular matrix (ECM) in and around the macroporous beads, generating the muTPs. The analysis reported that the ECM produced was rich of type I collagen. The cells and ECM layer around the muTPs allowed their biological sintering via cell-cell and cell-matrix communication after only few days of dynamic seeding. The assembling ability of muTPs was exploited by placing them in a maturation chamber. After 1 week of culture di! sc shaped constructs (1 cm in diameter, 1 mm in thickness) of completely assembled muTPs were collected. The obtained biohybrid presented both homogenous and compact aspect. Moreover histological and immunohistochemical analyses revealed an abundant ECM rich of type I collagen interconnecting the muTPs. Results obtained in this survey pave the way in realizing 3D dermal-tissue equivalent by means of bottom-up tissue engineering approach. PMID: 20102750 [PubMed - as supplied by publisher] | | |
| Potential of Endogenous Regenerative Technology for in situ regenerative medicine.
January 28, 2010 at 6:58 AM
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| | Potential of Endogenous Regenerative Technology for in situ regenerative medicine. Adv Drug Deliv Rev. 2010 Jan 23; Authors: Eduardo A, Sánchez M, Gorka O Endogenous Regenerative Technology (ERT) involves the use of patient's own biologically active proteins, growth factors and biomaterial scaffolds for therapeutic purposes. This technology provides a new approach for the stimulation and acceleration of tissue healing and bone regeneration. The versatility and biocompatibility of using patient-derived fibrin scaffold as an autologous, biocompatible and biodegradable drug delivery system opens the door to a personalized medicine that is currently being used in numerous medical and scientific fields including dentistry, oral implantology, orthopaedics, ulcer treatment, sports medicine and tissue engineering among others. This review discusses the state of the art and new directions in the use of endogenous technology in the repair and regeneration of injured tissues by means of a controlled and local protein and growth delivery. The next generations of engineering strategies together with some of the most interesting ! therapeutic applications are discussed together with the future challenges in the field. PMID: 20102730 [PubMed - as supplied by publisher] | | |
| Recombinant gelatin microspheres: novel formulations for tissue repair?
January 28, 2010 at 6:58 AM
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| | Recombinant gelatin microspheres: novel formulations for tissue repair? Tissue Eng Part A. 2010 Jan 26; Authors: Tuin A, Kluijtmans SG, Bouwstra JB, Harmsen MC, van Luyn M Microspheres (MS) can function as multifunctional scaffolds in different approaches of tissue repair (TR), either as a filler, a slow-release depot for growth factors or a delivery vehicle for cells. Natural cell-adhesion supporting extra cellular matrix (ECM) components like gelatin are good materials for these purposes. Recombinant production of gelatin allows for on demand design of gelatins, which is why we aim at developing recombinant gelatin (RG) MS for TR. Two types of MS (50<Ø<100 mum) were prepared by crosslinking two RGs, Syn-RG and the arginine-glycine-aspartate (RGD)-containing Hu-RG. The MS were characterized and their tissue reaction and degradation in rats was examined. Histological analysis of the explants after 14 and 28 days in vivo also showed that Syn-RG was degraded slower than Hu-RG, which correlated with the in vitro degradation assay. Hu-RG explants displayed more cellular ingrowth (60% vs 15% for Syn-RG at day 14), which was as! sociated with ECM disposition and vascularisation. The infiltrating cells consisted of mainly macrophages, part of which fused to giant cells locally, and fibroblasts. No differences were found in matrix metalloproteinase (MMP) mRNA levels whereas gelatinase activity was clearly higher in Hu-RG explants. In conclusion, the in vitro and in vivo results of these novel formulations pave the way for cell and/or factor driven TR by these RG MS. PMID: 20102269 [PubMed - as supplied by publisher] | | |
| Distinct differentiation properties of human dental pulp cells on collagen, gelatin, and chitosan scaffolds.
January 28, 2010 at 6:58 AM
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| | Distinct differentiation properties of human dental pulp cells on collagen, gelatin, and chitosan scaffolds. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Nov;108(5):e94-100 Authors: Kim NR, Lee DH, Chung PH, Yang HC OBJECTIVE: The growth and differentiation properties of human dental pulp cells (HDPC) were investigated on a variety of natural scaffolds, including 2 types of collagen, gelatin, and chitosan. STUDY DESIGN: Cell attachment and growth rates of HDPC on collagen (type I and type III), gelatin, and chitosan were observed. Alkaline phosphatase (ALP) activity, mRNA expression of differentiation-related genes, and mineralization of the HDPC on each scaffold were assessed. RESULTS: Dental pulp cells attached and proliferated rapidly on collagen and gelatin, but chitosan did not properly support cell growth. The cells plated on gelatin exhibited high ALP activity, but not as high as cells plated on collagen. The expression peak of osteocalcin (OCN) mRNA from cells grown on collagen was found earlier and followed by dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP-1) mRNA expression. In cells grown on gelatin, however, OCN mRNA transcripts appeared at a l! ater period of culture with no increase in DSPP or DMP-1 mRNA. Intensely mineralized extracellular matrix was seen in cells grown on collagen, but gelatin did not allow enough mineralization of cells in differentiation-inducing media. CONCLUSION: Collagen supported proliferation and differentiation of HDPC, and the expression of DSPP and DMP-1 mRNA was reduced on gelatin. PMID: 19836718 [PubMed - indexed for MEDLINE] | | |
| In vivo dynamics of human cord blood-derived CD34(-) SCID-repopulating cells using intra-bone marrow injection.
January 28, 2010 at 6:58 AM
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| | In vivo dynamics of human cord blood-derived CD34(-) SCID-repopulating cells using intra-bone marrow injection. Leukemia. 2010 Jan;24(1):162-8 Authors: Kimura T, Matsuoka Y, Murakami M, Kimura T, Takahashi M, Nakamoto T, Yasuda K, Matsui K, Kobayashi K, Imai S, Asano H, Nakatsuka R, Uemura Y, Sasaki Y, Sonoda Y The identification of human CD34-negative (CD34(-)) hematopoietic stem cells (HSCs) provides a new concept for the hierarchy in the human HSC compartment. This study investigated the long-term repopulating capacity and redistribution kinetics of human cord blood-derived CD34(-) severe combined immunodeficiency (SCID)-repopulating cells (SRCs) and compared them with those of CD34(+)CD38(+) and CD34(+)CD38(-) SRCs using the intra-bone marrow injection (IBMI) to clarify the characteristics of CD34(-) SRCs. On the basis of the limiting dilution analyses data, estimated numbers of CD34(+)CD38(+), CD34(+)CD38(-), and CD34(-) SRCs were transplanted to NOD/SCID mice by IBMI. The human cell repopulation at the site of injection and the other bones were serially investigated. Interestingly, CD34(+)CD38(+), CD34(+)CD38(-), and CD34(-) SRCs began to migrate to other bones 2 and 5 weeks after the transplantation, respectively. Accordingly, the initiation of migration seemed to! differ between the CD34(+) and CD34(-) SRCs. In addition, CD34(+)CD38(+) SRCs only sustained a short-term repopulation. However, both CD34(+)CD38(-) and CD34(-) SRCs had longer-term repopulation capacity. Taken together, these findings showed that CD34(-) SRCs show different in vivo kinetics, thus suggesting that the identified CD34(-) SRCs are a distinct class of primitive HSCs in comparison to the CD34(+)CD38(+) and CD34(+)CD38(-) SRCs. PMID: 19798093 [PubMed - indexed for MEDLINE] | | |
| Novel factor-loaded polyphosphazene matrices: potential for driving angiogenesis.
January 28, 2010 at 6:58 AM
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| | Novel factor-loaded polyphosphazene matrices: potential for driving angiogenesis. J Microencapsul. 2009 Sep;26(6):544-55 Authors: Oredein-McCoy O, Krogman NR, Weikel AL, Hindenlang MD, Allcock HR, Laurencin CT Currently employed bone tissue engineered scaffolds often lack the potential for vascularization, which may be enhanced through the incorporation of and regulated release of angiogenic factors. For this reason, the objective here was to fabricate and characterize protein-loaded amino acid ester polyphosphazene (Pphos)-based scaffolds and evaluate the novel sintering method used for protein incorporation, a method which will ultimately allow for the incorporation of proangiogenic agents. To test the hypothesis, Pphos and their composite microspheres with nanocrystalline hydroxyapatite (Pphos-HAp) were fabricated via the emulsion solvent evaporation method. Next, bovine serum albumin (BSA)-containing microsphere matrices were created using a novel solvent-non-solvent approach for protein loading. The resulting protein (BSA) loaded circular porous microsphere based scaffolds were characterized for morphology, porosity, protein structure, protein distribution and subs! equent protein release pattern. Scanning electron microscopy revealed porous microsphere scaffolds with a smooth surface and sufficient level of sintering, illustrated by fusion of adjacent microspheres. The porosity measured for the poly(ethyl phenylalanato:glycinato)phosphazene (PNPhGly) and poly(ethyl phenylalanato:glycinato)phosphazene-hydroxyapatite (PNPhGly-HAp) scaffolds were 23 +/- 0.11% and 18 +/- 4.02%, respectively, and within the range of trabecular bone. Circular dichroism confirmed an intact secondary protein structure for BSA following the solvent sintering method used for loading and confocal microscopy verified that FITC-BSA was successfully entrapped both between adjacent microspheres and within the surface of the microspheres while sintering. For both Pphos and their composite microsphere scaffolds, BSA was released at a steady rate over a 21 day time period, following a zero order release profile. HAp particles in the composite scaffolds served to improv! e the release profile pattern, underscoring the potential of H! Ap for g rowth factor delivery. Moreover, the results of this work suggest that the solvent-non-solvent technique for protein loading is an optimal one that will allow for future development of angiogenic factor-loaded Pphos matrices with the capacity to invoke neovascularization. PMID: 18972247 [PubMed - indexed for MEDLINE] | | | |
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