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| The roadmap to personalized medicine.
July 31, 2010 at 9:59 AM
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| | The roadmap to personalized medicine. Clin Transl Sci. 2008 Sep;1(2):93 Authors: Waldman SA, Terzic A PMID: 20443827 [PubMed - indexed for MEDLINE] | | |
| Age-Related Variation in Cell Density of Human Lumbar Intervertebral Disc.
July 31, 2010 at 9:59 AM
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| | Age-Related Variation in Cell Density of Human Lumbar Intervertebral Disc. Spine (Phila Pa 1976). 2010 Jul 27; Authors: Liebscher T, Haefeli M, Wuertz K, Nerlich AG, Boos N STUDY DESIGN.: Changes in cell density of endplate (EP), nucleus pulposus (NP), and anulus fibrosus (AF) during ageing were systematically investigated in defined regions of interest in complete human motion segments. OBJECTIVES.: To elucidate cell density and total cell number in distinct anatomic regions of the intervertebral disc; to test effects of gender, level and age on cell density; and to correlate changes in cell density with histologic signs of disc degeneration. SUMMARY OF BACKGROUND DATA.: The available information on the cell density within intervertebral discs and its age-related changes is sparse. This knowledge, however, is a crucial prerequisite for cell-based tissue engineering approaches of the intervertebral disc. METHODS.: In 49 complete cross-sections from lumbar motion segments (newborn to 86 years) from 22 specimens, cell density was determined by the Abercrombie method in EP, NP, and AF, and total cell number was counted per region of interest. RESULTS.: Cell density in EP, NP, and AF decreased significantly from 0 to 16 years with the main changes occuring from 0 to 3 years for NP and AF. No significant variations were observed thereafter. We found a significant correlation of cell density and histologic degeneration score between 0 and 1, but not for scores >1. Gender and disc level did not influence cell density. CONCLUSION.: This study provides data concerning the total number of cells in the various regions of the intervertebral disc for different age groups. This knowledge will be beneficial for cell-based treatment approaches, which may evolve in the future. PMID: 20671592 [PubMed - as supplied by publisher] | | |
| Neuregulin/ErbB Signaling Regulates Cardiac Subtype Specification in Differentiating Human Embryonic Stem Cells.
July 31, 2010 at 9:59 AM
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| | Neuregulin/ErbB Signaling Regulates Cardiac Subtype Specification in Differentiating Human Embryonic Stem Cells. Circ Res. 2010 Jul 29; Authors: Zhu WZ, Xie Y, Moyes KW, Gold JD, Askari B, Laflamme MA Rationale: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exhibit either a "working" chamber or a nodal-like phenotype. To generate optimal hESC-CM preparations for eventual clinical application in cell-based therapies, we will need to control their differentiation into these specialized cardiac subtypes. Objective: To demonstrate intact neuregulin (NRG)-1beta/ErbB signaling in hESC-CMs and test the hypothesis that this signaling pathway regulates cardiac subtype abundance in hESC-CM cultures. Methods and Results: All experiments used hESC-CM cultures generated using our recently reported directed differentiation protocol. To support subsequent action potential phenotyping approaches and provide a higher-throughput method of determining cardiac subtype, we first developed and validated a novel genetic label that identifies nodal-type hESC-CMs. Next, control hESC-CM preparations were compared to those differentiated in the presence of exogenous NRG-1beta, an anti-NRG-1beta neutralizing antibody, or the ErbB antagonist AG1478. We used 3 independent approaches to determine the ratio of cardiac subtypes in the resultant populations: direct action potential phenotyping under current-clamp, activation of the aforementioned genetic label, and subtype-specific marker expression by RT-PCR. Using all 3 end points, we found that inhibition of NRG-1beta/ErbB signaling greatly enhanced the proportion of cells showing the nodal phenotype. Conclusions: NRG-1beta/ErbB signaling regulates the ratio of nodal- to working-type cells in differentiating hESC-CM cultures and presumably functions similarly during early human heart development. We speculate that, by manipulating NRG-1beta/ErbB signaling, it will be possible to generate preparations of enriched working-type myocytes for infarct repair, or, conversely, nodal cells for potential use in a biological pacemaker. PMID: 20671236 [PubMed - as supplied by publisher] | | |
| Reconstructing the lung.
July 31, 2010 at 9:59 AM
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| | Reconstructing the lung. Science. 2010 Jul 30;329(5991):520-2 Authors: Wagner WR, Griffith BP PMID: 20671176 [PubMed - in process] | | |
| Generation of induced pluripotent stem cells in rabbits: potential experimental models for human regenerative medicine.
July 31, 2010 at 9:59 AM
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| | Generation of induced pluripotent stem cells in rabbits: potential experimental models for human regenerative medicine. J Biol Chem. 2010 Jul 29; Authors: Honda A, Hirose M, Hatori M, Matoba S, Miyoshi H, Inoue K, Ogura A Human induced pluripotent stem (iPS) cells have the potential to establish a new field of promising regenerative medicine. Therefore, the safety and the efficiency of iPS-derived cells must be tested rigorously using appropriate animal models before human trials can commence. Here, we report the establishment of rabbit iPS cells as the first human-type iPS cells generated from a small laboratory animal species. Using lentiviral vectors, four human reprogramming genes (c-MYC, KLF4, SOX2 and OCT3/4) were introduced successfully into adult rabbit liver and stomach cells. The resulting rabbit iPS cells closely resembled human iPS cells; they formed flattened colonies with sharp edges and proliferated indefinitely in the presence of bFGF. They expressed the endogenous pluripotency markers c-MYC, KLF4, SOX2, OCT3/4 and NANOG, while the introduced human genes were completely silenced. Using in vitro differentiating conditions, rabbit iPS cells readily differentiated into ectoderm, mesoderm and endoderm. They also formed teratomas containing a variety of tissues of all three germ layers in immunodeficient mice. Thus, the rabbit iPS cells fulfilled all of the requirements for the acquisition of the fully reprogrammed state and can be considered "true" iPS cells, which are very similar to their embryonic stem (ES) cell counterparts we recently generated. However, their global gene expression analysis revealed a slight, but rigid difference between these two types of rabbit pluripotent stem cells. The rabbit model should enable us to compare iPS cells and ES cells under the same standardized conditions in evaluating their ultimate feasibility for pluripotent cell-based regenerative medicine in humans. PMID: 20670936 [PubMed - as supplied by publisher] | | |
| Minimally-Invasive Implantation of Living Tissue Engineered Heart Valves A Comprehensive Approach From Autologous Vascular Cells to Stem Cells.
July 31, 2010 at 9:59 AM
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| | Minimally-Invasive Implantation of Living Tissue Engineered Heart Valves A Comprehensive Approach From Autologous Vascular Cells to Stem Cells. J Am Coll Cardiol. 2010 Aug 3;56(6):510-520 Authors: Schmidt D, Dijkman PE, Driessen-Mol A, Stenger R, Mariani C, Puolakka A, Rissanen M, Deichmann T, Odermatt B, Weber B, Emmert MY, Zund G, Baaijens FP, Hoerstrup SP OBJECTIVES: The aim of this study was to demonstrate the feasibility of combining the novel heart valve replacement technologies of: 1) tissue engineering; and 2) minimally-invasive implantation based on autologous cells and composite self-expandable biodegradable biomaterials. BACKGROUND: Minimally-invasive valve replacement procedures are rapidly evolving as alternative treatment option for patients with valvular heart disease. However, currently used valve substitutes are bioprosthetic and as such have limited durability. To overcome this limitation, tissue engineering technologies provide living autologous valve replacements with regeneration and growth potential. METHODS: Trileaflet heart valves fabricated from biodegradable synthetic scaffolds, integrated in self-expanding stents and seeded with autologous vascular or stem cells (bone marrow and peripheral blood), were generated in vitro using dynamic bioreactors. Subsequently, the tissue engineered heart valves (TEHV) were minimally-invasively implanted as pulmonary valve replacements in sheep. In vivo functionality was assessed by echocardiography and angiography up to 8 weeks. The tissue composition of explanted TEHV and corresponding control valves was analyzed. RESULTS: The transapical implantations were successful in all animals. The TEHV demonstrated in vivo functionality with mobile but thickened leaflets. Histology revealed layered neotissues with endothelialized surfaces. Quantitative extracellular matrix analysis at 8 weeks showed higher values for deoxyribonucleic acid, collagen, and glycosaminoglycans compared to native valves. Mechanical profiles demonstrated sufficient tissue strength, but less pliability independent of the cell source. CONCLUSIONS: This study demonstrates the principal feasibility of merging tissue engineering and minimally-invasive valve replacement technologies. Using adult stem cells is successful, enabling minimally-invasive cell harvest. Thus, this new technology may enable a valid alternative to current bioprosthetic devices. PMID: 20670763 [PubMed - as supplied by publisher] | | |
| Nanomedicine in Ophthalmology: The New Frontier.
July 31, 2010 at 9:59 AM
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| | Nanomedicine in Ophthalmology: The New Frontier. Am J Ophthalmol. 2010 Aug;150(2):144-162.e2 Authors: Zarbin MA, Montemagno C, Leary JF, Ritch R PURPOSE: To review the fields of nanotechnology and nanomedicine as they relate to the development of treatments for vision-threatening disorders. DESIGN: Perspective following literature review. METHODS: Analysis of relevant publications in the peer-reviewed scientific literature. RESULTS: Nanotechnology involves the creation and use of materials and devices at the size scale of intracellular structures and molecules and involves systems and constructs on the order of <100 nm. The aim of nanomedicine is the comprehensive monitoring, control, construction, repair, defense, and improvement of human biological systems at the molecular level, using engineered nanodevices and nanostructures, operating massively in parallel at the single cell level, ultimately to achieve medical benefit. The earliest impact of nanomedicine is likely to involve the areas of biopharmaceuticals (eg, drug delivery, drug discovery), implantable materials (eg, tissue regeneration scaffolds, bioresorbable materials), implantable devices (eg, intraocular pressure monitors, glaucoma drainage valves), and diagnostic tools (eg, genetic testing, imaging, intraocular pressure monitoring). Nanotechnology will bring about the development of regenerative medicine (ie, replacement and improvement of cells, tissues, and organs), ultrahigh-resolution in vivo imaging, microsensors and feedback devices, and artificial vision. "Regenerative nanomedicine," a new subfield of nanomedicine, uses nanoparticles containing gene transcription factors and other modulating molecules that allow for the reprogramming of cells in vivo. CONCLUSIONS: Nanotechnology already has been applied to the measurement and treatment of different disease states in ophthalmology (including early- and late-stage disease), and many additional innovations will occur during the next century. PMID: 20670739 [PubMed - as supplied by publisher] | | |
| Generating induced pluripotent stem cells from common marmoset (Callithrix jacchus) fetal liver cells using defined factors, including Lin28.
July 31, 2010 at 9:59 AM
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| | Generating induced pluripotent stem cells from common marmoset (Callithrix jacchus) fetal liver cells using defined factors, including Lin28. Genes Cells. 2010 Jul 28; Authors: Tomioka I, Maeda T, Shimada H, Kawai K, Okada Y, Igarashi H, Oiwa R, Iwasaki T, Aoki M, Kimura T, Shiozawa S, Shinohara H, Suemizu H, Sasaki E, Okano H Although embryonic stem (ES) cell-like induced pluripotent stem (iPS) cells have potential therapeutic applications in humans, they are also useful for creating genetically modified human disease models in nonhuman primates. In this study, we generated common marmoset iPS cells from fetal liver cells via the retrovirus-mediated introduction of six human transcription factors: Oct-3/4, Sox2, Klf4, c-Myc, Nanog, and Lin28. Four to five weeks after introduction, several colonies resembling marmoset ES cells were observed and picked for further expansion in ES cell medium. Eight cell lines were established, and validation analyses of the marmoset iPS cells followed. We detected the expression of ES cell-specific surface markers. Reverse transcription-PCR showed that these iPS cells expressed endogenous Oct-3/4, Sox2, Klf4, c-Myc, Nanog and Lin28 genes, whereas all of the transgenes were silenced. Karyotype analysis showed that two of three iPS cell lines retained a normal karyotype after a 2-month culture. Both embryoid body and teratoma formation showed that marmoset iPS cells had the developmental potential to give rise to differentiated derivatives of all three primary germ layers. In summary, we generated marmoset iPS cells via the transduction of six transcription factors; this provides a powerful preclinical model for studies in regenerative medicine. PMID: 20670273 [PubMed - as supplied by publisher] | | |
| Gene therapy and angiogenesis in patients with coronary artery disease.
July 31, 2010 at 9:59 AM
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| | Gene therapy and angiogenesis in patients with coronary artery disease. Expert Rev Cardiovasc Ther. 2010 Aug;8(8):1127-38 Authors: Kastrup J Not all patients with severe coronary artery disease can be treated satisfactorily with current recommended medications and revascularization techniques. Various vascular growth factors have the potential to induce angiogenesis in ischemic tissue. Clinical trials have only evaluated the effect of VEGF and FGF in patients with coronary artery disease. The initial small and unblinded studies with either recombinant growth factor proteins or genes encoding growth factors were encouraging, demonstrating both clinical improvement and evidence of angiogenesis. However, subsequent larger double-blind placebo-controlled trials could not confirm the initial high efficacy of either the growth factor protein or the gene therapy approaches observed in earlier small trials. The clinical studies so far have all been without any gene-related serious adverse events. Future trials will focus on whether an improvement in clinical results can be obtained with a cocktail of growth factors or by a combination of gene and stem cell therapy in patients with severe coronary artery disease, which cannot be treated effectively with current treatment strategies. PMID: 20670190 [PubMed - in process] | | |
| Tissue-level modeling of xenobiotic metabolism in liver: An emerging tool for enabling clinical translational research.
July 31, 2010 at 9:59 AM
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| | Tissue-level modeling of xenobiotic metabolism in liver: An emerging tool for enabling clinical translational research. Clin Transl Sci. 2009 Jun;2(3):228-37 Authors: Lerapetritou MG, Georgopoulos PG, Roth CM, Androulakis LP This review summarizes some of the recent developments and identifies critical challenges associated with in vitro and in silico representations of the liver and assesses the translational potential of these models in the quest of rationalizing the process of evaluating drug efficacy and toxicity. It discusses a wide range of research efforts that have produced, during recent years, quantitative descriptions and conceptual as well as computational models of hepatic processes such as biotransport and biotransformation, intra- and intercellular signal transduction, detoxification, etc. The above mentioned research efforts cover multiple scales of biological organization, from molecule-molecule interactions to reaction network and cellular and histological dynamics, and have resulted in a rapidly evolving knowledge base for a "systems biology of the liver." Virtual organ/organism formulations represent integrative implementations of particular elements of this knowledge base, usually oriented toward the study of specific biological endpoints, and provide frameworks for translating the systems biology concepts into computational tools for quantitative prediction of responses to stressors and hypothesis generation for experimental design. PMID: 20443896 [PubMed - indexed for MEDLINE] | | |
| Osmolarity effects on bovine articular chondrocytes during three-dimensional culture in alginate beads.
July 31, 2010 at 9:59 AM
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| | Osmolarity effects on bovine articular chondrocytes during three-dimensional culture in alginate beads. Osteoarthritis Cartilage. 2010 Mar;18(3):433-9 Authors: Xu X, Urban JP, Tirlapur UK, Cui Z OBJECTIVE: With the development of engineered cartilage, the determination of the appropriate culture conditions is vital in order to maximize extracellular matrix synthesis. As osmolarity could affect the fate of chondrocytes, the purpose of this study was to determine the effects of osmolarity on chondrocytes during relatively long-term culture. DESIGN: Bovine articular chondrocytes were cultured in alginate beads in a biocarbonate free system at 280, 380 and 550 mOsm at pH 7.4 for up to 12 days, respectively. Cell volume, intracellular pH (pH(i)), cell number, glucosaminoglycan (GAG) and collagen retention were measured at day 5 and 12. Cell viability and volume were monitored over the 12 days of culture. RESULTS: By day 5 and 12, compared to the cell volume at 380 mOsm, around 20% (P<0.01) swelling and 15% (P<0.05) shrinkage were observed when the cells were cultured at 280 and 550 mOsm. The pH(i) over the 12 days of culture varied with osmolarity of the culture medium. In comparison with fresh cells, pH(i) became slightly more acidic by 0.15 pH units at 280 mOsm at day 5. However, by day 12, an alkalization of pH(i), by 0.2 pH units, was noted. A higher proliferation rate was seen at 280 mOsm than at other osmolarities while less GAG was produced. CONCLUSIONS: Chronic exposure to anisotonic conditions results in cell swelling at 280 mOsm and shrinkage at 550 mOsm. The osmolarity of 280 mOsm appears to encourage proliferation of chondrocytes, but inhibits matrix production. PMID: 19840877 [PubMed - indexed for MEDLINE] | | | | 
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