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| IOM Study of CIRM to Come Before Stem Cell Directors in August
May 28, 2010 at 10:18 AM
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| Directors of the California stem cell agency are moving forward with a proposal to commission a blue-ribbon study of their $3 billion effort by the Institute of Medicine.
The directors' new Science Subcommittee on Tuesday voted to bring the proposal, which is now connected to legislation to remove the CIRM staff cap, to the full board in August, said a spokesman for CIRM.
In response to an | | |
| CIRM Grant Appeal Rules to Receive More Scrutiny
May 28, 2010 at 9:50 AM
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| Directors of the California stem cell agency plan to continue their review of key portions of the grant approval process, including the appeals that have been something of a bugaboo for both applicants and directors.
Don Gibbons, chief communications officer for CIRM, said in an email that the directors' Science Subcommittee on Tuesday concluded that "they need to devote a large chunk of a | | |
| Reading List on CIRM Grant Appeals
May 28, 2010 at 9:42 AM
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| Here are links to items related to the CIRM grant appeal process and other pertinent issues. They include CIRM documents and items from the California Stem Cell Report.
Competing for California Stem Cell Cash: Rules of the Game Coming Under Scrutiny 5/18/2010
Stem Cell Grant Competition: Remove CIRM Directors From Appeals? 5/23/10
Pre-application review – Most recent CIRM report (Jan. 2010) | | |
| Adult stem cells in the treatment of acute myocardial infarction.
May 28, 2010 at 8:04 AM
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| | Adult stem cells in the treatment of acute myocardial infarction. Catheter Cardiovasc Interv. 2010 Apr 30; Authors: Sharif F, Bartunek J, Vanderheyden M Stem cell therapy has emerged as a novel therapeutic treatment alternative for early and end stage LV dysfunction. The rapid translation into clinical trials has left many questions unanswered. Moreover, results of randomized trials in the setting of acute myocardial infarction are controversial, emphasizing a need for further basic and translational research to improve understanding of cell functionality. This review attempts to summarize some of the functional issues related to cell therapy and also evaluate the current status of stem cell clinical trials. Although results to date have shown modest improvement in left ventricular function, the progress should follow coordinated, multidisciplinary and well designed path to address issues of cell homing, cell retention and also look at outcomes beyond physiological parameters. (c) 2010 Wiley-Liss, Inc. PMID: 20506335 [PubMed - as supplied by publisher] | | |
| Potential and pitfalls of stem cell therapy in old age.
May 28, 2010 at 8:04 AM
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| | Potential and pitfalls of stem cell therapy in old age. Dis Model Mech. 2010 May 26; Authors: Piccin D, Morshead CM Our increasing understanding of resident stem cell populations in various tissues of the adult body provides promise for the development of cell-based therapies to treat trauma and disease. With the sharp rise in the aging population, the need for effective regenerative medicine strategies for the aged is more important then ever. Yet, the vast majority of research fuelling our understanding of the mechanisms that control stem cell behaviour, and their role in tissue regeneration, is conducted in young animals. Evidence collected in the last several years indicates that, although stem cells remain active into old age, changes in the stem cells and their microenvironments inhibit their regenerative potential. An understanding of both the cell-intrinsic stem cell changes, as well as concomitant changes to the stem cell niche and the systemic environment, are crucial for the development of regenerative medicine strategies that might be successful in aged patients. PMID: 20504968 [PubMed - as supplied by publisher] | | |
| Cell distribution after intracoronary bone marrow stem cell delivery in damaged and undamaged myocardium: implications for clinical trials.
May 28, 2010 at 8:04 AM
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| | Cell distribution after intracoronary bone marrow stem cell delivery in damaged and undamaged myocardium: implications for clinical trials. Stem Cell Res Ther. 2010;1(1):4 Authors: Forest VF, Tirouvanziam AM, Perigaud C, Fernandes S, Fusellier MS, Desfontis JC, Toquet CS, Heymann MF, Crochet DP, Lemarchand PF ABSTRACT : INTRODUCTION : Early randomized clinical trials of autologous bone marrow cardiac stem cell therapy have reported contradictory results highlighting the need for a better evaluation of protocol designs. This study was designed to quantify and compare whole body and heart cell distribution after intracoronary or peripheral intravenous injection of autologous bone marrow mononuclear cells in a porcine acute myocardial infarction model with late reperfusion. METHODS : Myocardial infarction was induced using balloon inflation in the left coronary artery in domestic pigs. At seven days post-myocardial infarction, 1 x 10(8) autologous bone marrow mononuclear cells were labeled with fluorescent marker and/or 99mTc radiotracer, and delivered using intracoronary or peripheral intravenous injection (leg vein). RESULTS : Scintigraphic analyses and Upsilon-emission radioactivity counting of harvested organs showed a significant cell fraction retained within the hea! rt after intracoronary injection (6 +/- 1.7% of injected radioactivity at 24 hours), whereas following peripheral intravenous cell injection, no cardiac homing was observed at 24 hours and cells were mainly detected within the lungs. Importantly, no difference was observed in the percentage of retained cells within the myocardium in the presence or absence of myocardial infarction. Histological evaluation did not show arterial occlusion in both animal groups and confirmed the presence of bone marrow mononuclear cells within the injected myocardium area. CONCLUSIONS : Intravenous bone marrow mononuclear cell injection was ineffective to target myocardium. Myocardial cell distribution following intracoronary injection did not depend on myocardial infarction presence, a factor that could be useful for cardiac cell therapy in patients with chronic heart failure of non-ischemic origin or with ischemic myocardium without myocardial infarction. PMID: 20504285 [PubMed - in process] | | |
| Extent of cell differentiation and capacity for cartilage synthesis in human adult adipose-derived stem cells: Comparison with fetal chondrocytes.
May 28, 2010 at 6:38 AM
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| | Extent of cell differentiation and capacity for cartilage synthesis in human adult adipose-derived stem cells: Comparison with fetal chondrocytes. Biotechnol Bioeng. 2010 May 18; Authors: Mahmoudifar N, Doran PM This study evaluated the extent of differentiation and cartilage biosynthetic capacity of human adult adipose-derived stem cells relative to human fetal chondrocytes. Both types of cell were seeded into nonwoven-mesh polyglycolic acid (PGA) scaffolds and cultured under dynamic conditions with and without addition of TGF-beta1 and insulin. Gene expression for aggrecan and collagen type II was upregulated in the stem cells in the presence of growth factors, and key components of articular cartilage such as glycosaminoglycan (GAG) and collagen type II were synthesized in cultured tissue constructs. However, on a per cell basis and in the presence of growth factors, accumulation of GAG and collagen type II were, respectively, 3.4- and 6.1-fold lower in the stem cell cultures than in the chondrocyte cultures. Although the stem cells synthesized significantly higher levels of total collagen than the chondrocytes, only about 2.4% of this collagen was collagen type II. Re! lative to cultures without added growth factors, treatment of the stem cells with TGF-beta1 and insulin resulted in a 59% increase in GAG synthesis, but there was no significant change in collagen production even though collagen type II gene expression was upregulated 530-fold. In contrast, in the chondrocyte cultures, synthesis of collagen type II and levels of collagen type II as a percentage of total collagen more than doubled after growth factors were applied. Although considerable progress has been achieved to develop differentiation strategies and scaffold-based culture techniques for adult mesenchymal stem cells, the extent of differentiation of human adipose-derived stem cells in this study and their capacity for cartilage synthesis fell considerably short of those of fetal chondrocytes. (c) 2010 Wiley Periodicals, Inc. PMID: 20506225 [PubMed - as supplied by publisher] | | |
| Selection and reliability of internal reference genes for quantitative PCR verification of transcriptomics during the differentiation process of porcine adult mesenchymal stem cells.
May 28, 2010 at 6:38 AM
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| | Selection and reliability of internal reference genes for quantitative PCR verification of transcriptomics during the differentiation process of porcine adult mesenchymal stem cells. Stem Cell Res Ther. 2010;1(1):7 Authors: Monaco E, Bionaz M, de Lima AS, Hurley WL, Loor JJ, Wheeler MB ABSTRACT : INTRODUCTION : The objective of this study was to find highly reliable internal-control genes (ICGs) for normalization of qPCR data from porcine adult mesenchymal stem cells induced to differentiate toward adipogenic and osteogenic lineages. METHODS : Stem cells were acquired from subcutaneous back fat and bone marrow of three castrated Yorkshire crossbred male pigs. Adipose and bone marrow-derived stem cells (ADSCs and BMSCs) were cultured in vitro with specific osteogenic or adipogenic differentiation medium for 4 weeks. Total RNA was extract for microarray (13,000 oligonucleotides) and qPCR analyses. Microarray data were used to uncover the most stably expressed genes (that is, potential ICGs). Co-regulation among potential ICGs was evaluated with Ingenuity Pathway Analysis. qPCR was performed on the non-coregulated ICGs candidates and on specific osteogenic (COL1A1) and adipogenic (DBI) genes. geNorm was used to uncover the most reliable ICGs by usi! ng qPCR data and the optimal number of ICGs to be used to calculate the normalization factor. RESULTS : Microarray data analysis revealed 27 potential ICGs. Among those, 10 genes without known co-regulation were selected to perform qPCR. geNorm performed on qPCR data uncovered high stability in expression ratio among the selected ICGs. However, especially reliable normalization was obtained by geometric mean of NSUN5, TIMM17B, and VPS4A. The effect of normalization, assessed on specific osteogenic (COL1A1) and adipogenic (DBI) genes, was apparent for the adipogenic and less apparent for the osteogenic differentiation. CONCLUSIONS : The combination of microarray data and pairwise gene analysis allowed identification of novel and highly reliable ICGs for qPCR data normalization of adult porcine stem cells induced to differentiate to adipogenic and osteogenic lineages. PMID: 20504288 [PubMed - in process] | | |
| Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton.
May 28, 2010 at 6:07 AM
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| | Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton. J Cell Biochem. 2010 May 19; Authors: Chanda D, Kumar S, Ponnazhagan S Mesenchymal stem cells (MSCs) are the most popular among the adult stem cells in tissue engineering and regenerative medicine. Since their discovery and functional characterization in the late sixties and early seventies, MSCs or MSC-like cells have been obtained from various mesodermal and non-mesodermal tissues, although majority of the therapeutic applications involved bone marrow derived MSCs. Based on its mesenchymal origin, it was predicted earlier that MSCs only can differentiate into mesengenic lineages like bone, cartilage, fat or muscle. However, varied isolation and cell culturing methods identified subsets of MSCs in the bone marrow which not only differentiated into mesenchymal lineages, but also into ectodermal and endodermal derivatives. Although, true pluripotent status is yet to be established, MSCs have been successfully used in bone and cartilage regeneration in osteoporotic fracture and arthritis respectively and in the repair of cardiac tissue! following myocardial infarction. Immunosuppressive properties of MSCs extend utility of MSCs to reduce complications of graft versus host disease and rheumatoid arthritis. Homing of MSCs to sites of tissue injury, including tumor, is well established. In addition to their ability in tissue regeneration, MSCs can be genetically engineered ex vivo for delivery of therapeutic molecule(s) to the sites of injury or tumorigenesis as cell therapy vehicles. MSCs tend to lose surface receptors for trafficking and have been reported to develop sarcoma in long-term culture. In this article, we reviewed the current status of MSCs with special emphasis to therapeutic application in bone-related diseases. J. Cell. Biochem. (c) 2010 Wiley-Liss, Inc. PMID: 20506559 [PubMed - as supplied by publisher] | | |
| Integration of Blood Outgrowth Endothelial Cells in Dermal Fibroblast Sheets Promotes Full Thickness Wound Healing.
May 28, 2010 at 6:07 AM
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| | Integration of Blood Outgrowth Endothelial Cells in Dermal Fibroblast Sheets Promotes Full Thickness Wound Healing. Stem Cells. 2010 May 18; Authors: Hendrickx B, Verdonck K, Van den Berge S, Dickens S, Eriksson E, Vranckx JJ, Luttun A Vascularization is the cornerstone of wound healing. We introduced human blood outgrowth endothelial cells (hBOEC) in a self-assembled human dermal fibroblast sheet (hDFS), intended as a tissue-engineered dermal substitute with inherent vascular potential. hBOEC were functionally and molecularly different from early endothelial progenitor cells (EPC) and human umbilical vein endothelial cells (HUVEC). hBOEC alone, unlike HUVEC, efficiently revascularized and re-oxygenated the wound bed, both by active incorporation into new vessels and by trophic stimulation of host angiogenesis in a dose-dependent manner. Furthermore, hBOEC alone, but not HUVEC, accelerated epithelial coverage and matrix organization of the wound bed. In addition, integration of hBOEC in hDFS not only further improved vascularization, epithelial coverage and matrix organization, but also prevented excessive wound contraction. In vitro analyses with hBOEC, fibroblasts and keratinocytes revealed th! at these effects were both due to growth factor cross-talk and to short cutting hypoxia. Among multiple growth factors secreted by hBOEC, placental growth factor (PlGF) mediated at least in part the beneficial effects on keratinocyte migration and proliferation. Overall, this combined tissue engineering approach paves the way for clinical development of a fully autologous vascularized dermal substitute for patients with large skin defects that do not heal properly. PMID: 20506500 [PubMed - as supplied by publisher] | | |
| miR-17-5p promotes human breast cancer cell migration and invasion through suppression of HBP1.
May 28, 2010 at 6:07 AM
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| | miR-17-5p promotes human breast cancer cell migration and invasion through suppression of HBP1. Breast Cancer Res Treat. 2010 May 27; Authors: Li H, Bian C, Liao L, Li J, Zhao RC MicroRNAs have been implicated in regulating diverse cellular pathways. Emerging evidence indicate that the miR-17-92 cluster may have a causal role in breast cancer tumorigenesis as a novel class of oncogenes, but the role of these miRNAs in breast cancer invasion and migration remains unexplored. The aims of this study were to verify the effect of miR-17-5p (an important member of the miR-17-92 cluster) on the invasive and migratory ability of breast cancer cells. The matching of miR-17-5p and HMG box-containing protein 1 (HBP1) was predicted by TargetScan and confirmed by DNA constructs and luciferase target assay. The expression levels of miR-17-5p and its candidate target-HBP1 in MCF7 and MDA-MB-231 breast cancer cells were measured by real-time PCR and western blotting. Effects of miR-17-5p in cell cycle progression, proliferation, invasion and migration were evaluated by flow cytometry assay, 3-(4,-dimethy -lthiazol-2-yl)-2,-diphenyl -tetrazoliumbromide ass! ay, soft-agar colony formation assay, and transwell invasive and migratory assay, respectively. The results showed that miR-17-5p was highly expressed in high-invasive MDA-MB-231 breast cancer cells but not in low-invasive MCF-7 breast cancer cells. Over-expression of miR-17-5p in MCF-7 cells rendered them the invasive and migratory abilities by targeting HBP1/beta-catenin pathway. On the other hand, down-regulation of endogenous miR-17-5p suppressed the migration and invasion of MDA-MB-231 cells in vitro. These findings suggest that miR-17-5p plays an important role in breast cancer cell invasion and migration by suppressing HBP1 and subsequent activation of Wnt/beta-catenin. PMID: 20505989 [PubMed - as supplied by publisher] | | |
| Stretched inverse opal colloid crystal substrates-induced orientation of fibroblast.
May 28, 2010 at 6:07 AM
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| | Stretched inverse opal colloid crystal substrates-induced orientation of fibroblast. Biomed Mater. 2010 May 27;5(3):035011 Authors: Wang YC, Tang ZM, Feng ZQ, Xie ZY, Gu ZZ Recently, there has been increasing interest in studying the interaction between mammalian cells and nanometer-sized structures. However, the effect of nanostructures on cell behavior, such as cell morphology and alignment, is still largely unknown. Inverse opal colloid crystal substrates, which can be stretched to produce nano-scale pore structures of different degrees of orientation, serve as a convenient model system to study the effect of nanotopography on cell morphology and cell alignment. In this work, we fabricated inverse opal colloidal crystal films that were either unstretched or stretched to three, four or six times their original length, producing pore structures of increasing degree of orientation. Human dermal fibroblast-fetal (HDF-f) cells were seeded and cultured on these four types of substrates. The results from fluorescence microscopy and scanning electron microscopy indicated that cells showed the highest degree of alignment when cultured on i! nverse opal colloid crystal films that were stretched the most (six times original length). The results also demonstrated that the orientation of nanostructures could affect both the morphology and growth direction of fibroblasts. The ability to control the direction of cell growth through the engineering of nanostructures could have important applications in tissue engineering, especially for tissues with anisotropic structures, such as cardiac muscle, blood vessel, tendon and ligament. PMID: 20505235 [PubMed - as supplied by publisher] | | |
| Comparative investigation of viability, metabolism and osteogenic capability of tissue-engineered bone preserved in sealed osteogenic media at 37 degrees C and 4 degrees C.
May 28, 2010 at 6:07 AM
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| | Comparative investigation of viability, metabolism and osteogenic capability of tissue-engineered bone preserved in sealed osteogenic media at 37 degrees C and 4 degrees C. Biomed Mater. 2010 May 27;5(3):035010 Authors: Wang H, Liu G, Zhou G, Cen L, Cui L, Cao Y Preservation of tissue-engineered (TE) bone is one of the key problems needed to be solved for its clinic application and industrialization. Traditional cryopreservation has been restricted because of the damages caused by ice formation and solution. Hypothermic preservation at 4 degrees C has been widely used for the preservation of transplanted organ despite potential negative effects on viability of cells and tissue. 37 degrees C is the best temperature for maintaining cellular bioactivities. However, 37 degrees C also has a potential negative effect on preserved cells due to consumption of nutrients and accumulation of by-products. No studies have reported which temperature is more suitable for the preservation of TE bone constructs. The current study explored the feasibility of preservation of TE bone constructs in sealed osteogenic media at 37 degrees C and 4 degrees C. Human bone marrow stromal cells (hBMSCs) were seeded into partially demineralized bone ma! trix (pDBM) scaffolds and cultured for 7 days to form TE bone constructs. The constructs were preserved in sealed osteogenic media at either 37 degrees C or 4 degrees C for 5, 7, 9 and 11 days, respectively. Growth kinetics, viability, metabolism and osteogenic capability were evaluated to explore the feasibility of preservation at 37 degrees C and 4 degrees C. The constructs cultured in osteogenic media at humidified 37 degrees C/5%CO(2) served as the positive control. The results demonstrated that all the constructs preserved at 4 degrees C showed negative osteogenic capability at all time points with a much lower level of growth kinetics, viability and metabolism compared to the positive control. However, the constructs preserved at 37 degrees C showed good osteogenic capability within 7 days with a certain level of growth kinetics, viability and metabolism, although an obvious decrease in osteogenic capability was observed in the constructs preserved at 37 degrees C ove! r 9 days. These results indicate that the preservation of TE b! one cons tructs is feasible at 37 degrees C within 7 days in sealed osteogenic media. PMID: 20505234 [PubMed - as supplied by publisher] | | |
| Customized Ca-P/PHBV nanocomposite scaffolds for bone tissue engineering: design, fabrication, surface modification and sustained release of growth factor.
May 28, 2010 at 6:07 AM
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| | Customized Ca-P/PHBV nanocomposite scaffolds for bone tissue engineering: design, fabrication, surface modification and sustained release of growth factor. J R Soc Interface. 2010 May 26; Authors: Duan B, Wang M Integrating an advanced manufacturing technique, nanocomposite material and controlled delivery of growth factor to form multifunctional tissue engineering scaffolds was investigated in this study. Based on calcium phosphate (Ca-P)/poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanocomposite microspheres, three-dimensional Ca-P/PHBV nanocomposite scaffolds with customized architecture, controlled porosity and totally interconnected porous structure were successfully fabricated using selective laser sintering (SLS), one of the rapid prototyping technologies. The cytocompatibility of sintered Ca-P/PHBV nanocomposite scaffolds, as well as PHBV polymer scaffolds, was studied. For surface modification of nanocomposite scaffolds, gelatin was firstly physically entrapped onto the scaffold surface and heparin was subsequently immobilized on entrapped gelatin. The surface-modification improved the wettability of scaffolds and provided specific binding site between conjuga! ted heparin and the growth factor recombinant human bone morphogenetic protein-2 (rhBMP-2). The surface-modified Ca-P/PHBV nanocomposite scaffolds loaded with rhBMP-2 significantly enhanced the alkaline phosphatase activity and osteogenic differentiation markers in gene expression of C3H10T1/2 mesenchymal stem cells. Together with osteoconductive nanocomposite material and controlled growth factor delivery strategies, the use of SLS technique to form complex scaffolds will provide a promising route towards individualized bone tissue regeneration. PMID: 20504805 [PubMed - as supplied by publisher] | | |
| Electrophoretic deposition of biomaterials.
May 28, 2010 at 6:07 AM
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| | Electrophoretic deposition of biomaterials. J R Soc Interface. 2010 May 26; Authors: Boccaccini AR, Keim S, Ma R, Li Y, Zhitomirsky I Electrophoretic deposition (EPD) is attracting increasing attention as an effective technique for the processing of biomaterials, specifically bioactive coatings and biomedical nanostructures. The well-known advantages of EPD for the production of a wide range of microstructures and nanostructures as well as unique and complex material combinations are being exploited, starting from well-dispersed suspensions of biomaterials in particulate form (microsized and nanoscale particles, nanotubes, nanoplatelets). EPD of biological entities such as enzymes, bacteria and cells is also being investigated. The review presents a comprehensive summary and discussion of relevant recent work on EPD describing the specific application of the technique in the processing of several biomaterials, focusing on (i) conventional bioactive (inorganic) coatings, e.g. hydroxyapatite or bioactive glass coatings on orthopaedic implants, and (ii) biomedical nanostructures, including biopolym! er-ceramic nanocomposites, carbon nanotube coatings, tissue engineering scaffolds, deposition of proteins and other biological entities for sensors and advanced functional coatings. It is the intention to inform the reader on how EPD has become an important tool in advanced biomaterials processing, as a convenient alternative to conventional methods, and to present the potential of the technique to manipulate and control the deposition of a range of nanomaterials of interest in the biomedical and biotechnology fields. PMID: 20504802 [PubMed - as supplied by publisher] | | |
| A modular approach to cardiac tissue engineering.
May 28, 2010 at 6:07 AM
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| | A modular approach to cardiac tissue engineering. Tissue Eng Part A. 2010 May 26; Authors: Leung B, Sefton MV Functional cardiac tissue was prepared using a modular tissue engineering approach with the goal of creating vascularized tissue. Rat aortic endothelial cells (RAEC) were seeded onto sub-millimetre size modules made of type I bovine collagen supplemented with MatrigelTM (25% v/v) embedded with cardiomyocyte (CM)-enriched neonatal rat heart cells and assembled into a contractile, macroporous sheet-like construct. Modules (without RAEC) cultured in 10% bovine serum were more contractile and responsive to external stimulus (lower excitation threshold, higher maximum capture rate and greater en face fractional area changes) than modules cultured in 10% fetal bovine serum. Incorporating 25% Matrigel in the matrix reduced the excitation threshold and increased the fractional area change relative to collagen only modules (without RAEC). A co-culture medium, containing 10% bovine serum, low Mg2+ (0.814 mM) and normal glucose (5.5 mM) was used to maintain RAEC junction mor! phology (VE-cadherin) and CM contractility, although the responsiveness of CM was attenuated with RAEC on the modules. Macroporous, sheet-like module constructs were assembled by partially immobilizing a layer of modules in alginate gel until day 8, with or without RAEC. RAEC/CM module sheets were electrically responsive, however, like modules with RAEC this responsiveness was attenuated relative to CM only sheets. Muscle bundles co-expressing cardiac troponin I and connexin 43 were evident near the perimeter of modules and at inter-module junctions. These results suggest the potential of the modular approach as a platform for building vascularised cardiac tissue. PMID: 20504074 [PubMed - as supplied by publisher] | | |
| A COMBINING METHOD TO ENHANCE THE IN VITRO DIFFERENTIATION OF HEPATIC PRECURSOR CELLS.
May 28, 2010 at 6:07 AM
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| | A COMBINING METHOD TO ENHANCE THE IN VITRO DIFFERENTIATION OF HEPATIC PRECURSOR CELLS. Tissue Eng Part C Methods. 2010 May 26; Authors: Carraro A, Flaibani M, Cillo U, Michelotto L, Magrofuoco E, Buggio M, Abatangelo G, Cortivo R, Herrera MB, Tetta C, Elvassore N, Zavan B The ideal bioartificial liver (BAL) should be designed to reproduce as nearly as possible in vitro the habitat that hepatic cells find in vivo. In the present work we investigated the in vitro perfusion condition with a view to improving the hepatic differentiation of pluripotent human liver stem cells (HLSCs) from adult liver. Tissue engineering strategies based on the co-cultivation of HLSCs with hepatic stellate cells (ITO) and with several combinations of medium were applied to improve viability and differentiation. A mathematical model estimated the best flow rate for perfused cultures lasting up to 7 days. Morphological and functional assays were performed. Morphological analyses confirmed that a flow of perfusion medium (assured by the bioreactor system), enabled the in vitro organization of the cells into liver-clusters even in the deeper levels of the sponge. Our results showed that, when co-cultured with ITO using stem cell medium, HLSCs synthesized a la! rge amounts of albumin and the MTT test confirmed an improvement in cell proliferation. In conclusion this study shows that our in vitro cell conditions promote the formation of clusters of HLSCs and enhance the functional differentiation into a mature hepatic population. PMID: 20504066 [PubMed - as supplied by publisher] | | |
| Stereolithographic Bone Scaffold Design Parameters: Osteogenic Differentiation and Signal Expression.
May 28, 2010 at 6:07 AM
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| | Stereolithographic Bone Scaffold Design Parameters: Osteogenic Differentiation and Signal Expression. Tissue Eng Part B Rev. 2010 May 26; Authors: Kim K, Yeatts A, Dean D, Fisher JP Scaffold design parameters including porosity, pore size, interconnectivity, and mechanical properties have a significant influence on osteogenic signal expression and differentiation. This review evaluates the influence of each of these parameters and then discusses the ability of stereolithography (SLA) to be used to tailor scaffold design to optimize these parameters. Scaffold porosity and pore size affect osteogenic cell signaling and ultimately in vivo bone tissue growth. Alternatively, scaffold interconnectivity has a great influence on in vivo bone growth but little work has been done to determine if interconnectivity causes changes in signaling levels. Osteogenic cell signaling could be also influenced by scaffold mechanical properties such as scaffold rigidity and dynamic relationships between the cells and their extracellular matrix. With knowledge of the effects of these parameters on cellular functions, an optimal tissue engineering scaffold can be des! igned, but the proper technology must exist to produce this design to specification in a repeatable manner. SLA has been shown to be capable of fabricating scaffolds with controlled architecture and micron-level resolution. Surgical implantation of these scaffolds is a promising clinical treatment for successful bone regeneration. By applying knowledge of how scaffold parameters influence osteogenic cell signaling to scaffold manufacturing using SLA, tissue engineers may move closer to creating the optimal tissue engineering scaffold. PMID: 20504065 [PubMed - as supplied by publisher] | | |
| Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering.
May 28, 2010 at 6:07 AM
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| | Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7251-6 Authors: Scotti C, Tonnarelli B, Papadimitropoulos A, Scherberich A, Schaeren S, Schauerte A, Lopez-Rios J, Zeller R, Barbero A, Martin I Mesenchymal stem/stromal cells (MSC) are typically used to generate bone tissue by a process resembling intramembranous ossification, i.e., by direct osteoblastic differentiation. However, most bones develop by endochondral ossification, i.e., via remodeling of hypertrophic cartilaginous templates. To date, endochondral bone formation has not been reproduced using human, clinically compliant cell sources. Here, we aimed at engineering tissues from bone marrow-derived, adult human MSC with an intrinsic capacity to undergo endochondral ossification. By analogy to embryonic limb development, we hypothesized that successful execution of the endochondral program depends on the initial formation of hypertrophic cartilaginous templates. Human MSC, subcutaneously implanted into nude mice at various stages of chondrogenic differentiation, formed bone trabeculae only when they had developed in vitro hypertrophic tissue structures. Advanced maturation in vitro resulted in ac! celerated formation of larger bony tissues. The underlying morphogenetic process was structurally and molecularly similar to the temporal and spatial progression of limb bone development in embryos. In particular, Indian hedgehog signaling was activated at early stages and required for the in vitro formation of hypertrophic cartilage. Subsequent development of a bony collar in vivo was followed by vascularization, osteoclastic resorption of the cartilage template, and appearance of hematopoietic foci. This study reveals the capacity of human MSC to generate bone tissue via an endochondral program and provides a valid model to study mechanisms governing bone development. Most importantly, this process could generate advanced grafts for bone regeneration by invoking a "developmental engineering" paradigm. PMID: 20406908 [PubMed - indexed for MEDLINE] | | |
| [Medical applications of rapid prototyping--three-dimensional bodies for planning and implementation of treatment and for tissue replacement]
May 28, 2010 at 6:07 AM
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| | [Medical applications of rapid prototyping--three-dimensional bodies for planning and implementation of treatment and for tissue replacement] Duodecim. 2010;126(2):143-51 Authors: Mäkitie A, Paloheimo KS, Björkstrand R, Salmi M, Kontio R, Salo J, Yan Y, Paloheimo M, Tuomi J The possibilities of medical applications of rapid prototyping are continuously expanding and developing. In current applications, five main groups are distinguished: (1) preoperative planning, surgical training and teaching, (2) inert implants, (3) surgical instruments and special equipment associated with the operations, (4) postoperative guides, long-term supports and aids and (5) artificial tissue. The first four of these are already in general use, whereas the last one is still under investigation. PMID: 20405599 [PubMed - indexed for MEDLINE] | | |
| Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton.
May 28, 2010 at 6:05 AM
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| | Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton. J Cell Biochem. 2010 May 19; Authors: Chanda D, Kumar S, Ponnazhagan S Mesenchymal stem cells (MSCs) are the most popular among the adult stem cells in tissue engineering and regenerative medicine. Since their discovery and functional characterization in the late sixties and early seventies, MSCs or MSC-like cells have been obtained from various mesodermal and non-mesodermal tissues, although majority of the therapeutic applications involved bone marrow derived MSCs. Based on its mesenchymal origin, it was predicted earlier that MSCs only can differentiate into mesengenic lineages like bone, cartilage, fat or muscle. However, varied isolation and cell culturing methods identified subsets of MSCs in the bone marrow which not only differentiated into mesenchymal lineages, but also into ectodermal and endodermal derivatives. Although, true pluripotent status is yet to be established, MSCs have been successfully used in bone and cartilage regeneration in osteoporotic fracture and arthritis respectively and in the repair of cardiac tissue! following myocardial infarction. Immunosuppressive properties of MSCs extend utility of MSCs to reduce complications of graft versus host disease and rheumatoid arthritis. Homing of MSCs to sites of tissue injury, including tumor, is well established. In addition to their ability in tissue regeneration, MSCs can be genetically engineered ex vivo for delivery of therapeutic molecule(s) to the sites of injury or tumorigenesis as cell therapy vehicles. MSCs tend to lose surface receptors for trafficking and have been reported to develop sarcoma in long-term culture. In this article, we reviewed the current status of MSCs with special emphasis to therapeutic application in bone-related diseases. J. Cell. Biochem. (c) 2010 Wiley-Liss, Inc. PMID: 20506559 [PubMed - as supplied by publisher] | | |
| OCT3/4 regulates transcription of histone deacetylase 4 (Hdac4) in mouse embryonic stem cells.
May 28, 2010 at 6:05 AM
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| | OCT3/4 regulates transcription of histone deacetylase 4 (Hdac4) in mouse embryonic stem cells. J Cell Biochem. 2010 May 19; Authors: Addis RC, Prasad M, Yochem RL, Zhan X, Sheets T, Axelman J, Patterson ES, Shamblott MJ OCT3/4 is a POU domain transcription factor that is critical for maintenance of pluripotency and self-renewal by embryonic stem (ES) cells and cells of the early mammalian embryo. It has been demonstrated to bind and regulate a number of genes, often in conjunction with the transcription factors SOX2 and NANOG. In an effort to further understand this regulatory network, chromatin immunoprecipitation was used to prepare a library of DNA segments specifically bound by OCT3/4 in undifferentiated mouse ES (mES) cell chromatin. One segment corresponds to a region within the first intron of the gene encoding histone deacetylase 4 (Hdac4), a Class II histone deacetylase. This region acts as a transcriptional repressor and contains at least two functional sites that are specifically bound by OCT3/4. HDAC4 is not expressed in the nuclei of OCT3/4+ mES cells and is upregulated upon differentiation. These findings demonstrate the participation of OCT3/4 in the repression of ! Hdac4 in ES cells. J. Cell. Biochem. (c) 2010 Wiley-Liss, Inc. PMID: 20506506 [PubMed - as supplied by publisher] | | |
| A theoretical method to improve and optimize the design of bioartificial livers.
May 28, 2010 at 6:05 AM
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| | A theoretical method to improve and optimize the design of bioartificial livers. Biotechnol Bioeng. 2010 Apr 16; Authors: Davidson AJ, Ellis MJ, Chaudhuri JB Bioartificial livers (BALs) are a potentially effective countermeasure against liver failure, particularly in cases of acute or fulminant liver failure. It is hoped these devices can sustain a patient's liver function until recovery or transplant. However, no large-scale clinical trial has yet proven that BALs are particularly effective and evidently design issues remain to be addressed. One aspect of BAL design that must be considered is the mass transfer of adequate oxygen to the hepatocytes within the device. We present here a mathematical modeling approach to oxygen mass transport in a BAL. A mathematical model based upon Krogh cylinders is outlined to describe a diffusion-limited hollow fiber bioreactor. In addition, operating constraints are defined on the system - cells should not experience hypoxia and the cell population should be of adequate size. By combining modeling results with these operating constraints and presenting the results graphically, 'oper! ating region' charts can be constructed for the hollow fiber BAL (HF-BAL). The effects of varying various operating parameters on the BAL are then established. It is found that smaller radii and short, thin walled fibers are generally advantageous while cell populations in excess of 10 billion could be supported in the BAL with a plasma flow rate of 200 ml/min. For fibers of intermediate length and lumen radius, the minimum number of fibers required to produce a viable design ranges approximately from 7000-10,000. In theory, this may be enough to support patients with failing livers. (c) 2010 Wiley Periodicals, Inc. PMID: 20506230 [PubMed - as supplied by publisher] | | |
| A Data Integration Approach to Mapping OCT4 Gene Regulatory Networks Operative in Embryonic Stem Cells and Embryonal Carcinoma Cells.
May 28, 2010 at 6:05 AM
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| | A Data Integration Approach to Mapping OCT4 Gene Regulatory Networks Operative in Embryonic Stem Cells and Embryonal Carcinoma Cells. PLoS One. 2010;5(5):e10709 Authors: Jung M, Peterson H, Chavez L, Kahlem P, Lehrach H, Vilo J, Adjaye J It is essential to understand the network of transcription factors controlling self-renewal of human embryonic stem cells (ESCs) and human embryonal carcinoma cells (ECs) if we are to exploit these cells in regenerative medicine regimes. Correlating gene expression levels after RNAi-based ablation of OCT4 function with its downstream targets enables a better prediction of motif-specific driven expression modules pertinent for self-renewal and differentiation of embryonic stem cells and induced pluripotent stem cells.We initially identified putative direct downstream targets of OCT4 by employing CHIP-on-chip analysis. A comparison of three peak analysis programs revealed a refined list of OCT4 targets in the human EC cell line NCCIT, this list was then compared to previously published OCT4 CHIP-on-chip datasets derived from both ES and EC cells. We have verified an enriched POU-motif, discovered by a de novo approach, thus enabling us to define six distinct modules! of OCT4 binding and regulation of its target genes.A selection of these targets has been validated, like NANOG, which harbours the evolutionarily conserved OCT4-SOX2 binding motif within its proximal promoter. Other validated targets, which do not harbour the classical HMG motif are USP44 and GADD45G, a key regulator of the cell cycle. Over-expression of GADD45G in NCCIT cells resulted in an enrichment and up-regulation of genes associated with the cell cycle (CDKN1B, CDKN1C, CDK6 and MAPK4) and developmental processes (BMP4, HAND1, EOMES, ID2, GATA4, GATA5, ISL1 and MSX1). A comparison of positively regulated OCT4 targets common to EC and ES cells identified genes such as NANOG, PHC1, USP44, SOX2, PHF17 and OCT4, thus further confirming their universal role in maintaining self-renewal in both cell types. Finally we have created a user-friendly database (http://biit.cs.ut.ee/escd/), integrating all OCT4 and stem cell related datasets in both human and mouse ES and EC cells! .In the current era of systems biology driven research, we env! isage th at our integrated embryonic stem cell database will prove beneficial to the booming field of ES, iPS and cancer research. PMID: 20505756 [PubMed - in process] | | |
| Fetal brain during a binge drinking episode: a dynamic susceptibility contrast MRI fetal brain perfusion study.
May 28, 2010 at 6:05 AM
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| | Fetal brain during a binge drinking episode: a dynamic susceptibility contrast MRI fetal brain perfusion study. Neuroreport. 2010 May 25; Authors: Kochunov P, Castro C, Davis DM, Dudley D, Wey HY, Purdy D, Fox PT, Simerly C, Schatten G We assessed the effects of a single episode of maternal alcohol intoxication on fetal brain blood perfusion in three pregnant dams (baboons) at the 24th week of pregnancy using dynamic susceptibility contrast magnetic resonance imaging. After the oral administration of alcohol, there was a four-fold increase in the peak contrast concentrations in the fetal brain. In addition, we observed a two- to three-fold increase in the contrast uptake and washout rates in the fetal brain. The underlying mechanisms of these changes are unknown, but we hypothesized that these could include the alcohol-mediated changes in placental permeability and fetal cerebral blood flow. Our findings indicate that alcohol intoxication produces profound changes, which may detrimentally influence neurodevelopmental processes in the brain. PMID: 20505549 [PubMed - as supplied by publisher] | | |
| Potential and pitfalls of stem cell therapy in old age.
May 28, 2010 at 6:05 AM
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| | Potential and pitfalls of stem cell therapy in old age. Dis Model Mech. 2010 May 26; Authors: Piccin D, Morshead CM Our increasing understanding of resident stem cell populations in various tissues of the adult body provides promise for the development of cell-based therapies to treat trauma and disease. With the sharp rise in the aging population, the need for effective regenerative medicine strategies for the aged is more important then ever. Yet, the vast majority of research fuelling our understanding of the mechanisms that control stem cell behaviour, and their role in tissue regeneration, is conducted in young animals. Evidence collected in the last several years indicates that, although stem cells remain active into old age, changes in the stem cells and their microenvironments inhibit their regenerative potential. An understanding of both the cell-intrinsic stem cell changes, as well as concomitant changes to the stem cell niche and the systemic environment, are crucial for the development of regenerative medicine strategies that might be successful in aged patients. PMID: 20504968 [PubMed - as supplied by publisher] | | |
| [In Process Citation]
May 28, 2010 at 6:05 AM
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| | [In Process Citation] Hist Sci Med. 2009 Oct-Dec;43(4):345-54; discussion 354-5 Authors: Chastel C In 1949, three American virologists, John F. Enders, Thomas H. Weller and Frederick C. Robbins, from the Harvard Medical Scholl and working at the Children's Medical Centre, Boston, Mass., have provoked a true revolution in Virology. Here, they have succeeded in readily multiplying the three poliomyelitis viruses in vitro, in non-nervous cells cultures. A few years afterwards (1954), they were collectively honoured by the Nobel Prize of Physiology and Medicine. This discovery not only has quickly led to the production of efficient poliomyelitis vaccines (J. E. Salk, 1953; A. B. Sabin, 1955) but also has permitted to easily isolate a number of already known viruses (measles, rubella, mumps, herpes simplex and herpes zoster) or until then totally unknown viruses (adenovirus, echovirus, cytomegalovirus). These progresses have significantly contributed to improve diagnosis, sanitary surveillance and vaccinal prophylaxis of human and animal viral diseases. Moreover, th! e cells cultures techniques have also benefited to other domains of fundamental Biology, such as cellular biology, genetics, cancerology, biology of the reproduction and regenerative medicine as well. PMID: 20503638 [PubMed - in process] | | |
| Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering.
May 28, 2010 at 6:05 AM
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| | Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7251-6 Authors: Scotti C, Tonnarelli B, Papadimitropoulos A, Scherberich A, Schaeren S, Schauerte A, Lopez-Rios J, Zeller R, Barbero A, Martin I Mesenchymal stem/stromal cells (MSC) are typically used to generate bone tissue by a process resembling intramembranous ossification, i.e., by direct osteoblastic differentiation. However, most bones develop by endochondral ossification, i.e., via remodeling of hypertrophic cartilaginous templates. To date, endochondral bone formation has not been reproduced using human, clinically compliant cell sources. Here, we aimed at engineering tissues from bone marrow-derived, adult human MSC with an intrinsic capacity to undergo endochondral ossification. By analogy to embryonic limb development, we hypothesized that successful execution of the endochondral program depends on the initial formation of hypertrophic cartilaginous templates. Human MSC, subcutaneously implanted into nude mice at various stages of chondrogenic differentiation, formed bone trabeculae only when they had developed in vitro hypertrophic tissue structures. Advanced maturation in vitro resulted in ac! celerated formation of larger bony tissues. The underlying morphogenetic process was structurally and molecularly similar to the temporal and spatial progression of limb bone development in embryos. In particular, Indian hedgehog signaling was activated at early stages and required for the in vitro formation of hypertrophic cartilage. Subsequent development of a bony collar in vivo was followed by vascularization, osteoclastic resorption of the cartilage template, and appearance of hematopoietic foci. This study reveals the capacity of human MSC to generate bone tissue via an endochondral program and provides a valid model to study mechanisms governing bone development. Most importantly, this process could generate advanced grafts for bone regeneration by invoking a "developmental engineering" paradigm. PMID: 20406908 [PubMed - indexed for MEDLINE] | | | | 
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