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| Combined impedance spectroscopy and Fourier domain optical coherence tomography to monitor cells in three-dimensional structures.
May 12, 2010 at 6:21 AM
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| | Combined impedance spectroscopy and Fourier domain optical coherence tomography to monitor cells in three-dimensional structures. Int J Artif Organs. 2010 Apr;33(4):238-43 Authors: Bagnaninchi PO Objectives: To assess non-invasively and in real time the three- dimensional organization of cells within porous matrices by combining Fourier Domain Optical Coherence Tomography (FDOCT) and Impedance Spectroscopy (IS). Materials and Methods: Broadband interferences resulting from the recombination of in-depth light scattering events within the sample and light from a reference arm are measured as a modulation of the spectrum generated by a superluminescent laser diode (?o = 930nm, FWHM 90nm). Fourier transform allows in-depth localization of the scatterers, and the 3D microstructure of the sample is reconstructed by raster scanning. Simultaneously impedance spectroscopy is performed with a dielectric probe connected to an impedance analyzer to gather additional cellular information, and synchronized with FDOCT measurements. Results: A combined IS-FDOCT system allowing an axial resolution of 5 micrometer in tissues and impedance measurements over the range 20MHz-1! GHz has been developed. Alginate matrices have been characterized in terms of microstructure and impedance. Matrices seeded with adipose-derived stem cells have been monitored without the use of labeling agent. ; PMID: 20458693 [PubMed - in process] | | |
| Raman spectroscopy as a tool for quality and sterility analysis for tissue engineering applications like cartilage transplants.
May 12, 2010 at 6:21 AM
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| | Raman spectroscopy as a tool for quality and sterility analysis for tissue engineering applications like cartilage transplants. Int J Artif Organs. 2010 Apr;33(4):228-37 Authors: Pudlas M, Koch S, Bolwien C, Walles H At present, the production of tissue engineered cartilage requires the concurrent production of two identical transplants. One transplant is used for destructive quality control and the second one is implanted into the patient. A non-invasive characterization of such tissue engineering samples would be a promising tool to achieve a production process of just one transplant that is both implanted and tested. Raman spectroscopy is a method that satisfies this requirement by analyzing cells without lysis, fixation or the use of any chemicals. This pure optical technique is based on inelastic scattering of laser photons by molecular vibrations of biopolymers. Characteristic peaks in Raman spectra of cells could be assigned to typical biochemical molecules present in biological samples. For the analysis of chondrocytes present in cartilage transplants, the determination of the cell vitality as well as the discrimination of another cell type have been studied by Raman s! pectroscopy. Another bottleneck in such biological processes under GMP conditions is sterility control, as most of the commonly used methods require long cultivation times. Raman spectroscopy provides a good alternative to conventional methods in terms of time saving. In this study, the potential of Raman spectroscopy as a quality and sterility control tool for tissue engineering applications was studied by analyzing and comparing the spectra of cell and bacteria cultures. ; PMID: 20458692 [PubMed - in process] | | |
| Two-photon techniques in tissue engineering.
May 12, 2010 at 6:21 AM
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| | Two-photon techniques in tissue engineering. Int J Artif Organs. 2010 May 11;33(4):219-228 Authors: Schade R, Weiß T, Berg A, Schnabelrauch M, Liefeith K Methods: Primary bovine chondrocytes were cultivated on collagen I/III scaffolds using a flow chamber system coupled with a two-photon laser scanning microscope (2PLSM). During the incubation the cell population was hydrostatically stimulated. The selective visualization of unlabeled cells and scaffolds was achieved by spectral autofluorescence imaging. To gain some insight into scaffold-mediated effects on cell growth and cell differentiation, hydrogel-like scaffolds with well defined 3D structures were generated by two-photon polymerization (2PP) using methacrylated urethane and polyethyleneglycol diacrylate. Results: We were able to show that spectral autofluorescence imaging provides spatially resolved data for the non-invasive online control of the tissue engineering process as well as the quantification of cell distribution within the scaffold. The fabrication of 3D 2PP scaffolds made from hydrogel-forming monomers and their effect on cell attachment and cel! l growth were also shown. Conclusions: Two-photon techniques provide powerful tools for both the non-invasive online visualization of 3D cell-scaffold constructs and the structuring of 3D cultivation environments. The application of these techniques is also suitable for integration into micro-systems technology (e.g. BioMEMS, Cells-on-Chip, Lab-on-a Chip). ; PMID: 20458691 [PubMed - as supplied by publisher] | | |
| The Response of Bone Marrow-Derived Mesenchymal Stem Cells to Dynamic Compression Following TGF-beta3 Induced Chondrogenic Differentiation.
May 12, 2010 at 6:21 AM
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| | The Response of Bone Marrow-Derived Mesenchymal Stem Cells to Dynamic Compression Following TGF-beta3 Induced Chondrogenic Differentiation. Ann Biomed Eng. 2010 May 11; Authors: Thorpe SD, Buckley CT, Vinardell T, O'Brien FJ, Campbell VA, Kelly DJ The objective of this study was to investigate the hypothesis that the application of dynamic compression following transforming growth factor-beta3 (TGF-beta3) induced differentiation will further enhance chondrogenesis of mesenchymal stem cells (MSCs). Porcine MSCs were encapsulated in agarose hydrogels and cultured in a chemically defined medium with TGF-beta3 (10 ng/mL). Dynamic compression (1 Hz, 10% strain, 1 h/day) was initiated at either day 0 or day 21 and continued until day 42 of culture; with TGF-beta3 withdrawn from some groups at day 21. Biochemical and mechanical properties of the MSC-seeded constructs were evaluated up to day 42. The application of dynamic compression from day 0 inhibited chondrogenesis of MSCs. This inhibition of chondrogenesis in response to dynamic compression was not observed if MSC-seeded constructs first underwent 21 days of chondrogenic differentiation in the presence of TGF-beta3. Spatial differences in sGAG accumulation in! response to both TGF-beta3 stimulation and dynamic compression were observed within the constructs. sGAG release from the engineered construct into the surrounding culture media was also dependent on TGF-beta3 stimulation, but was not effected by dynamic compression. Continued supplementation with TGF-beta3 appeared to be a more potent chondrogenic stimulus than the application of 1 h of daily dynamic compression following cytokine initiated differentiation. In the context of cartilage tissue engineering, the results of this study suggest that MSC seeded constructs should be first allowed to undergo chondrogenesis in vitro prior to implantation in a load bearing environment. PMID: 20458627 [PubMed - as supplied by publisher] | | |
| Advances in cardiovascular molecular imaging for tracking stem cell therapy.
May 12, 2010 at 6:21 AM
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| | Advances in cardiovascular molecular imaging for tracking stem cell therapy. Thromb Haemost. 2010 May 10;104(1) Authors: Ransohoff KJ, Wu JC The high mortality rate associated with cardiovascular disease is partially due to the lack of proliferative cells in the heart. Without adequate repair following myocardial infarction, progressive dilation can lead to heart failure. Stem cell therapies present one promising option for treating cardiovascular disease, though the specific mechanisms by which they benefit the heart remain unclear. Before stem cell therapies can be used safely in human populations, their biology must be investigated using innovative technologies such as multi-modality molecular imaging. The present review will discuss the basic principles, labelling techniques, clinical applications, and drawbacks associated with four major modalities: radionuclide imaging, magnetic resonance imaging, bioluminescence imaging, and fluorescence imaging. PMID: 20458434 [PubMed - as supplied by publisher] | | |
| Phase II Study of Cediranib, an Oral Pan-Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma.
May 12, 2010 at 6:21 AM
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| | Phase II Study of Cediranib, an Oral Pan-Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma. J Clin Oncol. 2010 May 10; Authors: Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK PURPOSE Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. METHODS Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Results Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking cor! ticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. CONCLUSION Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identif! ied early changes in circulating molecules as potential biomar! kers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials. PMID: 20458050 [PubMed - as supplied by publisher] | | |
| Potential Therapeutic Implications of Cancer Stem Cells in Glioblastoma.
May 12, 2010 at 6:21 AM
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| | Potential Therapeutic Implications of Cancer Stem Cells in Glioblastoma. Biochem Pharmacol. 2010 May 7; Authors: Cheng L, Bao S, Rich JN Glioblastoma is the most common and lethal type of primary brain tumor. Despite recent therapeutic advances in other cancers, the treatment of glioblastomas remains ineffective and essentially palliative. The treatment failure is a result of a number of causes, but we and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called glioblastoma stem cells (GSCs) display relative resistance to radiation and chemotherapy. GSCs also contribute to tumor growth through the stimulation of angiogenesis, which has been shown to be a useful therapeutic target in the treatment of recurrent or progressive malignant gliomas. Cancer stem cells also have been hypothesized as a contributor to systemic metastases. While glioblastomas rarely metastasize beyond the central nervous system, glioblastomas invade into brain structures to prevent surgical cure and GSCs have an extremely invasive phenotype. Collectively, these studies and others suggest that GS! Cs may be important therapeutic targets not only to achieve cure but even reduce tumor relapse and improve overall survival. Many recent studies suggest that GSCs share core regulatory pathways with normal embryonic and somatic stem cells, but display important distinctions that provide clues into useful treatment targets. The cancer stem cell hypothesis may also modify our approaches in tumor imaging and biomarker development, but clinical validation waits. In this review, we summarize the current understanding of GSC biology with a focus on potential anti-GSC therapies. PMID: 20457135 [PubMed - as supplied by publisher] | | |
| Stem cell therapy for chronic lung diseases: Hope and reality.
May 12, 2010 at 6:21 AM
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| | Stem cell therapy for chronic lung diseases: Hope and reality. Respir Med. 2010 Apr 22; Authors: Agostini C A number of recently published results have suggested the possibility of using stem cells to regenerate lung tissue. Several groups have developed various animal models employing haematopoietic stem cells, mesenchymal and endothelial progenitors, and embryonic cells, in which it has been possible to ameliorate the diseased lung. Despite these stimulating in vivo results a number of questions are pending before stem cell derivatives can be used in human lung disorders. This brief review will examine encouraging data that suggest the possibility of using stem cells in the therapy of lung diseases. In parallel, controversial findings are reviewed indicating that caution should be recommended before proposing to utilize stem cells in human lung diseases. PMID: 20456933 [PubMed - as supplied by publisher] | | |
| G-CSF depresses angiogenesis in vivo and in vitro: implications for sourcing cells for vascular regeneration therapy.
May 12, 2010 at 6:21 AM
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| | G-CSF depresses angiogenesis in vivo and in vitro: implications for sourcing cells for vascular regeneration therapy. J Thromb Haemost. 2010 May 4; Authors: Tura O, Crawford J, Barclay GR, Samuel K, Hadoke PW, Roddie H, Davies J, Turner ML Summary Background: The most common source of haematopoietic progenitor cells (HPC) for haematopoietic reconstitution is G-CSF mobilised peripheral blood stem cells (PBSC). It has been proposed that endothelial progenitor cells (EPC) share precursors with HPC and that EPC release may accompany HPC mobilisation to the circulation following G-CSF administration. Objective: We investigated EPC activity following HSC mobilisation and the direct effects of exogenous G-CSF administration on HUVEC and EOC (endothelial outgrowth cells) using in vitro and in vivo correlates of angiogenesis. Patients/Methods: Heparinised venous blood samples were collected from healthy volunteers and from cord blood at parturition. G-CSF mobilised samples were collected before administration, at aphaeresis harvest and at follow-up. PBSC were phenotyped by flow cytometry and cultured in standard CFU-EPC and EOC assays. The effect of exogenous G-CSF was investigated by addition to HUVEC and E! OC in standard tubule formation, aortic ring assays and in vivo sponge implantation model. Results: Our data shows that G-CSF mobilisation of PBSC produces a profound, reversible depression of circulating CFU-EPC. Further, G-CSF administration did not mobilise CD34 (+) CD133(-) cells which include precursors of EOC. No EOC were cultured from any mobilised PBSC studied. Exogenous G-CSF inhibited CFU-EPC generation, HUVEC and EOC tubule formation, microvessel outgrowth, and implanted sponge vascularisation in mice. Conclusions: G-CSF administration depresses both endothelial cell angiogenesis and monocyte pro-angiogenic activity, and we suggest that any angiogenic benefit observed following implantation of cells mobilised by G-CSF may come only from a paracrine effect from HPC. PMID: 20456757 [PubMed - as supplied by publisher] | | |
| Lidocaine/Monoethylglycinexylidide Test, Galactose Elimination Test, and Sorbitol Elimination Test for Metabolic Assessment of Liver Cell Bioreactors.
May 12, 2010 at 6:21 AM
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| | Lidocaine/Monoethylglycinexylidide Test, Galactose Elimination Test, and Sorbitol Elimination Test for Metabolic Assessment of Liver Cell Bioreactors. Artif Organs. 2010 Apr 27; Authors: Gerlach JC, Brayfield C, Puhl G, Borneman R, Müller C, Schmelzer E, Zeilinger K Abstract Various metabolic tests were compared for the performance characterization of a liver cell bioreactor as a routine function assessment of cultures in a standby for patient application in clinical studies. Everyday quality assessment (QA) is essential to ensure a continuous level of cellular functional capacity in the development of hepatic progenitor cell expansion systems providing cells for regenerative medicine research; it is also of interest to meet safety requirements in bioartificial extracorporeal liver support systems under clinical evaluation. Quality criteria for the description of bioreactor cultures were developed using primary porcine liver cells as a model. Porcine liver cells isolated by collagenase perfusion with an average of 3 x 10(9) primary cells were used in 39 bioreactors for culture periods up to 33 days. Measurements of monoethylglycinexylidide synthesis and elimination of lidocaine, galactose elimination, and sorbitol elimination! proved to be useful for routine QA of primary liver cell cultures. We demonstrate two methods for dispensing test substances, bolus administration and continuous, steady-state administration. Bolus test data were grouped in Standard, Therapy, Infection/Contamination, and Cell-free control groups. Statistical analyses show significant differences among all groups for every test substance. Post hoc comparisons indicated significant differences between Standard and Cell-free groups for all elimination parameters. For continuous tests, results were categorized according to number of culture days and time-dependent changes were analyzed. Continuous administration enables a better view of culture health and the time dependency of cellular function, whereas bolus administration is more flexible. Both procedures can be used to define cell function. Assessment of cellular function and bioreactor quality can contribute significantly to the quality of experimental or clinical studies! in the field of hepatic bioreactor development. PMID: 20456323 [PubMed - as supplied by publisher] | | |
| Tissue-Engineered Vascular Adventitia with Vasa Vasorum Improves Graft Integration and Vascularization Through Inosculation.
May 12, 2010 at 6:21 AM
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| | Tissue-Engineered Vascular Adventitia with Vasa Vasorum Improves Graft Integration and Vascularization Through Inosculation. Tissue Eng Part A. 2010 May 10; Authors: Guillemette MD, Gauvin R, Perron C, Labbé R, Germain L, Auger FA Tissue-engineered blood vessel is one of the most promising living substitutes for coronary and peripheral artery bypass graft surgery. However, one of the main limitations in tissue engineering is vascularization of the construct before implantation. Such a vascularization could play an important role in graft perfusion and host integration of tissue-engineered vascular adventitia. Using our self-assembly approach, we developed a method to vascularize tissue-engineered blood vessel constructs by coculturing endothelial cells in a fibroblast-laden tissue sheet. After subcutaneous implantation, enhancement of graft integration within the surrounding environment was noted after 48 h and an important improvement in blood circulation of the grafted tissue at 1 week postimplantation. The distinctive branching structure of end arteries characterizing the in vivo adventitial vasa vasorum has also been observed in long-term postimplantation follow-up. After a 90-day impla! ntation period, hybrid vessels containing human and mouse endothelial cells were still perfused. Characterization of the mechanical properties of both control and vascularized adventitia demonstrated that the ultimate tensile strength, modulus, and failure strain were in the same order of magnitude of a pig coronary artery. The addition of a vasa vasorum to the tissue-engineered adventitia did not influence the burst pressure of these constructs. Hence, the present results indicate a promising answer to the many challenges associated with the in vitro vascularization and in vivo integration of many different tissue-engineered substitutes. PMID: 20455774 [PubMed - as supplied by publisher] | | |
| Achieving reimbursement for regenerative medicine products in the USA.
May 12, 2010 at 6:21 AM
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| | Achieving reimbursement for regenerative medicine products in the USA. Regen Med. 2010 May;5(3):463-9 Authors: Ginty PJ, Singh PB, Smith D, Hourd P, Williams DJ Achieving reimbursement for regenerative medicine products is potentially a greater challenge than gaining US FDA approval, making it a decisive factor in the success or failure of small businesses. However, the mechanisms by which reimbursement is achieved are still seen as something of a 'black box', especially to those outside of the USA. This report aims to provide insights into the mechanisms of reimbursement and variety of payers in the USA, and to act as a starting point for a successful US reimbursement strategy. Fundamental concepts such as coverage, payment and coding are explained and linked with the factors that potentially determine the successful reimbursement of regenerative medicine products, including cost of goods and clinical study design. Finally, important considerations for the design of clinical studies that satisfy both the payers and the FDA are discussed and the key elements of a successful company strategy identified. PMID: 20455656 [PubMed - in process] | | |
| Proximal to distal patterning during limb development and regeneration: a review of converging disciplines.
May 12, 2010 at 6:21 AM
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| | Proximal to distal patterning during limb development and regeneration: a review of converging disciplines. Regen Med. 2010 May;5(3):451-62 Authors: Mariani FV Regeneration of lost structures typically involves distinct events: wound healing at the damaged site, the accumulation of cells that will be used as future building blocks and, finally, the initiation of molecular signaling pathways that dictate the form and pattern of the regenerated structures. Amphibians and urodeles in particular, have long been known to have exceptional regenerative properties. For many years, these animals have been the model of choice for understanding limb regeneration, a complex process that involves reconstructing skin, muscle, bone, connective tissue and nerves into a functional 3D structure. It appears that this process of rebuilding an adult limb has many similarities with how the limb forms in the first place--for example, in the embryo, all the components of the limb need to be formed and this requires signaling mechanisms to specify the final pattern. Thus, both limb formation and limb regeneration are likely to employ the same mo! lecular pathways. Given the available tools of molecular biology and genetics, this is an exciting time for both fields to share findings and make significant progress in understanding more about the events that dictate embryonic limb pattern and control limb regeneration. This article focuses particularly on what is known about the molecular control of patterning along the proximal-distal axis. PMID: 20455655 [PubMed - in process] | | |
| Role of transcription factors in cell replacement therapies for neurodegenerative conditions.
May 12, 2010 at 6:21 AM
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| | Role of transcription factors in cell replacement therapies for neurodegenerative conditions. Regen Med. 2010 May;5(3):441-50 Authors: Thomas M Parkinson's disease is the second most common neurological condition, behind dementia, for which there is currently no cure. A promising curative treatment approach is cell replacement therapy, which involves the introduction of new dopaminergic cells into a degenerative Parkinson's disease brain. The future progression of this field into a clinically viable treatment option is reliant on generating replacement dopaminergic cells. Furthermore, as the ability of transplanted dopaminergic neurons to form connections with host tissue is dependent on where the cells are derived from, the replacement dopaminergic cells will need to be phenotypically similar to substantia nigra dopaminergic neurons. This article focuses on how developmental transcription factors have been utilized to assist the progression of stem cell therapies for Parkinson's disease. Key transcription factor-mediated stages of substantia nigra dopaminergic neuronal development is described in the bel! ief that a comprehensive understanding of this specific dopaminergic differentiation pathway is necessary for the progression of successful cell therapies for Parkinson's disease. PMID: 20455654 [PubMed - in process] | | |
| Stem cells in genetic myelin disorders.
May 12, 2010 at 6:21 AM
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| | Stem cells in genetic myelin disorders. Regen Med. 2010 May;5(3):425-39 Authors: Kemp K, Mallam E, Scolding N, Wilkins A The genetic myelin disorders are a range of diseases that manifest with severe neurological problems, often from infancy. It has been postulated for some time that stem cells might be an effective treatment for these disorders, primarily as agents to restore dysfunctional or lost myelin. Stem cells, however, may offer a wider range of therapeutic potential, for instance as vehicles to replace abnormal enzymes or genes, or to provide trophic support for residual CNS tissue. This article will review several of the more common genetic myelin disorders and currently available therapies, including bone marrow transplantation for adrenoleukodystrophy. Specific stem cell subtypes and their relevance to potential therapeutic use will be discussed and stem cell transplantation in animal model studies will also be reviewed. PMID: 20455653 [PubMed - in process] | | |
| Red blood cells from pluripotent stem cells for use in transfusion.
May 12, 2010 at 6:21 AM
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| | Red blood cells from pluripotent stem cells for use in transfusion. Regen Med. 2010 May;5(3):411-23 Authors: Mountford JC, Olivier E, Jordanides NE, de Sousa P, Turner ML The use of donated red blood cells in transfusion is a well-established cellular therapy. However, problems including insufficient supply, transfusion-transmitted infections and the need for immunological matching hamper even in the best services. These issues may be eliminated by using pluripotent stem cells to generate universal donor group O, Rhesus D-negative red blood cells. Human embryonic stem cells can be maintained and expanded indefinitely and can, therefore, produce the very large cell numbers required for this application. Red blood cell production is also an attractive goal for pluripotent stem cell-derived therapeutics because it is a well-characterized single cell suspension, lacking nucleated cells and with a low expression of HLA molecules. Much progress has been made; however, a number of challenges remain including scale-up, clinical effectiveness and product safety. PMID: 20455652 [PubMed - in process] | | |
| Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins.
May 12, 2010 at 6:21 AM
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| | Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins. Regen Med. 2010 May;5(3):403-10 Authors: Mantovani C, Mahay D, Kingham M, Terenghi G, Shawcross SG, Wiberg M AIMS: PNS myelin is formed by Schwann cells (SCs). In this study, we applied an in vitro model to study myelin formation, using bone marrow mesenchymal stem cells and adipose-derived stem cells differentiated into SC-like cells and co-cultured with dissociated adult dorsal root ganglia neurons. METHODS: Immunocytochemistry, reverse transcription-PCR and western blotting techniques were used to investigate the expression of myelin proteins at both the transcriptional and translational level. RESULTS: Transcripts for protein zero, peripheral myelin protein 22 and myelin basic protein were detected in differentiated stem cells following co-culture with neuronal cells. Furthermore, protein zero, peripheral myelin protein 22 and myelin basic proteins were recognized in the co-cultures. These results were consistent with immunostaining of myelin proteins and with observation by electron microscopy. CONCLUSION: Both types of adult stems cells differentiated into SC-like ! cells have potential to myelinate neuronal cells during regeneration, being functionally identical to SCs of the PNS. PMID: 20455651 [PubMed - in process] | | |
| Using poly(lactide-co-glycolide) electrospun scaffolds to deliver cultured epithelial cells to the cornea.
May 12, 2010 at 6:21 AM
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| | Using poly(lactide-co-glycolide) electrospun scaffolds to deliver cultured epithelial cells to the cornea. Regen Med. 2010 May;5(3):395-401 Authors: Deshpande P, McKean R, Blackwood KA, Senior RA, Ogunbanjo A, Ryan AJ, MacNeil S AIMS: To assess the potential of electrospun poly(lactide-co-glycolide) membranes to provide a biodegradable cell carrier system for limbal epithelial cells. MATERIAL & METHODS: 50:50 poly(lactide-co-glycolide) scaffolds were spun, sterilized and seeded with primary rabbit limbal epithelial cells. Cells were cultured on the scaffolds for 2 weeks and then examined by confocal microscopy, cryosectioning and scanning-electron microscopy. The tensile strength of scaffolds before and after annealing and sterilization was also studied. RESULTS: The limbal cells had formed a continuous multilayer of cells on either side of the scaffold. Scaffolds with cells showed signs of the onset of degradation within 2 weeks in culture media at 37 degrees C. Scaffolds that were annealed resulted in a more brittle and stiff mat. CONCLUSIONS: We suggest this carrier membrane could be used as a replacement for the human amniotic membrane in the treatment of limbal stem cell deficien! cy, lowering the risk of disease transmission to the patient. PMID: 20455650 [PubMed - in process] | | |
| Isolation, characterization and preclinical development of human glial-restricted progenitor cells for treatment of neurological disorders.
May 12, 2010 at 6:21 AM
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| | Isolation, characterization and preclinical development of human glial-restricted progenitor cells for treatment of neurological disorders. Regen Med. 2010 May;5(3):381-94 Authors: Sandrock RW, Wheatley W, Levinthal C, Lawson J, Hashimoto B, Rao M, Campanelli JT AIM: Glial-restricted progenitor cells (GRPs), a neural cell population that gives rise to astrocytes and oligodendrocytes both in vitro and in vivo, hold great promise as a cellular therapeutic for the treatment of demyelinating and neurodegenerative diseases of the CNS. The manufacturing and characterization protocols of human-derived GRPs (hGRPs; trade name Q-Cells) for use in a clinical setting that adhere to rigorous standards for their isolation, propagation, characterization and storage are presented. MATERIALS & METHODS: hGRPs, defined by their immunoreactivity with A2B5 antibodies, were isolated from fetal cadaver forebrain tissue of mice 17-24 weeks gestational age using Miltenyi paramagnetic bead cell separation technology. GRPs were grown in a defined xenobiotic-free medium for 6 days. At harvest, hGRPs were characterized using immunocytochemical techniques. Long-term cryopreservation and storage conditions, and viability upon freeze-thaw were dete! rmined. The phenotypic differentiation potential of hGRPs was determined by implantation experiments into the CNS of shiverer mice. RESULTS: hGRPs were isolated from over 50 neural tissues of either sex during gestational ages of 17-24 weeks. Cells expanded out to 6 days in vitro in a xenobiotic-free medium demonstrated very consistent immunocytochemical profiles. No residual antibody used in the purification process was detected after 6 days of growth in vitro. GRPs could be frozen at up to 24 million cells/ml and were over 70% viable upon freeze-thaw. Thawed hGRPs transplanted into the brain of the dysmyelinated shiverer mouse model were observed to differentiate into both glial fibrillary acidic protein-positive astrocytes and myelin basic protein-positive oligodendrocytes; no human-derived NeuN-positive neuronal cells were observed and no abnormal cell proliferation was observed. CONCLUSION: We demonstrate that hGRPs can be consistently obtained, propagated, cryopreserv! ed and characterized using protocols that can be transferred t! o a good laboratory practice/good manufacturing practice setting for the manufacture of clinical-grade hGRP cellular therapeutics. Functional data demonstrate that cells manufactured under these conditions are able to differentiate into appropriate cellular phenotypes in an animal model of dysmyelination. PMID: 20455649 [PubMed - in process] | | |
| In vitro differentiation potential of human embryonic versus adult stem cells.
May 12, 2010 at 6:21 AM
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| | In vitro differentiation potential of human embryonic versus adult stem cells. Regen Med. 2010 May;5(3):365-79 Authors: Rooney GE, Nistor GI, Barry FB, Keirstead HS BACKGROUND: There is widespread controversy regarding the potential of human neural stem cells and human mesenchymal stem cells (hMSCs) to form cell types outside of their normal developmental lineage. A greater understanding of the differentiation potential and bias of these stem cell types would allow researchers to select the cell type that best suits the research or clinical need at hand. MATERIALS & METHODS: We used identical in vitro protocols to quantitatively compare the potential of human embryonic stem cells, human neural stem cells and hMSCs to differentiate into specific ectodermal or mesodermal lineages. RESULTS: Our findings demonstrate that human embryonic stem cells and human neural stem cells have the ability to differentiate into high purity neuronal progenitor or oligodendrocyte progenitor cultures. By contrast, hMSCs generated exceedingly limited numbers of neural lineages. Both human embryonic stem cells and hMSCs generated adipocytes and ! osteocytes when exposed to mesodermal differentiation conditions. CONCLUSION: These studies underscore the importance of distinguishing differentiation potential from differentiation bias, an important consideration in the development of cell replacement strategies. PMID: 20455648 [PubMed - in process] | | |
| Gene- and cell-based approaches for neurodegenerative disease.
May 12, 2010 at 6:21 AM
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| | Gene- and cell-based approaches for neurodegenerative disease. Adv Exp Med Biol. 2010;671:117-30 Authors: Urbaniak Hunter K, Yarbrough C, Ciacci J Neurodegenerative diseases comprise an important group ofchronic diseases that increase in incidence with rising age. In particular, the two most common neurodegenerative diseases are Alzheimer's disease and Parkinson's disease, both of which will be discussed below. A third, Huntington's disease, occurs infrequently, but has been studied intensely. Each of these diseases shares characteristics which are also generalizeable to other neurodegenerative diseases: accumulation ofproteinaceous substances that leads inexorably to selective neuronal death and decline in neural function. Treatments for these diseases have historically focused on symptomatic relief, but recent advances in molecular research have identified more specific targets. Additionally, stem cell therapy, immunotherapy and trophic-factor delivery provide avenues for neuronal protection that may alter the natural progression of these devastating illnesses. Upcoming clinical trials will evaluate treatm! ent strategies and provide hope that translational research will decrease the onset of debilitating disability associated with neurodegenerative disease. PMID: 20455500 [PubMed - in process] | | |
| Stem cells in the treatment of stroke.
May 12, 2010 at 6:21 AM
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| | Stem cells in the treatment of stroke. Adv Exp Med Biol. 2010;671:105-16 Authors: Urbaniak Hunter K, Yarbrough C, Ciacci J Stroke is an often devastating insult resulting in neurological deficit lasting greater than 24 hours. In the United States, stroke is the third leading cause of death. In those who do not succumb, any outcome from total recovery over a period of weeks to months to persistent profound neurological deficits is possible. Present treatment centers on the decision to administer tissue plasminogen activator, subsequent medical stabilization and early intervention with rehabilitation and risk factor management. The advent of stem cell therapy presents an exciting new frontier for research in stroke treatment, with the potential to cause a paradigm shift from symptomatic control and secondary prevention to reconstitution of neural networks and prevention of neuronal cell death after neurologic injury. PMID: 20455499 [PubMed - in process] | | |
| [Effects of UO-126 on proliferation and fbw7 expression of HeLa cells]
May 12, 2010 at 6:21 AM
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| | [Effects of UO-126 on proliferation and fbw7 expression of HeLa cells] Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2010 Feb;26(2):138-40 Authors: Sun D, Shen Y, Wang SH, Xiang ZW, Xie YS, Jiang X AIM: To observe the effects of UO-126 on the expression of F-box and WD repeat domain-containing protein 7(FBW7)and on the proliferation of human cervical cancer cell lines (HeLa cells). METHODS: HeLa cells were treated with different concentrations of UO-126, MTT assay was used to observe the proliferation of HeLa cells. Immunofluorescence showed the location and expression of FBW7 in HeLa cells. The mRNA and protein expression of FBW7 were detected by RT-PCR and Western blot before and after mitogen-activated protein kinases (MAPK)signal was blocked by UO-126 a MAPK inhibitor. RESULTS: MTT results showed that the concentration range of MAPK signaling pathway inhibitor UO-126 inhibited the proliferation of HeLa cells in a concentration-and time-dependent manner(P<0.05). Immunofluorescence showed that the expression of positive FBW7 had increased after HeLa cells were treated with UO-126. RT-PCR and Western blot exhibited that the FBW7 mRNA and protein expressi! on had significantly increased before and after HeLa cells were treated with UO-126(P<0.05). CONCLUSION: UO-126 could inhibit HeLa cells proliferation, FBW7 lied downstream of MAPK signaling pathway. PMID: 20230673 [PubMed - indexed for MEDLINE] | | |
| Engineering strategies to emulate the stem cell niche.
May 12, 2010 at 6:21 AM
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| | Engineering strategies to emulate the stem cell niche. Trends Biotechnol. 2010 Mar;28(3):117-24 Authors: Vazin T, Schaffer DV The stem cell niche is an anatomical site that contains a reservoir of multipotent stem cells (SCs) that can maintain normal tissue, or replenish injured or aged cell populations, in response to mechanisms that regulate whether they should remain quiescent, undergo self-renewal, or differentiate. The choice among these hallmark SC behaviors is governed by intricate soluble and "solid phase" signals that are systemic or presented by the local niche cells. In this review, we discuss the progress achieved in understanding the mechanisms and principles that govern microenvironmental regulation of SC behavior, and focus on novel approaches that have been developed to synthesize this basic information to engineer creative strategies for harnessing and controlling SCs ex vivo and in vivo. PMID: 20042248 [PubMed - indexed for MEDLINE] | | |
| Mechanical loading regimes affect the anabolic and catabolic activities by chondrocytes encapsulated in PEG hydrogels.
May 12, 2010 at 6:21 AM
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| | Mechanical loading regimes affect the anabolic and catabolic activities by chondrocytes encapsulated in PEG hydrogels. Osteoarthritis Cartilage. 2010 Jan;18(1):126-37 Authors: Nicodemus GD, Bryant SJ OBJECTIVE: Mechanical loading of cell-laden synthetic hydrogels is one strategy for regenerating functional cartilage. This work tests the hypothesis that type of loading (continuous vs intermittent) and timing when loading is applied (immediate vs delayed) influence anabolic and catabolic activities of chondrocytes when encapsulated in poly(ethylene glycol) (PEG) hydrogels. METHODS: Primary bovine chondrocytes encapsulated in PEG hydrogels were subjected to unconfined dynamic compressive strains applied continuously or intermittently for 1 week (i.e., immediate) or intermittently for 1 week but after a 1 week free-swelling (FS) period (i.e., delayed). Anabolic activities were assessed by gene expression for collagen II and aggrecan (AGC) and extracellular matrix (ECM) deposition by (immuno)histochemistry. Catabolic activities were assessed by gene expression for matrix metalloproteinases, MMP-1, 3, and 13. RESULTS: Intermittent loading (IL) upregulated ECM and MM! P expressions, e.g., 2-fold, 16-fold and 8-fold for collagen II, MMP-1, MMP-3, respectively. Continuous loading upregulated AGC expression 1.5-fold but down-regulated MMP-1 (3-fold) and -3 (2-fold) expressions. For delayed loading, chondrocytes responded to FS conditions by down-regulating MMP expressions (P<0.01), but were less sensitive to loading when applied during week 2. Spatially, deposition of ECM molecules was dependent on the timing of loading, where immediate loading favored enhanced collagen II deposition. CONCLUSIONS: The type and timing of dynamic loading dramatically influenced ECM and MMP gene expression and to a lesser degree matrix deposition. Our findings suggest that early applications of IL is necessary to stimulate both anabolic and catabolic activities, which may be important in regenerating and restructuring the engineered tissue long-term. PMID: 19748607 [PubMed - indexed for MEDLINE] | | |
| Mechanical load inhibits IL-1 induced matrix degradation in articular cartilage.
May 12, 2010 at 6:21 AM
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| | Mechanical load inhibits IL-1 induced matrix degradation in articular cartilage. Osteoarthritis Cartilage. 2010 Jan;18(1):97-105 Authors: Torzilli PA, Bhargava M, Park S, Chen CT OBJECTIVE: Osteoarthritis is a disease process of cellular degradation of articular cartilage caused by mechanical loads and inflammatory cytokines. We studied the cellular response in native cartilage subjected to a mechanical load administered simultaneously with an inflammatory cytokine interleukin-1 (IL-1), hypothesizing that the combination of load and cytokine would result in accelerated extracellular matrix (ECM) degradation. METHODS: Mature bovine articular cartilage was loaded for 3 days (stimulation) with 0.2 and 0.5 MPa stresses, with and without IL-1 (IL-1alpha, 10 ng/ml), followed by 3 days of no stimulation (recovery). Aggrecan and collagen loss were measured as well as aggrecan cleavage using monoclonal antibodies AF-28 and BC-3 for cleavage by aggrecanases (ADAMTS) and matrix metalloproteinases (MMPs), respectively. RESULTS: Incubation with IL-1 caused aggrecan cleavage by aggrecanases and MMPs during the 3 days of stimulation. A load of 0.5 MPa in! hibited the IL-1-induced aggrecan loss while no inhibition was found for the 0.2 MPa stress. There was no collagen loss during the treatments but upon load and IL-1 removal proteoglycan and collagen loss increased. Load itself under these conditions was found to have no effect when compared to the unloaded controls. CONCLUSIONS: A mechanical load of sufficient magnitude can inhibit ECM degradation by chondrocytes when stimulated by IL-1. The molecular mechanisms involved in this process are not clear but probably involve altered mechanochemical signal transduction between the ECM and chondrocyte. PMID: 19747586 [PubMed - indexed for MEDLINE] | | |
| Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage.
May 12, 2010 at 6:21 AM
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| | Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage. Osteoarthritis Cartilage. 2010 Jan;18(1):12-23 Authors: Rutgers M, van Pelt MJ, Dhert WJ, Creemers LB, Saris DB OBJECTIVE: Regeneration of hyaline cartilage has been the focus of an increasing number of research groups around the world. One of the most important outcome measures in evaluation of its success is the histological quality of cartilaginous tissue. Currently, a variety of histological scoring systems is used to describe the quality of osteoarthritic, in vivo repaired or in vitro engineered tissue. This review aims to provide an overview of past and currently used histological scoring systems, in an effort to aid cartilage researchers in choosing adequate and validated cartilage histological scoring systems. METHODS: Histological scoring systems for analysis of osteoarthritic, tissue engineered and in vivo repaired cartilage were reviewed. The chronological development as well as the validity and practical applicability of the scoring systems is evaluated. RESULTS: The Histological-Histochemical Grading System (HHGS) or a HHGS-related score is most often used for ! evaluation of osteoarthritic cartilage, however the Osteoarthritis Research Society International (OARSI) Osteoarthritis Cartilage Histopathology Assessment System seems a valid alternative. The O'Driscoll score and the International Cartilage Repair Society (ICRS) II score may be used for in vivo repaired cartilage. The 'Bern score' seems most adequate for evaluation of in vitro engineered cartilage. CONCLUSION: A great variety of histological scoring systems exists for analysis of osteoarthritic or normal, in vivo repaired or tissue-engineered cartilage, but only few have been validated. Use of these validated scores may considerably improve exchange of information necessary for advances in the field of cartilage regeneration. PMID: 19747584 [PubMed - indexed for MEDLINE] | | |
| Reconstruction of a tissue-engineered cornea with porcine corneal acellular matrix as the scaffold.
May 12, 2010 at 6:21 AM
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| | Reconstruction of a tissue-engineered cornea with porcine corneal acellular matrix as the scaffold. Cells Tissues Organs. 2010;191(3):193-202 Authors: Fu Y, Fan X, Chen P, Shao C, Lu W Interest in developing tissue-engineered cornea has increased with the decrease in the supply of donor tissue. The aim of the present study was to investigate the feasibility and method of reconstructing corneal equivalents with porcine corneal acellular matrix as the scaffold in a dynamic culturing system. Applying the detergent Triton X-100 (1%) and a freeze-drying process, porcine corneas were decellularized and prepared as a scaffold, and hematoxylin-eosin staining and scanning electron microscopy showed no cells in the decellularized stroma. In order to measure the in vivo biocompatibility, part of the scaffold was transplanted into a pocket of rabbit corneal stroma and observed for 3 months. No sign of rejection were observed, and the acellular matrix gradually integrated in the rabbit cornea, indicating that the scaffold had good biocompatibility. To reconstruct a tissue-engineered cornea, cultured rabbit keratocytes were seeded into the scaffold. After 1 w! eek of culture in a culturing vessel, rabbit epithelial and endothelial cells were seeded on both sides of the stroma, respectively. The reconstructed cornea consisted of three layers in histological structure: the epithelium, stoma and endothelium. Stratified epithelial cells formed on the surface, which were cytokeratin 3 positive in the cytoplasm; endothelial cell monolayers were located on the inner side, and pump-related aquaporin 1 was found in the cells. These results confirmed that the corneal acellular matrix can be used as a scaffold for tissue-engineered cornea, and a biological corneal equivalent can be reconstructed in a dynamic culturing system. PMID: 19690400 [PubMed - indexed for MEDLINE] | | |
| Macromer density influences mesenchymal stem cell chondrogenesis and maturation in photocrosslinked hyaluronic acid hydrogels.
May 12, 2010 at 6:21 AM
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| | Macromer density influences mesenchymal stem cell chondrogenesis and maturation in photocrosslinked hyaluronic acid hydrogels. Osteoarthritis Cartilage. 2009 Dec;17(12):1639-48 Authors: Erickson IE, Huang AH, Sengupta S, Kestle S, Burdick JA, Mauck RL OBJECTIVE: Engineering cartilage requires that a clinically relevant cell type be situated within a 3D environment that supports cell viability, the production and retention of cartilage-specific extracellular matrix (ECM), and eventually, the establishment of mechanical properties that approach that of the native tissue. In this study, we investigated the ability of bone marrow derived mesenchymal stem cells (MSCs) to undergo chondrogenesis in crosslinked methacrylated hyaluronic acid hydrogels (MeHA) of different macromer concentrations (1, 2, and 5%). DESIGN: Over a 6 week culture period under pro-chondrogenic conditions, we evaluated cartilage-specific gene expression, ECM deposition within constructs and released to the culture media, and mechanical properties in both compression and tension. Further, we examined early matrix assembly and long term histological features of the forming tissues, as well as the ability of macromolecules to diffuse within hydroge! ls as a function of MeHA macromer concentration. RESULTS: Findings from this study show that variations in macromer density influence MSC chondrogenesis in distinct ways. Increasing HA macromer density promoted chondrogenesis and matrix formation and retention, but yielded functionally inferior constructs due to limited matrix distribution throughout the construct expanse. In 1% MeHA constructs, the equilibrium compressive modulus reached 0.12MPa and s-GAG content reached nearly 3% of the wet weight, values that matched or exceeded those of control agarose constructs and that are 25 and 50% of native tissue levels, respectively. CONCLUSIONS: These data provide new insight into how early matrix deposition regulates long term construct development, and defines new parameters for optimizing the formation of functional MSC-based engineered articular cartilage using HA hydrogels. PMID: 19631307 [PubMed - indexed for MEDLINE] | | |
| Morphological and immunocytochemical characteristics indicate the yield of early progenitors and represent a quality control for human mesenchymal stem cell culturing.
May 12, 2010 at 6:21 AM
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| | Morphological and immunocytochemical characteristics indicate the yield of early progenitors and represent a quality control for human mesenchymal stem cell culturing. J Anat. 2009 May;214(5):759-67 Authors: Haasters F, Prall WC, Anz D, Bourquin C, Pautke C, Endres S, Mutschler W, Docheva D, Schieker M Human mesenchymal stem cells (hMSC) are a heterogeneous cell population, which is reflected in varying morphological and biological properties. Three subpopulations with intrinsic characteristics can be distinguished: small rapidly self-renewing cells, spindle-shaped cells and large, flattened cells. Unfortunately, it has neither been possible to morphologically define these distinct cells consistently, nor to relate them to specific surface marker features. Here, the primary hMSC subpopulations of three donors are clearly defined by maximum cell diameter and area. Furthermore, these cells were stained for the putative hMSC surface markers CD105, CD90 as well as CD73, and evaluated by three-colour flow cytometry and simultaneous multicolour immunocytochemistry. Interestingly, cell cultures with a high rate of triple-positive hMSC featured a higher content of rapidly self-renewing cells. On the other hand, a higher fraction of flattened cells correlated with a loss! of one or more hMSC surface markers. The expression of CD73 showed the highest heterogeneity. Immunocytochemistry further confirmed that flattened cells mainly lack CD73 expression, whereas rapidly self-renewing cells were steadily positive for all three hMSC markers. In the literature, hMSC properties are especially conceded to rapidly self-renewing cells, whereas flattened cells have been suggested to represent early stages of lineage-specific progenitors. We reveal that among the recently suggested surface markers, CD73 is the most sensitive, as it seems to be down-regulated in the early stages of differentiation. Our morphological and immunocytochemical characterization of hMSC subpopulations indicates the yield of early multipotent hMSC and thereby provides a quality control approach for hMSC culturing. PMID: 19438770 [PubMed - indexed for MEDLINE] | | | | 
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