|  |  |  | | | | | TE-RegenMed-StemCell feed | | | | | | | | | | | | | | | | | | | Immunological tolerance in a mouse model of immune-mediated liver injury induced by 16,16 dimethyl PGE2 and PGE2-containing nanoscale hydrogels. Biomaterials. 2011 Apr 7; Authors: Okamoto T, Saito T, Tabata Y, Uemoto S Although immunosuppressive agents play a pivotal role in the success of organ transplantation, chronic toxicity has been a major issue for long-term treatment. The development of therapies that induce donor-specific immunological tolerance remains an important clinical challenge. In the present study, we investigated the underlying mechanisms and applications of prostaglandin (PG) E2 for the induction of immunological tolerance in mice with concanavalin A(Con A)-induced immune-mediated liver injury. The immunological tolerogenic effect of 16,16 dimethyl PGE2 (dmPGE2) pretreatment in C57B/6 male mice with Con A-induced liver injury was observed, and it was revealed that its response was partially associated with the expression of interleukin (IL)-10, an anti-inflammatory cytokine, in Kupffer cells. To apply native eicosanoids of PGE2 for tolerance induction in vivo, PGE2 was incorporated into l-lactic acid oligomer-grafted pullulan of an amphiphilic polymer to form a nano-sized hydrogel (PGE2-nanogel). Pharmacokinetics studies revealed that nanogel incorporation enabled PGE2 to have a prolonged life-time in circulating blood, and a tolerogenic effect was also observed in Con A-induced liver injury, the same as with dmPGE2 pretreatment. Nanogel-based prostaglandin administration might be developed as a therapeutic agent to induce immunological tolerance, which is necessary in allogenic organ and cell transplantation. PMID: 21477856 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Stem Cell and Tissue Engineering Therapies for Ocular Regeneration. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Silva GA, Silva NM, Fortunato TM The eye is a relatively small but very complex organ. It is responsible for vision. Most of its cells are terminally differentiated, and several pathologies affecting those cells lead to vision loss and eventual blindness. Several years ago, a group of cells, located in the limbus, was identified as having the capacity of self-renewal and later on found to feed the renewal of the corneal epithelial layer. Since then, this niche of stem cells has been studied in order to provide clues that can be valuable for the regeneration of ocular structures. The worldwide shortage of donors, increased risk of transmissible diseases and immune rejection and the increased life expectancy, all contributed for the development of strategies to regenerate or repair ocular tissues. In this review we focus on two approaches for ocular regeneration: one based on stem cells and the other one based on tissue engineering strategies, and present examples where these two strategies overlap. We review the sources of cells and tissue engineering strategies for the regeneration of the cornea and of the retina, summarizing the most relevant and recent findings. PMID: 21476978 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Stem Cells and Bioactive Scaffolds as a Treatment for Traumatic Brain Injury. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Stabenfeldt SE, Irons HR, Laplaca MC Successful repair of the injured brain is critical, as traumatic brain injury pathology often involves a secondary cascade of insults that may ultimately lead to worsened neurologic dysfunction. Damage is balanced by the brain's attempt to repair itself, the genetic profile of the person, underlying health issues, and age, among other factors. The challenge in using a tissue engineering approach to repair and regeneration is centered at the heterogeneous and complex environment, variables that are difficult to measure and interpret. The brain must be in a state that minimizes rejection, inflammation, immune response, and donor cell death to maximize the intended benefit. Tissue engineering, using a bioactive based scaffold to both counter some of the hostile factors and to chaperone donor cells into the brain, has merit, yet the complexity of transplanting a combination biologic construct to the brain has yet to be successfully transferred to the clinic. Several options, such as cell source, scaffold composition, as well as delivery methods will be discussed. PMID: 21476977 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Adult Stem Cells and Tissue Engineering in Central Nervous System Regenerative Medicine. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Salgado AJ PMID: 21476983 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Fluid Flow Mechanotransduction in Vascular Smooth Muscle Cells and Fibroblasts. Ann Biomed Eng. 2011 Apr 9; Authors: Shi ZD, Tarbell JM Understanding how vascular wall endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) sense and transduce the stimuli of hemodynamic forces (shear stress, cyclic strain, and hydrostatic pressure) into intracellular biochemical signals is critical to prevent vascular disease development and progression. ECs lining the vessel lumen directly sense alterations in blood flow shear stress and then communicate with medial SMCs and adventitial FBs to regulate vessel function and disease. Shear stress mechanotransduction in ECs has been extensively studied and reviewed. In the case of endothelial damage, blood flow shear stress may directly act on the superficial layer of SMCs and transmural interstitial flow may be elevated on medial SMCs and adventitial FBs. Therefore, it is also important to investigate direct shear effects on vascular SMCs as well as FBs. The work published in the last two decades has shown that shear stress and interstitial flow have significant influences on vascular SMCs and FBs. This review summarizes work that considered direct shear effects on SMCs and FBs and provides the first comprehensive overview of the underlying mechanisms that modulate SMC secretion, alignment, contraction, proliferation, apoptosis, differentiation, and migration in response to 2-dimensional (2D) laminar, pulsatile, and oscillating flow shear stresses and 3D interstitial flow. A mechanistic model of flow sensing by SMCs is also provided to elucidate possible mechanotransduction pathways through surface glycocalyx, integrins, membrane receptors, ion channels, and primary cilia. Understanding flow-mediated mechanotransduction in SMCs and FBs and the interplay with ECs should be helpful in exploring strategies to prevent flow-initiated atherosclerosis and neointima formation and has implications in vascular tissue engineering. PMID: 21479754 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Adult Stem Cells and Bioengineering Strategies for the Treatment of Cerebral Ischemic Stroke. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Yu F, Morshead CM The adult central nervous system (CNS) contains a population of neural stem cells, yet unlike many other tissues, has a very limited capacity for self-repair. Promoting tissue repair and functional recovery following CNS injury or disease is a high priority as there are currently no effective treatments towards this end for the treatment of disorders such as stroke, traumatic brain injury and spinal cord injury. Recent advances in stem cell biology have offered a number of enticing potential avenues and we will discuss these possibilities along with the associated challenges as they pertain to stroke. We will consider exogenous therapies involving the transplantation of adult stem cells, and the mobilization of endogenous stem cells, as well as drug delivery and tissue engineering strategies that enhance and complement the cell based strategies. PMID: 21476981 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Mesenchymal Stem Cells in the Umbilical Cord: Phenotypic Characterization, Secretome and Applications in Central Nervous System Regenerative Medicine. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Carvalho MM, Teixeira FG, Reis RL, Sousa N, Salgado AJ Mesenchymal Stem Cells (MSCs), have been defined and characterized by: 1) their ability to adhere to plastic culture flasks; 2) the positive expression of CD105, CD73, CD90 membrane antigens, and the lack of expression of others (e.g CD45 and CD34) and 3) the ability of differentiation under adequate conditions along the osteogenic, chondrogenic and adipogenic lineages. In recent years cells with these characteristics have been isolated from the Wharton Jelly (WJ) of the Umbilical Cord (UC). Similarly to bone marrow MSCs they have shown multilineage differentiation potential and to be able to provide trophic support to neighboring cells. According to the literature, there are two main populations of cells with a mesenchymal character within the WJ: Wharton Jelly Stem Cells (WJSCs) and Human Umbilical Cord Perivascular Cells (HUCPVCs). In the present work our aim is to make a comprehensive review on the MSCs populations of the WJ and how these cell populations may be used for future applications in CNS regenerative medicine. Following a brief insight on the general characteristics of MSC like cells, we will discuss the possible sources of stem cells within the WJ and the cord itself (apart UC blood), as well as their phenotypic character. As it has already been shown that these cells hold a strong trophic support to neighbouring cell populations, we will then focus on their secretome, namely which molecules have already been identified within it and their role in phenomena such as immunomodulation. The possible applications of these cells populations to CNS regenerative medicine will be addressed by critically reviewing the work that has been performed so far in this field. Finally, a brief insight will be made on what in the authors' opinion are the major challenges in the field for the future application of these cell populations in CNS regenerative medicine. PMID: 21476975 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Functional Evaluation of Neural Stem Cell Differentiation by Single Cell Calcium Imaging. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Eiriz MF, Grade S, Rosa A, Xapelli S, Bernardino L, Agasse F, Malva JO Neurogenesis in the adult mammalian brain occurs in two specific brain areas, the subventricular zone (SVZ) bordering the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. Although these regions are prone to produce new neurons, cultured cells from the neurogenic niches tend to be mixed cultures, containing both neurons and glial cells. Several reports highlight the potential of the self-healing capacity of the brain following injury. Even though much knowledge has been produced on the neurogenesis itself, brain repairing strategies are still far away from patients cure. Here we review general concepts in the neurogenesis field, also addressing the methods available to study neural stem cell differentiation. However, a major problem faced by research groups and companies dedicated to brain regenerative medicine resides on the lack of good methods to functionally identify neural stem cell differentiation and novel drug targets. To address this issue, we developed a unique single cell calcium imaging-based method to functionally discriminate different cell types derived from SVZ neural stem cell cultures. The unique functional profile of each SVZ cell type was correlated at the single cell level with the immunodetection of specific phenotypic markers. This platform was raised on the basis of the functional response of neurons, oligodendrocytes and immature cells to depolarising agents, to thrombin and to histamine, respectively. We also outline key studies in which our new platform was extremely relevant in the context of drug discovery and development in the area of brain regenerative medicine. PMID: 21476976 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Adult Stem Cells and Tissue Engineering in Central Nervous System Regenerative Medicine. Curr Stem Cell Res Ther. 2011 Apr 11; Authors: Salgado AJ PMID: 21476983 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Potential barriers to therapeutics utilizing pluripotent cell derivatives: intrinsic immunogenicity of in vitro maintained and matured populations. Semin Immunopathol. 2011 Apr 11; Authors: Tang C, Drukker M The potential to develop into any tissue makes pluripotent stem cells (PSCs) one of the most promising sources for cellular therapeutics. However, numerous hurdles exist to their clinical applications, three of the most concerning include the inability to separate therapeutic population from heterogeneously differentiated cultures, the risk of teratoma formation from residual pluripotent cells, and immunologic rejection of engrafted cells. The recent development of induced PSCs has been proposed as a solution to the histocompatibility barrier. Theoretically, creation of patient-specific induced PSC lines would exhibit a complete histocompatibility antigen match. However, regardless of the PSC source, in vitro propagation and nonphysiologic differentiation may result in other, likely less powerful, mechanisms of immune rejection. In light of recent progress towards clinical application, this review focuses on two such potential immunologic mechanisms applicable to isogenic PSC derivates: namely, the immunogenicity of aberrant antigens resulting from long-term in vitro maintenance and alterations in immunologic properties due to rapid in vitro differentiation. These issues will be considered with attention to their relation to effector cells in the adult immune system. In addition, we highlight immunosuppressive approaches that could potentially address the immunogenicity of these proposed mechanisms. PMID: 21479877 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Short-Term In Vivo Preclinical Biocompatibility Evaluation of FW-II Axial Blood Pump in a Sheep Model. ASAIO J. 2011 Apr 7; Authors: Chen H, Zhou J, Sun H, Tang Y, Zhang Y, Liu G, Hu S We investigated the outcome of FW-II axial pump on healthy sheep (weight, 60-70 kg) for 2 weeks by perioperatively hematological and chemical tests, and circulating activated platelet and leukocyte-platelet aggregates measurements by flow cytometry assays. Complete necropsy and histopathological examinations and thorough pump inspection were performed at study termination for evidence of thrombi. In this experimental series, one sheep died of pulmonary edema, the other four sheep reached the scheduled endpoint of 14 days without device-related problems, and flow range was maintained at 2.5-4.0 L/min. The number of red blood cells and platelets decreased within first 3 days but increased gradually after the first postoperative week. In all animals, serum glutamic oxaloacetic transaminase increased significantly after surgery but gradually returned to normal limits within 2 weeks. Platelet activation, granulocyte-platelet aggregates, and monocyte-platelet aggregates reached the peak at postoperative day 2. Postexplant examinations indicated round thrombus in the hub areas of pumps. No evidence of ischemia or infarction was found in the explanted hearts, livers, spleens, kidneys, and brains of the five animals. Our results demonstrate that FW-II ventricular assist device (VAD) is a promising device for left ventricular (LV) support with moderate anticoagulation. PMID: 21478737 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The cell cycle inhibitor p27Kip1 controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist. Cell Cycle. 2011 May 1;10(9) Authors: Menchón C, Edel MJ, Belmonte JC The continued turn over of human embryonic stem cells (hESC) while maintaining an undifferentiated state is dependent on the regulation of the cell cycle. Here we asked the question if a single cell cycle gene could regulate the self-renewal or pluripotency properties of hESC. We identified that the protein expression of the p27 (Kip1) cell cycle inhibitor is low in hESC cells and increased with differentiation. By adopting a gain and loss of function strategy we forced or reduced its expression in undifferentiating conditions to define its functional role in self-renewal and pluripotency. Using undifferentiation conditions, overexpression of p27 (Kip1) in hESC lead to a G 1 phase arrest with an enlarged and flattened hESC morphology and consequent loss of self-renewal ability. Loss of p27 (Kip1) caused an elongated/scatter cell-like phenotype involving up-regulation of Brachyury and Twist gene expression. We demonstrate the novel finding that p27 (Kip1 ) protein occupies the Twist1 gene promoter and manipulation of p27 (Kip1) by gain and loss of function is associated with Twist gene expression changes. These results define p27 (Kip1 ) expression levelsas critical for self-renewal and pluripotency in hESC and suggest a role for p27 (Kip1 ) in controlling an epithelial to mesenchymal transition (EMT) in hESC. PMID: 21478681 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Method for autologous single skin cell isolation for regenerative cell spray transplantation with non-cultured cells. Int J Artif Organs. 2011 Mar;34(3):271-279 Authors: Gerlach JC, Johnen C, Ottoman C, Bräutigam K, Plettig J, Belfekroun C, Münch S, Hartmann B Background: There is a therapeutic gap for patients with deep partial thickness wounds (Grade IIb) of moderate size that were initially not treated with split- or mesh grafting to avoid overgrafting, but developed delayed wound healing around two weeks after injury - at which time grafting is typically not indicated anymore. Delayed wound healing is often associated with esthetically unsatisfactory results and sometimes functional problems. An innovative cell isolation method for cell spray transplantation at the point of care, which eliminates cell culture prior to treatment, was implemented for this population of burn patients in our center. Methods: Autologous skin cell spray transplantation was initiated by taking healthy skin. The dermal/epidermal layers were separated using enzymatic digestion with 40 min dispase application, followed by 15 min trypsin application for basal kerationcyte isolation, 7 min cell washing by centrifugation, followed by transferring the cells for spraying into Ringer lactate solution. The procedure was performed on site in a single session immediately following the biopsy. After sharp wound debridement, cells were immediately transplanted by deposition with a cell sprayer for even distribution of the cell suspension. Results and conclusions: Eight patients were treated (mean age 30.3 years, mean burn total body surface area 14%, mean Abbreviated Burn Severity Index (5 points). The mean time to complete re-epithelialization was 12.6 days. All patients exhibited wound healing with improved esthetic and functional quality. Our initial experience for the use of non-cultured cells using a two-enzyme approach with cell washing suggests shortened time for wound closure, suggesting that the method may potentially avoid longer-term complications. PMID: 21480179 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Mesenchymal stromal cell therapy: a revolution in Regenerative Medicine? Bone Marrow Transplant. 2011 Apr 11; Authors: Bernardo ME, Pagliara D, Locatelli F Because of their immunomodulatory and engraftment-promoting properties, mesenchymal stromal cells (MSCs) have been tested in the clinical setting both to facilitate haematopoietic recovery and to treat steroid-resistant acute GVHD. More recently, experimental findings and clinical trials have focused on the ability of MSCs to home to damaged tissue and to produce paracrine factors with anti-inflammatory properties, resulting in functional recovery of the damaged tissue. The mechanisms through which MSCs exert their therapeutic potential rely on some key properties of the cells: the ability to secrete soluble factors capable of stimulating survival and recovery of injured cells; the capacity to home to sites of damage and the ability to blunt exaggerated immune responses. These fundamental properties are being tested within a novel therapeutic field defined as Regenerative Medicine. This review deals with recent research on the anti-inflammatory/reparative properties of MSCs and considers the possible mechanisms of function responsible for these effects. Moreover, current and potential clinical applications of MSC-based treatment strategies in the context of Regenerative Medicine are being discussed. Key issues such as optimal timing of MSC administration, cell dose and schedule of administration, advantages and disadvantages of using autologous or allogeneic cells are still open. Nonetheless, MSCs promise to represent a revolution for many severe or presently untreatable disorders.Bone Marrow Transplantation advance online publication, 11 April 2011; doi:10.1038/bmt.2011.81. PMID: 21478914 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | MHC Mismatch Inhibits Neurogenesis and Neuron Maturation in Stem Cell Allografts. PLoS One. 2011;6(3):e14787 Authors: Chen Z, Phillips LK, Gould E, Campisi J, Lee SW, Ormerod BK, Zwierzchoniewska M, Martinez OM, Palmer TD BACKGROUND: The role of histocompatibility and immune recognition in stem cell transplant therapy has been controversial, with many reports arguing that undifferentiated stem cells are protected from immune recognition due to the absence of major histocompatibility complex (MHC) markers. This argument is even more persuasive in transplantation into the central nervous system (CNS) where the graft rejection response is minimal. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluate graft survival and neuron production in perfectly matched vs. strongly mismatched neural stem cells transplanted into the hippocampus in mice. Although allogeneic cells survive, we observe that MHC-mismatch decreases surviving cell numbers and strongly inhibits the differentiation and retention of graft-derived as well as endogenously produced new neurons. Immune suppression with cyclosporine-A did not improve outcome but non-steroidal anti-inflammatory drugs, indomethacin or rosiglitazone, were able to restore allogeneic neuron production, integration and retention to the level of syngeneic grafts. CONCLUSIONS/SIGNIFICANCE: These results suggest an important but unsuspected role for innate, rather than adaptive, immunity in the survival and function of MHC-mismatched cellular grafts in the CNS. PMID: 21479168 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Efficient gene delivery of primary human cells using peptide linked polyethylenimine polymer hybrid. Biomaterials. 2011 Apr 7; Authors: Dey D, Inayathullah M, Lee AS, Lemieux MC, Zhang X, Wu Y, Nag D, De Almeida PE, Han L, Rajadas J, Wu JC Polyethylenimine (PEI) based polymers are efficient agents for cell transfection. However, their use has been hampered due to high cell death associated with transfection thereby resulting in low efficiency of gene delivery within the cells. To circumvent the problem of cellular toxicity, metal binding peptides were linked to PEI. Eight peptide-PEI derivatives were synthesized to improve cell survival and transfection efficiency. TAT linked PEI was used as a control polymer. Peptides linked with PEI amines formed nanogels as shown by electron microscopy and atomic force microscopic measurements. Polymers were characterized by spectroscopic methods and their ability to form complexes with plasmids was tested using electrophoretic studies. These modifications improved polymer biocompatibility as well as cell survival markedly, when compared to PEI alone. A subset of the modified peptide-polymers also showed significantly higher transfection efficiency in primary human cells with respect to the widely used transfection agent, lipofectamine. Study of the underlying mechanism of the observed phenomena revealed lower levels of 'reactive oxygen species' (ROS) in the presence of the peptide-polymers when compared to PEI alone. This was further corroborated with global gene expression analysis which showed upregulation of multiple genes and pathways involved in regulating intracellular oxidative stress. PMID: 21477858 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Quantitative gait analysis in essential tremor reveals impairments that are maintained into advanced age. Gait Posture. 2011 Apr 6; Authors: Rao AK, Gillman A, Louis ED BACKGROUND: Essential tremor (ET) patients seem to have impaired gait and balance, yet surprisingly few studies have utilized quantitative analysis to study these impairments. With one exception, these prior studies examined gait on a treadmill, which does not approximate functional environmental conditions (level ground). Moreover, these studies tested middle-aged subjects so it remains unclear whether ET patients maintain a pattern of deficits that is in excess of that seen in controls, even into advanced ages. METHODS: 104 ET subjects (86.0±4.6, range=75-97 years) and 40 similarly aged controls (84.1±4.2, range=74-94 years) underwent gait testing using the GAITRite(®) mat under standard walk and tandem walk conditions on level ground. RESULTS: In standard walk, ET patients demonstrated deficits related to gait speed (lower velocity and cadence, p=0.0001), dynamic imbalance (increased double support percent, p=0.01), and gait asymmetry (increased step time difference, p=0.003). During tandem walk, ET patients had lower velocity (p=0.002) and cadence (p=0.003), and more mis-steps (p<0.008) compared with controls. For all variables, ET patients performed more poorly than controls even into advanced ages, as demonstrated in linear regression models. CONCLUSIONS: ET patients demonstrated decrement in gait speed, dynamic balance and gait symmetry during standard walk and clear balance impairment during tandem walk. This constellation of impairments is consistent with a cerebellar deficit. ET patients maintained this pattern of deficits, in excess of that seen in controls, into advanced age, reinforcing the importance of gait and balance impairment in this disorder. PMID: 21478017 [PubMed - as supplied by publisher] | | | | | | | | | |  | |  | |  |
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