|  |  |  | | | | | TE-RegenMed-StemCell feed | | | | | | | | | | | | | | | | | | California's $3 billion stem cell agency has created a broad-based, 43-member, interstate consortium of researchers and businesses to work with the FDA to develop "well-defined regulatory pathways for stem cell therapies."
CIRM President Alan Trounson is high on the effort, which will be making another quasi-public appearance in just a few days. Last spring, Trounson told CIRM directors that | | | | | | | | | | | | | | | | | | | | | | | | | Controlling Cell Behavior Through the Design of Polymer Surfaces. Small. 2010 Sep 16; Authors: Alves NM, Pashkuleva I, Reis RL, Mano JF Polymers have gained a remarkable place in the biomedical field as materials for the fabrication of various devices and for tissue engineering applications. The initial acceptance or rejection of an implantable device is dictated by the crosstalk of the material surface with the bioentities present in the physiological environment. Advances in microfabrication and nanotechnology offer new tools to investigate the complex signaling cascade induced by the components of the extracellular matrix and consequently allow cellular responses to be tailored through the mimicking of some elements of the signaling paths. Patterning methods and selective chemical modification schemes at different length scales can provide biocompatible surfaces that control cellular interactions on the micrometer and sub-micrometer scales on which cells are organized. In this review, the potential of chemically and topographically structured micro- and nanopolymer surfaces are discussed in hopes of a better understanding of cell-biomaterial interactions, including the recent use of biomimetic approaches or stimuli-responsive macromolecules. Additionally, the focus will be on how the knowledge obtained using these surfaces can be incorporated to design biocompatible materials for various biomedical applications, such as tissue engineering, implants, cell-based biosensors, diagnostic systems, and basic cell biology. The review focusses on the research carried out during the last decade. PMID: 20848593 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The emergence of phosphate as a specific signaling molecule in bone and other cell types in mammals. Cell Mol Life Sci. 2010 Sep 17; Authors: Khoshniat S, Bourgine A, Julien M, Weiss P, Guicheux J, Beck L Although considerable advances in our understanding of the mechanisms of phosphate homeostasis and skeleton mineralization have recently been made, little is known about the initial events involving the detection of changes in the phosphate serum concentrations and the subsequent downstream regulation cascade. Recent data has strengthened a long-established hypothesis that a phosphate-sensing mechanism may be present in various organs. Such a phosphate sensor would detect changes in serum or local phosphate concentration and would inform the body, the local environment, or the individual cell. This suggests that phosphate in itself could represent a signal regulating multiple factors necessary for diverse biological processes such as bone or vascular calcification. This review summarizes findings supporting the possibility that phosphate represents a signaling molecule, particularly in bone and cartilage, but also in other tissues. The involvement of various signaling pathways (ERK1/2), transcription factors (Fra-1, Runx2) and phosphate transporters (PiT1, PiT2) is discussed. PMID: 20848155 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Redox Imbalance in T Cell-Mediated Skin Diseases. Mediators Inflamm. 2010;2010 Authors: Pastore S, Korkina L The skin is permanently exposed to physical, chemical, and biological aggression by the environment. In addition, acute and chronic inflammatory events taking place in the skin are accompanied by abnormal release of pro-oxidative mediators. In this paper, we will briefly overview the homeostatic systems active in the skin to maintain the redox balance and also to counteract abnormal oxidative stress. We will concentrate on the evidence that a local and/or systemic redox dysregulation accompanies the chronic inflammatory disorder events associated to psoriasis, contact dermatitis, and atopic dermatitis. We will also discuss the fact that several well-established treatments for the therapy of chronic inflammatory skin disorders are based on the application of strong physical or chemical oxidants onto the skin, indicating that, in selected conditions, a further increase of the oxidative imbalance may lead to a beneficial outcome. PMID: 20847812 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Subconjunctival Injection of Bevacizumab in the Treatment of Corneal Neovascularization Associated With Lipid Deposition. Cornea. 2010 Sep 15; Authors: Chu HS, Hu FR, Yang CM, Yeh PT, Chen YM, Hou YC, Chen WL PURPOSE:: To determine the effects on corneal neovascularization (NV) and lipid deposition after subconjunctival injection of bevacizumab in patients who had NV associated with lipid keratopathy. METHODS:: A case interventional study enrolled 18 patients (18 eyes) with lipid keratopathy. We gave monthly subconjunctival injections of bevacizumab from 3 to 10 times during the follow-up period according to the clinical response. We evaluated the centricity, extent, and percentage of involved corneal surface (PICS) of the corneal NV; the density and PICS of the corneal lipid deposition; and best-corrected visual acuity before and after treatment. We analyzed the treatment effects using Wilcoxon and Student t tests. RESULTS:: After the treatment, the change in best-corrected visual acuity was less than 2 lines. The extent, centricity, and PICS of the corneal NV and the density and PICS of the corneal lipid deposition decreased significantly after treatment (P = 0.014/0.002/0.001 and 0.001/<0.001, respectively). No eyes had side effects. CONCLUSIONS:: The effects of subconjunctival injection of bevacizumab in treating corneal NV associated with lipid deposition were significant in some patients. PMID: 20847676 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Controlling matrix formation and cross-linking by hypoxia in cardiovascular tissue engineering. J Appl Physiol. 2010 Sep 16; Authors: van Vlimmeren MA, Driessen-Mol A, van den Broek M, Bouten CV, Baaijens FP In vivo functionality of cardiovascular tissue engineered constructs requires in vitro control of tissue development to obtain a well-developed extracellular matrix (ECM). We hypothesize that ECM formation and maturation is stimulated by culturing at low oxygen concentrations. Gene expression levels of monolayers of human vascular-derived myofibroblasts, exposed to 7, 4, 2, 1 and 0.5% O(2) (n=9 per group) for 24 hours, were measured for vascular endothelial growth factor (VEGF), procollagen α1(I) and α1(III), elastin, and cross-link enzymes lysyl oxidase (LOX) and lysyl hydroxylase 2 (LH2). After 4 days of exposure to 7, 2 and 0.5% O(2) (n=3 per group) protein synthesis was evaluated. All analyses were compared to control cultures at 21% O(2). Human myofibroblasts turned to hypoxia-driven gene expression, indicated by VEGF expression, at oxygen concentrations of 4% and lower. Gene expression levels of procollagen α1(I) and α1(III) increased to 138±26% and 143±19% respectively, for all oxygen concentrations below 4%. At 2% O(2), LH2 and LOX gene expression levels were higher than control cultures (340±53% and 136±29% respectively) and these levels increased even further with decreasing oxygen concentrations (611±176% and 228±45% at 0.5% O(2) respectively). Elastin gene expression levels remained unaffected. Collagen synthesis and LH2 protein levels increased at oxygen concentrations of 2% and lower. Oxygen concentrations below 4% induce enhanced ECM production by human myofibroblasts. Implementation of these results in cardiovascular tissue engineering approaches enables in vitro control of tissue development. PMID: 20847132 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The role of SCF and c-KIT in keloid pathogenesis: Do tyrosine kinase inhibitors have a potential therapeutic role? Br J Dermatol. 2010 Sep 16; Authors: Mukhopadhyay A, Do DV, Ong CT, Khoo YT, Masilamani J, Chan SY, Vincent AS, Wong PK, Lim CP, Cao X, Lim IJ, Phan TT Background:  Keloids are fibroproliferative disorders characterized by increased deposition of extracellular matrix components. SCF and its receptor c-KIT are expressed in a wide variety of cells and have also been demonstrated to be important modulators of the wound healing process. Objectives:  The present study is aimed at examining the role of SCF/c-KIT system in keloid pathogenesis Methods:  Immunohistochemical staining and Western blot analyses were used to examine localization and expression of SCF and c-KIT in keloid and normal skin tissue. This was followed by the detection of SCF and c-KIT expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial-mesenchymal interactions, a two-chamber system was employed in which keratinocytes on membrane inserts were co-cultured with the fibroblasts. SCF and c-KIT expression levels in all cell extracts and conditioned media were assayed by Western blotting. In another set of experiments, the effect of Gleevec on keloid fibroblasts (KF) was examined. Results:  SCF and c-KIT were upregulated in keloid scar tissues.and in cultured fibroblasts stimlulated with serum, highlighting their importance in the initial phase of wound healing. We further demonstrated that epithelial-mesenchymal interactions, mimicked by coculture of keratinocytes and fibroblasts in vitro, not only stimulated secretion of soluble form of SCF in keloid co-cultures but also brought about shedding of the extracellular domain of c-KIT perhaps by upregulation of TACE which was also upregulated in keloid scars in vivo and keloid cocultures in vitro. In addition keloid cocultures expressed increased levels of phospho-c-KIT highlighting an activation of the SCF/c-KIT system. We finally demonstrated Gleevec, a Tyrosine kinase inhibitor, to be a possible therapeutic agent for keloids. Conclusion:  These data indicate that SCF/c-KIT system play an important role in scar pathogenesis, and underscore the role of Gleevec as a key therapeutic agent in keloid scars. PMID: 20846303 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Engineering lungs. Lab Anim (NY). 2010 Aug;39(8):228 Authors: Dorans K PMID: 20664564 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | In vitro evaluation of the compatibility of a novel collagen-heparan sulfate biological scaffold with olfactory ensheathing cells. Chin Med J (Engl). 2010 May;123(10):1299-304 Authors: Tang ZP, Liu N, Li ZW, Xie XW, Chen Y, Shi YH, Zeng WG, Wang SX, Chen J, Yang J, Pan DJ BACKGROUND: Stroke and traumatic injury to the nerve system may trigger axonal destruction and the formation of scar tissue, cystic cavitations and physical gaps. Olfactory ensheathing cells (OECs) can secrete neurotrophic factors to promote neurite growth and thus act as a prime candidate for autologous transplantation. Biological scaffolds can provide a robust delivery vehicle to injured nerve tissue for neural cell transplantation strategies, owing to the porous three-dimensional structures (3D). So transplantation of the purposeful cells seeded scaffolds may be a promising method for nerve tissue repair. This study aimed to evaluate the compatibility of a novel collagen-heparan sulfate biological scaffold with olfactory ensheathing cells in vitro. METHODS: Collagen-heparan sulfate (CHS) biological scaffolds were made, and then the scaffolds and OECs were co-cultured in vitro. The viability of OECs was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay at days 1, 3, 5 and 7. Statistical analysis was evaluated by student's t test. Significance was accepted at P < 0.05. OECs were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE), and the CFSE-labeled OECs were seeded into CHS scaffolds. The attachment and growth of OECs in CHS scaffolds were observed and traced directly by fluorescent microscopy and environmental scanning electron microscope (ESEM). RESULTS: CHS biological scaffolds had steady porous 3D structures and no cytotoxicity to OECs (F = 0.14, P = 0.9330). CHS biological scaffolds were good bridging materials for OECs attachment and proliferation, and they promoted the axonal growth. CONCLUSION: The compatibility of CHS biological scaffolds with OECs is pretty good and CHS biological scaffold is a promising cell carrier for the implantation of OECs in nerve tissue bioengineering. PMID: 20529585 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Harnessing the purinergic receptor pathway to develop functional engineered cartilage constructs. Osteoarthritis Cartilage. 2010 Jun;18(6):864-72 Authors: Waldman SD, Usprech J, Flynn LE, Khan AA OBJECTIVE: Mechanical stimulation is a widely used method to enhance the formation and properties of tissue-engineered cartilage. While this approach can be highly successful, it may be more efficient and effective to harness the known underlying mechanotransduction pathways responsible. With this aim, the purpose of this study was to assess the effect of directly stimulating the purinergic receptor pathway through exogenous adenosine 5'-triphosphate (ATP) in absence of externally applied forces. METHODS: Isolated bovine articular chondrocytes were seeded in high density, 3D culture and supplemented with varying doses of ATP for up to 4 weeks. The effects on biosynthesis, extracellular matrix accumulation and mechanical properties were then evaluated. Experiments were also conducted to assess whether exogenous ATP elicited any undesirable effects, such as: inflammatory mediator release, matrix turn-over and mineralization. RESULTS: Supplementation with ATP had a profound effect on the growth and maturation of the developed tissue. Exogenous ATP (62.5-250 microM) increased biosynthesis by 80-120%, and when stimulated for a period of 4 weeks resulted in increased matrix accumulation (80% increase in collagen and 60% increase in proteoglycans) and improved mechanical properties (6.5-fold increase in indentation modulus). While exogenous ATP did not stimulate the release of inflammatory mediators or induce mineralization, high doses of ATP (250 microM) elicited a 2-fold increase in matrix metalloproteinase-13 expression suggesting the emergence of a catabolic response. CONCLUSIONS: Harnessing the ATP-purinergic receptor pathway is a highly effective approach to improve tissue formation and impart functional mechanical properties. However, the dose of ATP needs to be controlled as not to elicit a catabolic response. PMID: 20346406 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Vascularization--the conduit to viable engineered tissues. Tissue Eng Part B Rev. 2009 Jun;15(2):159-69 Authors: Kaully T, Kaufman-Francis K, Lesman A, Levenberg S Long-term viability of thick three-dimensional engineered tissue constructs is a major challenge. Addressing it requires development of vessel-like network that will allow the survival of the construct in vitro and its integration in vivo owing to improved vascularization after implantation. Resulting from work of various research groups, several approaches were developed aiming engineered tissue vascularization: (1) embodiment of angiogenesis growth factors in the polymeric scaffolds for prolonged release, (2) coculture of endothelial cells with target tissue cells and angiogenesis signaling cells, (3) use of microfabrication methods for creating designed channels for allowing nutrients to flow and/or for directing endothelial cells attachment, and (4) decellularization of organs and blood vessels for creating extracellular matrix. A synergistic effect is expected by combining several of these approaches as already demonstrated in some of the latest studies. Current paper reviews the progress in each approach and recent achievements toward vascularization of engineered tissues. PMID: 19309238 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Low doses of BMP4 increases the survival of human adipose-derived stem cells maintaining their stemness and multipotency. Stem Cells Dev. 2010 Sep 16; Authors: Vicente López MA, Vázquez GarcÃa MN, Entrena A, Olmedillas Lopez S, GarcÃa-Arranz M, GarcÃa-Olmo D, Zapata AG Mesenchymal stem cells (MSC) have emerged as important tools for cell therapy and, therefore, identification of factors capable of governing their ex vivo expansion become essential. In this study we demonstrate human Adipose-derived Stem Cell (ASC) express all components of the BMP/BMPR signalling pathway and respond to BMP4 inducing up-regulated expression of its specific target genes Id1-Id4. Moreover, ASC grown in a medium reduced in serum produce endogenous BMP4 that could affect autocrinely ASC growth. On the contrary, dorsomorphin, an inhibitor of BMP signalling pathway, decreases cell numbers yielded from ASC cultures in correlation with increased apoptosis and decreased cycling cells. Therefore, BMP4 emerges as a possible factor for ex vivo expanding human ASC. Remarkably, our results demonstrate that, as other morphogens, BMP4 effects on human MSC are doses dependent. High doses significantly increased apoptosis and drastically reduced cell proliferation whereas low doses of BMP4 (0.01-0.1 ng/ml) significantly increase culture cell content, reduce the numbers of apoptotic cells and increase that of cycling cells. Furthermore, treatment of human ASC with low doses of BMP4 does nor modify the expression of Nanog and Oct4, two transcription factors involved in self-renewal and pluripotency of stem cells neither avoid their osteogenic or osteoblastic differentiation capacities when are cultured in adequate inducing media, as shown by the induction of specific gene expression (CEBP, PPAR γ, RUNX2). Our results therefore support BMP4 as a promising factor for expanding human adipose tissue-derived MSC maintaining their properties of stemness and multipotency. PMID: 20846028 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Wound Care: The Role of Advanced Wound-healing Technologies. J Am Podiatr Med Assoc. 2010 September-October;100(5):385-394 Authors: Wu SC, Marston W, Armstrong DG Wound repair and regeneration is a highly complex combination of matrix destruction and reorganization. Although major hurdles remain, advances during the past generation have improved the clinician's armamentarium in the medical and surgical management of this problem. The purpose of this article is to review the current literature regarding the pragmatic use of three of the most commonly used advanced therapies: bioengineered tissue, negative-pressure wound therapy, and hyperbaric oxygen therapy, with a focus on the near-term future of wound healing, including stem cell therapy. PMID: 20847352 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Significantly higher frequencies of alloreactive CD4+ T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities. Blood. 2010 Sep 16;116(11):1991-1992 Authors: Sizzano F, Zito L, Crivello P, Crocchiolo R, Vago L, Zino E, Fleischhauer K PMID: 20847212 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Controlling Cell Behavior Through the Design of Polymer Surfaces. Small. 2010 Sep 16; Authors: Alves NM, Pashkuleva I, Reis RL, Mano JF Polymers have gained a remarkable place in the biomedical field as materials for the fabrication of various devices and for tissue engineering applications. The initial acceptance or rejection of an implantable device is dictated by the crosstalk of the material surface with the bioentities present in the physiological environment. Advances in microfabrication and nanotechnology offer new tools to investigate the complex signaling cascade induced by the components of the extracellular matrix and consequently allow cellular responses to be tailored through the mimicking of some elements of the signaling paths. Patterning methods and selective chemical modification schemes at different length scales can provide biocompatible surfaces that control cellular interactions on the micrometer and sub-micrometer scales on which cells are organized. In this review, the potential of chemically and topographically structured micro- and nanopolymer surfaces are discussed in hopes of a better understanding of cell-biomaterial interactions, including the recent use of biomimetic approaches or stimuli-responsive macromolecules. Additionally, the focus will be on how the knowledge obtained using these surfaces can be incorporated to design biocompatible materials for various biomedical applications, such as tissue engineering, implants, cell-based biosensors, diagnostic systems, and basic cell biology. The review focusses on the research carried out during the last decade. PMID: 20848593 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Comparative analysis of angiogenic gene expression in normal and impaired wound healing in diabetic mice: effects of extracorporeal shock wave therapy. Angiogenesis. 2010 Sep 17; Authors: Zins SR, Amare MF, Tadaki DK, Elster EA, Davis TA Impaired wound healing is a persistent clinical problem which has been treated with mixed results. Studies aimed at elucidating the mechanism of impaired wound healing have focused on small cohorts of genes which leave an incomplete picture of the wound healing process. We aimed to investigate impaired wound healing via a comprehensive panel of angiogenic/inflammation-related genes and wound closure kinetics with and without the application of extracorporeal shock wave therapy (ESWT), which has been demonstrated to improve wound healing. Full-thickness skin from the dorsal surface of "normal" (BALB/c) and "impaired" (db (+)/db (+)) mice was excised, and wound margin tissue was harvested 2, 7, and 10 days post injury. A separate, but identical wound model was established over 40 days in order to measure wound closure kinetics. Over time, the normal non-ESWT treated wounds exhibited varying patterns of elevated expression of 25-30 genes, whereas wounds with impaired healing displayed prolonged elevated expression of only a few genes (CXCL2, CXCL5, CSF3, MMP9, TGF-α). In response to ESWT, gene expression was augmented in both types of wounds, especially in the expression of PECAM-1; however, ESWT had no effect on wound closure in either model. In addition, multiple doses of ESWT exacerbated the delayed wound healing, and actually caused the wounds to initially increase in size. These data provide a more complete picture of impaired wound healing, and a way to evaluate various promising treatments. PMID: 20848181 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Effectiveness of In Vivo Confocal Microscopy in Detecting Filamentous Fungi During Clinical Course of Fungal Keratitis. Cornea. 2010 Sep 15; Authors: Takezawa Y, Shiraishi A, Noda E, Hara Y, Yamaguchi M, Uno T, Ohashi Y PURPOSE:: To determine the effectiveness of laser confocal microscopy in detecting filamentous fungi in the cornea of patients with fungal keratitis (FK) and in evaluating the effectiveness of the treatment. METHODS:: The corneas of 6 patients clinically diagnosed with FK were examined with the Heidelberg Retina Tomograph II-Rostock Cornea Module (HRT II-RCM). Three of these patients were also monitored periodically with the HRT II-RCM after antifungal treatment. RESULTS:: The HRT II-RCM examination showed interlocking and branching, white, septated, hyphae-like lines in the cornea of all patients. All 6 patients had positive corneal smears and/or laboratory cultures. Three patients were monitored with HRT II-RCM after antifungal treatment. One patient, whose initial smear was negative, was diagnosed by HRT II-RCM before the positive culture results. In another case, the epithelial regeneration was impaired even 3 weeks after the initial treatment and HRT II-RCM revealed a mass of hyphae in the corneal ulcerated lesion. These findings indicated the necessity of surgical debridement. After the surgical debridement, the corneal epithelial defect was healed. HRT II-RCM was able to detect the morphological changes of hyphae after antifungal treatment and helped in the treatment modifications during the clinical course in all 3 patients. CONCLUSIONS:: These results indicate that HRT II-RCM can be used to diagnose FK and to monitor the effect of therapy on FK. PMID: 20847667 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Significantly higher frequencies of alloreactive CD4+ T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities. Blood. 2010 Sep 16;116(11):1991-1992 Authors: Sizzano F, Zito L, Crivello P, Crocchiolo R, Vago L, Zino E, Fleischhauer K PMID: 20847212 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects Mucopolysaccharidosis type I phenotype in the mouse model. Blood. 2010 Sep 16; Authors: Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D'Isa R, Ungaro D, Stok M, Sanvito F, Mariani E, Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder K, Naldini L, Biffi A Type I Mucopolysaccharidosis (MPS I) is a lysosomal storage disorder caused by the deficiency of α-L-iduronidase, which results in glycosaminoglycan accumulation in tissues. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly and mental retardation, the latter being present exclusively in the severe Hurler variant. The available treatments - enzyme replacement therapy and hematopoietic stem cell transplantation (HCT) - can ameliorate most disease manifestations, but their outcome on the skeletal and brain disease could be further improved. We here demonstrate that hematopoietic stem cell (HSC) gene therapy based on lentiviral vectors (LV) completely corrects the disease manifestations in the mouse model. Of note, the therapeutic benefit provided by gene therapy on critical MPS I manifestations, such as the neurological and skeletal disease, greatly exceeds the one exerted by HCT, the standard of care treatment for Hurler patients. Interestingly, therapeutic efficacy of HSC gene therapy is strictly dependent from the achievement of supra-normal enzyme activity in the hematopoietic system of transplanted mice, which allows enzyme delivery to the brain and skeleton for disease correction. Overall, our data provides evidence of an efficacious treatment for MPS I Hurler patients warranting future development towards clinical testing. PMID: 20847202 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Isolation, Characterization, and Expansion (ICE) Methods for Defined Primary Renal Cell Populations from Rodent, Canine, and Human Normal and Diseased Kidneys. Tissue Eng Part C Methods. 2010 Sep 16; Authors: Presnell SC, Bruce AT, Wallace SM, Choudhury S, Genheimer C, Cox B, Guthrie KI, Werdin ES, Tatsumi-Ficht P, Ilagan R, Kelley RW, Rivera EA, Ludlow JW, Wagner BJ, Jayo MJ, Bertram T Chronic kidney disease (CKD) is a global health problem; the growing gap between the number of patients awaiting transplant and organs actually transplanted highlight the need for new treatments to restore renal function. Regenerative medicine is a promising approach from which treatments for organ-level disorders (e.g., neurogenic bladder) have emerged and translated to clinics. Regenerative templates, composed of biodegradable material and autologous cells, isolated and expanded ex vivo, stimulate native-like organ tissue regeneration following implantation. A critical step for extending this strategy from bladder to kidney is the ability to isolate, characterize, and expand functional renal cells with therapeutic potential from diseased tissue. In this study, we developed methods that yield distinct subpopulations of primary kidney cells that are compatible with process development and scale-up. These methods were translated to rodent, large mammal, and human kidneys, then to rodent and human tissues with advanced chronic kidney disease (CKD). Comparative in vitro studies demonstrated that phenotype and key functional attributes were retained consistently in ex vivo cultures regardless of species or disease state, suggesting that autologous sourcing of cells that contribute to in situ kidney regeneration after injury is feasible, even with biopsies from patients with advanced CKD. PMID: 20846053 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Supramolecular Cross-Linked Networks via Host-Guest Complexation with Cucurbit[8]uril. J Am Chem Soc. 2010 Sep 16; Authors: Appel EA, Biedermann F, Rauwald U, Jones ST, Zayed JM, Scherman OA The ability to finely tune the solution viscosity of an aqueous system is critical in many applications ranging from large-scale fluid-based industrial processes to free-standing hydrogels important in regenerative medicine, controlled drug delivery, and 'green' self-healing materials. Herein we demonstrate the use of the macrocyclic host molecule cucurbit[8]uril (CB[8]) to facilitate reversible cross-linking of multivalent copolymers with high binding constants (K(a) > 10(11)-10(12) M(-2)) leading to a supramolecular hydrogel. Multivalent copolymers were prepared by free radical polymerization techniques and contained either pendant methyl viologen (a good first guest for CB[8]) or naphthoxy derivatives (good second guests for CB[8]). A colorless solution of the two multivalent copolymers bearing first and second guests, respectively, can be transformed into a highly viscous, colored supramolecular hydrogel with the cross-link density being easily controlled through CB[8] addition. Moreover, the cross-links (1:1:1 supramolecular ternary complexes of CB[8]/viologen/naphthoxy) are dynamic and stimuli-responsive, and the material properties can be modulated by temperature or other external stimuli. Rheological characterization of the bulk material properties of these dynamically cross-linked networks provided insight into the kinetics of CB[8] ternary complexation responsible for elastically active cross-linking with a second guest dissociation rate constant (k(d)) of 1200 s(-1) for the ternary complex. These materials exhibited intermediate mechanical properties at 5 wt % in water (plateau modulus = 350-600 Pa and zero-shear viscosity = 5-55 Pa·s), which is complementary to existing supramolecular hydrogels. Additionally, these supramolecular hydrogels exhibited thermal reversibility and subsequent facile modulation of microstructure upon further addition of CB[8] and thermal treatment. The fundamental knowledge gained from the study of these dynamic materials will facilitate progress in the field of smart, self-healing materials, self-assembled hydrogels, and controlled solution viscosity. PMID: 20845973 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Immune mechanisms and novel pharmacological therapies of acute kidney injury. Curr Drug Targets. 2009 Dec;10(12):1196-204 Authors: Bajwa A, Kinsey GR, Okusa MD Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and both innate and adaptive immunity contribute to the pathogenesis. Kidney resident cells promote inflammation after IRI by increasing endothelial cell adhesion molecule expression and vascular permeability. Kidney epithelial cells bind complement and express toll-like receptors and resident and infiltrating cells produce cytokines/chemokines. Early activation of kidney dendritic cells (DCs) initiates a cascade of events leading to accumulation of interferon-gamma-producing neutrophils, infiltrating macrophages, CD4(+) T cells, B cells and invariant natural killer T (NKT) cells. Recent studies from our laboratory now implicate the IL23/IL17 pathway in kidney IRI. Following the initial early phase of inflammation, the late phase involves infiltration of anti-inflammatory cells including regulatory T cells, alternatively activated macrophages and stem cells leading to attenuation of inflammation and initiation of repair. Based upon these immune mechanisms of injury, recent studies hold promise for novel drug therapies. These pharmacological agents have been shown to reduce inflammation or cytotoxicity in rodent models of AKI and some show early promise in clinical trials. This review summarizes recent advances to further our understanding of the immune mechanisms of AKI and potential pharmacological therapies. PMID: 19715538 [PubMed - indexed for MEDLINE] | | | | | | | | | |  | |  | |  |
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