|  |  |  | | | | | TERMSC | | | | | | | | | | | | | | | | | | | Advanced maturation by electrical stimulation: Differences in response between C2C12 and primary muscle progenitor cells. J Tissue Eng Regen Med. 2010 Dec 9; Authors: Langelaan ML, Boonen KJ, Rosaria-Chak KY, van der Schaft DW, Post MJ, Baaijens FP Skeletal muscle tissue engineering still does not result in the desired functional properties and texture as preferred for regenerative medicine and meat production applications. Electrical stimulation has been appropriately used as a tool to advance muscle cell maturation in vitro, thereby simulating nerve stimulation, as part of the muscle cell niche in vivo. We first investigated the effects of electrical stimulation protocols in two-dimensional (2D) monolayers of C2C12 and translated these protocols to a three-dimensional (3D) model system, based on a collagen type I/Matrigel(™) hydrogel. More importantly, we addressed the ongoing debate of the translation of results found in cell lines (C2C12) to a primary cell source [muscle progenitor cells (MPCs)] in our 3D system. Striking differences in maturation level were found between the different cell sources. Constructs with MPCs were much more mature than C2C12 constructs, based on developed cross-striations and expression levels of mature myosin heavy chain (MHC) isoforms. Overall, electrical stimulation, when optimally timed, accelerated sarcomere assembly in both 2D and 3D. In addition, MPC constructs were more susceptible to the electrical stimulus, resulting in a shift of MHC expression to slower isoforms. Copyright © 2010 John Wiley & Sons, Ltd. PMID: 21154683 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Effect of capillary shear stress on recovery and osteogenic differentiation of muscle-derived precursor cell populations. J Tissue Eng Regen Med. 2010 Dec 10; Authors: Mulhall H, Patel M, Alqahtani K, Mason C, Lewis MP, Wall I Both chemical and physical stimuli can influence the fate of precursor cell populations. Therefore, the impact they have on promoting unwanted differentiation events must be understood to improve the yield and purity of therapeutic cells for regenerative medicine approaches. Capillary shear forces, similar to those encountered during cell processing, can impact upon production of regenerative cell populations. As shear stress can promote osteogenic differentiation in adhered bone marrow-derived stromal cells, we sought to determine whether the same is true for populations of muscle-derived precursor cells (MDPCs) that were isolated from a muscle niche environment. We isolated MDPCs from craniofacial muscle of 5 day-old Royal College of Surgeons rats and subjected them to capillary shear events similar to those encountered during manual bioprocessing of cells. We then assessed whether viability and ectopic osteogenic differentiation of MDPCs was affected. We found that whilst immediate recovery of MDPCs was not significantly affected by shear, viability after 24 h was reduced in comparison to non-sheared MDPCs. By 48 h, sheared MDPCs had all recovered and had similar viability to non-sheared MDPCs. Ostegenic differentiation was enhanced following exposure to capillary shear in both osteogenic and myogenic medium. This indicates that shear forces similar to those encountered during the bioprocessing of cell populations for therapy can have a significant influence on the fate of MDPCs. Copyright © 2010 John Wiley & Sons, Ltd. PMID: 21154676 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells. J Neurosci Res. 2010 Dec 8; Authors: Morizane A, Doi D, Kikuchi T, Nishimura K, Takahashi J The balance of bone morphogenic protein (BMP), transforming growth factor-β (TGFβ)/activin/nodal, and Wnt signals regulates the early lineage segregation of human embryonic stem cells (ESCs). Here we demonstrate that a combination of small-molecule inhibitors of BMP (Dorsomorphin) and TGFβ/activin/nodal (SB431542) signals promotes highly efficient neural induction from both human ESCs and induced pluripotent stem cells (iPSCs). The combination of small molecules had effects on both cell survival and purity of neural differentiation, under conditions of stromal (PA6) cell coculture and feeder-free floating aggregation culture, for all seven pluripotent stem cell lines that we studied, including three ESC and four iPSC lines. Small molecule compounds are stable and cost effective, so our findings provide a promising strategy for controlled production of neurons in regenerative medicine. © 2010 Wiley-Liss, Inc. PMID: 21154416 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | 2010 World Stem Cell Summit - Part 2. IDrugs. 2010 Dec;13(12):822-824 Authors: Vertès A The 2010 World Stem Cell Summit, held in Detroit, included topics covering new developments in the field of regenerative medicine. This conference report highlights selected presentations on the cancer stem cell hypothesis, stem cell therapy for amyotrophic lateral sclerosis, GRNOPC-1 for spinal cord injury, the use of cord blood stem cells for spinal cord injury, mesenchymal stem cell research and applications in cardiac therapy, tissue engineering, and very small embryonic-like stem cells. Investigational drugs discussed include NSI-566RSC (Neuralstem) and GRNOPC-1 (Geron Corp). PMID: 21154133 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | 2010 World Stem Cell Summit - Part 1. IDrugs. 2010 Dec;13(12):819-821 Authors: Vertès A The 2010 World Stem Cell Summit, held in Detroit, included topics covering new developments in the field of regenerative medicine. This conference report highlights selected presentations on government support for stem cell research in Michigan, financing stem cell development, regulatory and ethical considerations, Pharma's interest in allogeneic cell therapies, and the US Armed forces investment in regenerative medicine. PMID: 21154132 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Labeling of Mesenchymal Stem Cells with Bioconjugated Quantum Dots. Methods Mol Biol. 2011;680:61-75 Authors: Shah BS, Mao JJ Quantum dots (QDs) are semiconductor nanocrystals, and recently they have been shown as effective probes for cell labeling. Due to their unique spectral, physical, and chemical properties, QDs can concurrently tag multiple intercellular and intracellular components of live cells for time ranging from seconds to months. Different color QDs can label different cell components that can be visualized with fluorescent microscopy or in vivo. Here, we provide a detailed protocol for labeling postnatal and differentiated stem/progenitor cells with bioconjugated quantum dots. For example, peptide CGGGRGD is immobilized on CdSe-ZnS QDs with free carboxyl groups. These bioconjugates label selected integrins on cell membrane of human mesenchymal stem cells (hMSCs). QD concentration and incubation time to effectively label hMSCs is optimized. We discovered that bioconjugated QDs effectively label hMSCs not only during population doubling, but also during multi-lineage differentiation into osteoblasts, chondrocytes, and adipocytes. Undifferentiated and differentiated stem cells labeled with bioconjugated QDs can be readily imaged by fluorescent microscopy. Thus, quantum dots represent an effective cell labeling probe and an alternative to organic dyes and fluorescent proteins for cell labeling and cell tracking. PMID: 21153373 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | [Human adipose-derived stem cells: current challenges and clinical perspectives.] An Bras Dermatol. 2010 Oct;85(5):647-656 Authors: Yarak S, Okamoto OK Adult or somatic stem cells hold great promise for tissue regeneration. Currently, one major scientific interest is focused on the basic biology and clinical application of mesenchymal stem cells. Adipose tissue-derived stem cells share similar characteristics with bone marrow mesenchymal stem cells, but have some advantages including harvesting through a less invasive surgical procedure. Moreover, adipose tissue-derived stem cells have the potential to differentiate into cells of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle, as well as cells of non-mesodermal lineage, such as hepatocytes, pancreatic endocrine cells, neurons, cardiomyocytes, and vascular endothelial cells. There are, however, inconsistencies in the scientific literature regarding methods for harvesting adipose tissue and for isolating, characterizing and handling adipose tissue-derived stem cells. Future clinical applications of adipose tissue-derived stem cells rely on more defined and widespread methods for obtaining cells of clinical grade quality. In this review, current methods in adipose tissue-derived stem cell research are discussed with emphasis on strategies designed for future applications in regenerative medicine and possible challenges along the way. PMID: 21152789 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Lung assist device technology with physiologic blood flow developed on a tissue engineered scaffold platform. Lab Chip. 2010 Dec 13; Authors: Hoganson DM, Pryor Ii HI, Bassett EK, Spool ID, Vacanti JP There is no technology available to support failing lung function for patients outside the hospital. An implantable lung assist device would augment lung function as a bridge to transplant or possible destination therapy. Utilizing biomimetic design principles, a microfluidic vascular network was developed for blood inflow from the pulmonary artery and blood return to the left atrium. Computational fluid dynamics analysis was used to optimize blood flow within the vascular network. A micro milled variable depth mold with 3D features was created to achieve both physiologic blood flow and shear stress. Gas exchange occurs across a thin silicone membrane between the vascular network and adjacent alveolar chamber with flowing oxygen. The device had a surface area of 23.1 cm(2) and respiratory membrane thickness of 8.7 ± 1.2 μm. Carbon dioxide transfer within the device was 156 ml min(-1) m(-2) and the oxygen transfer was 34 ml min(-1) m(-2). A lung assist device based on tissue engineering architecture achieves gas exchange comparable to hollow fiber oxygenators yet does so while maintaining physiologic blood flow. This device may be scaled up to create an implantable ambulatory lung assist device. PMID: 21152606 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Hyaluronan Esters Drive Smad Gene Expression and Signaling Enhancing Cardiogenesis in Mouse Embryonic and Human Mesenchymal Stem Cells. PLoS One. 2010;5(11):e15151 Authors: Maioli M, Santaniello S, Montella A, Bandiera P, Cantoni S, Cavallini C, Bianchi F, Lionetti V, Rizzolio F, Marchesi I, Bagella L, Ventura C BACKGROUND: Development of molecules chemically modifying the expression of crucial orchestrator(s) of stem cell commitment may have significant biomedical impact. We have recently developed hyaluronan mixed esters of butyric and retinoic acids (HBR), turning cardiovascular stem cell fate into a high-yield process. The HBR mechanism(s) remain still largely undefined. METHODOLOGY/PRINCIPAL FINDINGS: We show that in both mouse embryonic stem (ES) cells and human mesenchymal stem cells from fetal membranes of term placenta (FMhMSCs), HBR differentially affected the patterning of Smad proteins, one of the major conductors of stem cell cardiogenesis. Real-time RT-PCR and Western blot analyses revealed that in both cell types HBR enhanced gene and protein expression of Smad1,3, and 4, while down-regulating Smad7. HBR acted at the transcriptional level, as shown by nuclear run-off experiments in isolated nuclei. Immunofluorescence analysis indicated that HBR increased the fluorescent staining for Smad1,3, and 4, confirming that the transcriptional action of HBR encompassed the upregulation of the encoded Smad proteins. Chromatin immune precipitation and transcriptional analyses showed that HBR increased the transcription of the cardiogenic gene Nkx-2.5 through Smad4 binding to its own consensus Smad site. Treatment of mouse ES cells and FMhMSCs with HBR led to the concomitant overexpression of both Smad4 and α-sarcomeric actinin. Smad4 silencing by the aid of lentiviral-mediated Smad4 shRNA confirmed a dominant role of Smad4 in HBR-induced cardiogenesis. CONCLUSIONS/SIGNIFICANCE: The use of HBR may pave the way to novel combinatorial strategies of molecular and stem cell therapy based on fine tuning of targeted Smad transciption and signaling leading to a high-throughput of cardiogenesis without the needs of gene transfer technologies. PMID: 21152044 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Surgical Approaches to Create Murine Models of Human Wound Healing. J Biomed Biotechnol. 2011;2011:969618 Authors: Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC Wound repair is a complex biologic process which becomes abnormal in numerous disease states. Although in vitro models have been important in identifying critical repair pathways in specific cell populations, in vivo models are necessary to obtain a more comprehensive and pertinent understanding of human wound healing. The laboratory mouse has long been the most common animal research tool and numerous transgenic strains and models have been developed to help researchers study the molecular pathways involved in wound repair and regeneration. This paper aims to highlight common surgical mouse models of cutaneous disease and to provide investigators with a better understanding of the benefits and limitations of these models for translational applications. PMID: 21151647 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Differentiation of Mouse Induced Pluripotent Stem Cells into a Multipotent Keratinocyte Lineage. J Invest Dermatol. 2010 Dec 9; Authors: Bilousova G, Chen J, Roop DR Recent breakthroughs in the generation of induced pluripotent stem cells (iPSCs) have provided a novel renewable source of cells with embryonic stem cell-like properties, which may potentially be used for gene therapy and tissue engineering. Although iPSCs have been differentiated into various cell types, iPSC-derived keratinocytes have not yet been obtained. In this study, we report the in vitro differentiation of mouse iPSCs into a keratinocyte lineage through sequential applications of retinoic acid and bone-morphogenetic protein-4 and growth on collagen IV-coated plates. We show that iPSCs can be differentiated into functional keratinocytes capable of regenerating a fully differentiated epidermis, hair follicles, and sebaceous glands in an in vivo environment. Keratinocytes derived from iPSCs displayed characteristics similar to those of primary keratinocytes with respect to gene and protein expression, as well as their ability to differentiate in vitro and to reconstitute normal skin and its appendages in an in vivo assay. At present, no effective therapeutic treatments are available for many genetic skin diseases. The development of methods for the efficient differentiation of iPSCs into a keratinocyte lineage will enable us to determine whether genetically corrected autologous iPSCs can be used to generate a permanent corrective therapy for these diseases.Journal of Investigative Dermatology advance online publication, 9 December 2010; doi:10.1038/jid.2010.364. PMID: 21150926 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Development of Skin-Humanized Mouse Models of Pachyonychia Congenita. J Invest Dermatol. 2010 Dec 9; Authors: García M, Larcher F, Hickerson RP, Baselga E, Leachman SA, Kaspar RL, Del Rio M Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p.Asn171Lys mutation of the keratin 6a gene (KRT6A), we were able to regenerate PC-derived human skin that appeared phenotypically normal, but developed sustained PC features after the use of an acute hyperproliferative stimulus (i.e., tape stripping). In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p.Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease.Journal of Investigative Dermatology advance online publication, 9 December 2010; doi:10.1038/jid.2010.353. PMID: 21150925 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Pancreas transplantation for type 2 diabetes mellitus. Curr Opin Organ Transplant. 2010 Dec 9; Authors: Orlando G, Stratta RJ, Light J PURPOSE OF REVIEW: This review will provide evidence that selected patients with type 2 diabetes mellitus (T2DM) may benefit from vascularized pancreas transplantation (PTX). RECENT FINDINGS: Initial experience with simultaneous pancreas-kidney transplantation (SPKT) in patients with T2DM and end-stage renal disease (ESRD) suggested that augmentation of endogenous insulin production by PTX in patients with C-peptide-positive, insulin-requiring diabetes resulted in insulin independence, improved glucose counter-regulation, and enhanced quality of life. A number of single-center retrospective studies have documented equivalent outcomes in patients with either type 1 diabetes mellitus (T1DM) or T2DM undergoing predominantly SPKT, although clearly a selection bias exists for patients in the latter category. Selection criteria for SPKT in T2DM include patients less than 55-60 years of age with a BMI less than 30-32 kg/m, insulin-requiring for a minimum of 5 years with a total daily insulin requirement less than 1 u/kg/day, a fasting C-peptide level less than 10 ng/ml, absence of severe vascular disease or tobacco abuse, adequate cardiac function, and presence of 'complicated' diabetes. Data from the International Pancreas Transplant Registry show that up to 7% of SPKT recipients are classified as having T2DM and that outcomes in these patients are comparable to those undergoing SPKT and classified as having T1DM. SUMMARY: Consequently, characterization of the 'type' of diabetes may be irrelevant and insulin-requiring diabetic patients with ESRD should be evaluated for PTX based exclusively on their predicted ability to tolerate the surgical procedure and requisite immunosuppression as well as comply with a stringent posttransplant follow-up regimen. PMID: 21150617 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Stem cells of the skin and cornea: their clinical applications in regenerative medicine. Curr Opin Organ Transplant. 2010 Dec 9; Authors: Proulx S, Fradette J, Gauvin R, Larouche D, Germain L PURPOSE OF REVIEW: The use of stem cells is of great interest for the treatment of various pathologies and ultimately for the restoration of organ function. Progress pointing towards future treatments of skin and corneal epithelial stem cell defects are reviewed, including the transplantation of living tissue-engineered substitutes. RECENT FINDINGS: This article focuses on substitutes optimized for permanent replacement of skin and cornea. New skin substitutes for burn care are currently under development. More complex tissue-engineered skin substitutes in which stroma, adipose tissue, capillaries, and neurons are combined with the epithelium are being developed. Some dermal/epidermal substitutes have been applied to the treatment of patients. Cultured corneal epithelial cells have been characterized and more complete corneal substitutes are being designed. Long-term clinical results on the transplantation of cultured corneal stem cells for the treatment of limbal stem cell deficiency have been reported. SUMMARY: Advances in tissue engineering for the development of substitutes that will benefit patients suffering from skin or corneal stem cell deficiencies are reviewed. These products are often a combination of cells, scaffolds and other factors. Key considerations in the development of corneal and skin substitutes for clinical applications are discussed. PMID: 21150608 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Mesenchymal stem cell therapy of intestinal disease: are their effects systemic or localized? Curr Opin Gastroenterol. 2010 Dec 9; Authors: Manieri NA, Stappenbeck TS PURPOSE OF REVIEW: Stem cell therapy for intestinal diseases is an emerging area in clinical gastroenterology. We will review recent literature regarding mesenchymal stem cells, which have been utilized in preclinical models and are now headed for clinical trials in several gastrointestinal diseases including inflammatory bowel disease. RECENT FINDINGS: Important studies over the last 2 years have made significant inroads into understanding the mechanisms of action of these cell types. The two major competing hypotheses are that mesenchymal stem cells home to areas of injury where they repair based on their stem cell activity or that mesenchymal stem cells act as a source of secreted factors that stimulate repair and inhibit inflammation. SUMMARY: Mesenchymal stem cells show promise for therapy in a number of intestinal diseases. Further understanding of their mechanism of action should improve our ability to use them therapeutically. PMID: 21150589 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Congestive heart failure in Indians: How do we improve diagnosis & management? Indian J Med Res. 2010 Nov;132(5):549-560 Authors: Reddy S, Bahl A, Talwar KK Heart failure is a common cardiovascular disease with high morbidity and mortality. Unlike western countries where heart failure is predominantly a disease of the elderly, in India it affects younger age group. Important risk factors include coronary artery disease, hypertension, diabetes mellitus, valvular heart disease and cardiomyopathies. Plasma brain natriuretic peptide levels are helpful in the diagnosis of heart failure. Echocardiography is the primary imaging modality of choice, through recently cardiac magnetic resonance imaging (MRI) has been found to play an increasing role. Aim of management is to improve symptoms & enhance survival. Diuretics are important in relieving symptoms. Beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and adosterone antagonists improve survival in patients with impaired systolic function. Device therapy including cardiac resynchronization therapy and implantable cardiac defibrillators, though expensive are useful in selected patients. Unlike in patients with systolic heart failure where several therapies have been shown to improve survival, clinical trial results in diastolic heart failure have been disappointing and therapy in these patients is restricted to symptom improvement and risk factor control. Therapies like stem cell therapy are being evaluated in clinical trials and appear promising. Early diagnosis and appropriate therapy helps in reversing the process of remodelling and clinical improvement in most of the patients. PMID: 21150007 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Large-scale phosphoproteome profiles comprehensive features of mouse embryonic stem cells. Mol Cell Proteomics. 2010 Dec 13; Authors: Li QR, Xing XB, Chen TT, Li RX, Dai J, Sheng QH, Xin SM, Zhu LL, Jin Y, Pei G, Kang JH, Li YX, Zeng R Embryonic stem cells are pluripotent and capable of unlimited self-renewal. Elucidation of the underlying molecular mechanism may contribute to the advancement of cell-based regenerative medicine. In the present work, we performed a large-scale analysis of the phosphoproteome in mouse embryonic stem (mES) cells. Using multiplex strategies, we detected 4581 proteins and 3970 high-confidence distinct phosphosites in 1642 phosphoproteins. Notably, 22 prominent phosphorylated stem cell marker proteins with 39 novel phosphosites were identified for the first time by mass spectrometry, including phosphorylation sites in Nanog (S65) and REST (S950, T953). Quantitative profiles of Nanog peptides obtained during the differentiation of mES cells revealed that the abundance of phosphopeptides and non-phosphopeptides decreased with different trends. To our knowledge, this study presents the largest global characterization of phosphorylation in mES cells. Compared with a study of ultimately differentiated tissue cells, a bioinformatics analysis of the phosphorylation dataset revealed a consistent phosphorylation motif in human and mouse ES cells. Moreover, investigations into phosphorylation conservation suggested that phosphoproteins were more conserved in the undifferentiated ES cell state than in the ultimately differentiated tissue cell state. However, the opposite conclusion was drawn from this conservation comparison with phosphosites. Overall, this work provides an overview of phosphorylation in mES cells and is a valuable resource for the future understanding of basic biology in mES cells. PMID: 21149613 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Bone marrow stromal cells (bone marrow-derived multipotent mesenchymal stromal cells) for alveolar bone tissue engineering: basic science to clinical translation. Int J Biochem Cell Biol. 2010 Dec 10; Authors: Kagami H, Agata H, Tojo A Bone tissue engineering is a promising field of regenerative medicine in which cultured cells, scaffolds, and osteogenic inductive signals are used to regenerate bone. This technology has already been used in several clinical studies and its efficacy has been reported. In this review, we focus on bone marrow stromal cells, which are the most commonly used cell source for bone tissue engineering. The nature of the cells, suitable culture conditions for bone tissue engineering, and their potential therapeutic applications are reviewed with possible caveats. Furthermore, recent advances in bone marrow stromal cell biology are discussed with reference to clinical translation. PMID: 21147252 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Understanding gene circuits at cell-fate branch points for rational cell reprogramming. Trends Genet. 2010 Dec 10; Authors: Zhou JX, Huang S Cell-type reprogramming, the artificial induction of a switch of cell lineage and developmental stage, holds great promise for regenerative medicine. However, how does the metazoan body itself 'program' the various cell lineages in the first place? Knowledge of how multipotent cells make cell-fate decisions and commit to a particular lineage is crucial for a rational reprogramming strategy and to avoid trial-and-error approaches in choosing the appropriate set of transcription factors to use. In the past few years, a general principle has emerged in which small gene circuits of cross-inhibition and self-activation govern the decision at branch points of cell development. A formal theoretical treatment of such circuits that deal with their dynamics on the 'epigenetic landscape' could offer some guidance to find the optimal way of cell reprogramming. PMID: 21146896 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Brainstem Hap1-Ahi1 is involved in insulin-mediated feeding control. FEBS Lett. 2010 Dec 9; Authors: Niu SN, Huang ZB, Wang H, Rao XR, Kong H, Xu J, Li XJ, Yang C, Sheng GQ The function of the brainstem Hap1-Ahi1 complex in the regulation of feeding behavior was investigated. When mice were fasted or treated with 2-deoxy-D-glucose (2-DG), Hap1-Ahi1 was significantly upregulated. By uUsing streptozotocin (STZ) to decrease the circulating insulin in mice, Hap1-Ahi1 was significantly increased. Furthermore, intra-brain injection of insulin decreased the expression of Hap1-Ahi1 in the brainstem. Moreover, when we downregulated knocked down the expression of the brainstem Hap1 by RNAi, the mice showed decreased food intake and lower body weights. Collectively, our results indicate that the complex of Hap1-Ahi1 complex in the brainstem works as a sensor forof insulin signalsto regulate its expression in the brainstem in feeding control. STRUCTURED SUMMARY: Ahi1physically interacts with Hap1: shown by anti bait coimmunoprecipitation (view interactions 1, 2). PMID: 21146532 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Regenerative medicine of the kidney. Adv Drug Deliv Rev. 2010 Dec 8; Authors: Perin L, Da Sacco S, De Filippo RE End stage renal disease is a major health problem in this country and worldwide. Although dialysis and kidney transplantation are currently used to treat this condition, kidney regeneration resulting in complete healing would be a desirable alternative. In this review we focus our attention on current therapeutic approaches used clinically to delay the onset of kidney failure. In addition we describe novel approaches, like Tissue Engineering, Stem cell Applications, Gene Therapy, and Renal Replacement Therapy that may one day be possible alternative therapies for patients with the hope of delaying kidney failure or even stopping the progression of renal disease. PMID: 21145933 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice. Cell. 2010 Dec 9; Authors: Sacco A, Mourkioti F, Tran R, Choi J, Llewellyn M, Kraft P, Shkreli M, Delp S, Pomerantz JH, Artandi SE, Blau HM In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. We postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdx phenotype results from greater MuSC reserve fueled by longer telomeres. We report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. These data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD. PMID: 21145579 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Perspectives in regenerative medicine and tissue engineering of bone. Br J Oral Maxillofac Surg. 2010 Dec 6; Authors: Ripamonti U, Tsiridis E, Ferretti C, Kerawala CJ, Mantalaris A, Heliotis M This final review in a series of three focuses on how the advances made in the realm of molecular and cellular bone biology have been translated into experimental animal and human surgery. PMID: 21144628 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | 2R and remodeling of vertebrate signal transduction engine. BMC Biol. 2010 Dec 13;8(1):146 Authors: Huminiecki L, Heldin CH ABSTRACT: BACKGROUND: Whole genome duplication (WGD) is a special case of gene duplication, observed rarely in animals, where all genes duplicate simultaneously through polyploidisation. Two rounds of WGD (2R-WGD) occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis of functional consequences of this event has not yet been performed. Results: We show that 2R-WGD affected overwhelming majority (74%) of signaling genes, in particular developmental pathways involving receptor tyrosine kinases, Wnt and TGF-beta ligands, GPCRs, and the apoptosis pathway. 2R-retained genes, in contrast to tandem duplicates, were enriched in protein interaction domains, and multifunctional signaling modules of Ras and MAP-kinase cascades. 2R-WGD had a fundamental impact on the cell-cycle machinery; redefined molecular building blocks of the neuronal synapse; and was formative for vertebrate brains. We investigated 2R-associated nodes in context of the human signaling network, as well as an inferred ancestral pre-2R (AP2R) network, and found that hubs (particularly involving negative regulations), were preferentially retained, with high-connectivity driving retention. Finally, microarrays and proteomics demonstrated a trend for gradual paralog expression divergence, independent of the duplication mechanism; but inferred ancestral expression states suggested preferential sub-functionalisation among 2R-ohnologs (2ROs). Conclusions: The 2R event left an indelible imprint on vertebrate signaling and cell-cycle. We show that 2R-WGD preferentially retained genes are associated with higher organismal complexity (e.g. locomotion, nervous system, morphogenesis), while genes associated with basic cellular functions (e.g. translation, replication, splicing, recombination; with the notable exception of cell-cycle) tended to be excluded. 2R-WGD set the stage for the emergence of key vertebrate functional novelties (such as complex brains, circulatory system, heart, bone, cartilage, musculature, and the adipose tissue). Full explanation of the impact of 2R on evolution, function, and the flow of information in vertebrate signaling networks is likely to have practical consequences for regenerative medicine, stem cell therapies, and cancer treatment. PMID: 21144020 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Persistence of functional hepatocyte-like cells in immune-compromised mice. Liver Int. 2010 Dec 10; Authors: Payne CM, Samuel K, Pryde A, King J, Brownstein D, Schrader J, Medine CN, Forbes SJ, Iredale JP, Newsome PN, Hay DC Background: Human embryonic stem cells (hESCs) can be efficiently differentiated to hepatocyte-like cells (HLCs) in vitro and demonstrate many of the functions and gene expression found in the adult liver. Aims: In this study, we assess the therapeutic value of HLCs in long-term cell-based therapies in vivo. Methods: hESC-derived HLCs were injected into the spleen of acutely injured NODscid(IL-2Rγ) null mice and analysed at various time points post-transplantation up to 3 months. Results: Large clusters of human cells engrafted in the spleen after 3 days and had expanded considerably by 31 days. At these time points, we identified human cells expressing parenchymal hepatocyte markers, exhibiting biliary duct-like structures and expressing myofibroblast markers. Three months after transplantation, we could detect human HLCs that were positive for albumin and CK18 by immunostaining and human DNA by fluorescent in situ hybridisation. Moreover, we could detect secretion of human serum albumin by enzyme-linked immunoabsorbant assay. Conclusions: We observed the persistence, engraftment and function of HLCs in vivo up to 3 months post-translation; however, all murine recipients developed large splenic and liver tumours that contained endodermal and mesodermal cell types. Although our studies demonstrate that hESC-derived HLCs have the potential to play an important role in cell-based therapies, current methodologies and transplantation strategies require substantial refinement before they can be deployed safely. PMID: 21143581 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Glycosylated Serum Protein May Improve Our Ability to Predict Endothelial and Erectile Dysfunction in Nonorganic Patients. J Sex Med. 2010 Dec 8; Authors: Huang Y, Sun X, Liu G, Yao F, Zheng F, Dai Y, Tu X, Xie X, Deng L, Zhang D, Zhang Y, Bian J, Gao Y, Ye Y, Deng C, Zhang Y Introduction. Early prediction of erectile dysfunction (ED) is critical in the treatment of impotence. Underlying pathogenesis may be the reason for ED without organic causes in young men. Aim. We evaluated the early predictive value of glycosylated serum protein (GSP) in young patients whose ED was diagnosed as "nonorganic" in origin according to general criteria. Methods. A total of 150 young men with ED and 27 healthy men without ED were evaluated, including International Index of Erectile Function-5 (IIEF-5), causes of ED, influential or risk factors for ED, vascular parameters, and serum biochemical markers. Fifty-two ED patients aged 20-40 years without known etiology and 22 age-matched normal subjects were enrolled. The further assessment of two groups focused on vascular endothelial function and glycometabolic state. Main Outcome Measures. Relationships among the IIEF-5 scores, flow-mediated dilation (FMD), and GSP were analyzed in cases vs. controls, using Pearson's correlation and multiple linear regression analysis. Results. No significant differences in baseline characteristics, cardiovascular risks, and conventional biomarkers were found between testing and control groups, except fasting blood glucose level (4.69 ± 0.50 vs. 4.29 ± 0.48, P = 0.003). FMD values were significantly reduced in cases compared with controls and correlated positively with IIEF-5 scores (r = 0.629, P < 0.001). GSP levels were significantly increased in the ED cases compared with controls and correlated negatively with IIEF-5 scores (r = -0.504, P < 0.001) and FMD values (r = -0.469, P < 0.001). These parameters independently predicted ED presence. The positive predictive value of FMD > 11.55% for excluding ED and of GSP > 210.50 mg/L for diagnosing ED were 86.4% (area under the curve [AUC]: 0.942, specificity: 88.4%) and 84.5% (AUC: 0.864, specificity: 72.7%), respectively. Conclusions. Underlying glycometabolic disorder and subclinical endothelial dysfunction may be served as early markers for organic ED in young ED patients without well-known related risk factors. GSP level may improve our ability to predict endothelial dysfunction and erectile dysfunction. Huang Y, Sun X, Liu G, Yao F, Zheng F, Dai Y, Tu X, Xie X, Deng L, Zhang D, Zhang Y, Bian J, Gao Y, Ye Y, Deng C, and Zhang Y. Glycosylated serum protein may improve our ability to predict endothelial and erectile dysfunction in non-organic patients. J Sex Med **;**:**-**. PMID: 21143415 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Low-serum culture system improves the adipogenic ability of visceral adipose tissue-derived stromal cells. Cell Biol Int. 2010 Dec 8; Authors: Nagasaki H, Shang Q, Suzuki T, Hashimoto H, Yoshimura T, Kondo TA, Ozaki T, Maruyama S, Jomori T, Oiso Y, Hamada Y In obese adipose tissue, infiltrating macrophages release proinflammatory cytokines that trigger insulin resistance. An adipocyte-based platform from visceral fat would be useful to elucidate the pathology of adipose inflammation and to develop therapeutic drugs for insulin resistance. Adipose tissue-derived mesenchymal stromal cells (ADSCs) expanded from subcutaneous fat are intensively studied as sources for regenerative medicine. However, the adipocyte culture system from visceral fat tissue has not been utilized yet. We aimed to establish the bioactive adipocyte platform using ADSCs from visceral fat pad. Stromal vascular fractions were processed from epididymal fat pads of Sprague Dawley rats and three human omental fat pads, and the ADSCs were expanded using a low-serum culture method. The responses of ADSCs and their adipogenic lineages (ADSC-adipocytes) to pioglitazone, a therapeutic drug for diobesity, were evaluated by gene expressions and ELISA. ADSCs (1×108) were expanded from 10 g of rat epididymal fat pads or human omental fat pads over five passages. Cell surface marker expressions revealed that visceral ADSCs were equivalent to mesenchymal stem cells. ADSC-adipocytes expanded in the low-serum culture system significantly showed higher expression of adipogenic markers (PPARγ, LPL and FABP4) and adipocytokines (adiponectin, Resistin, Leptin, PAI-1 and IL-10) than those expanded in a high-serum culture system. Pioglitazone accelerated the adipogenic induction and increased adiponectin expression in human ADSCs by 57.9±5.8-fold (mean ± SEM) relative to control cells (p<0.001). Both in rat and human ADSC-adipocytes, TNF-α significantly induced proinflammatory cytokines (MCP-1 and IL-6) and suppressed adiponectin expression, while pioglitazone antagonized these effects. The present findings suggest that visceral ADSC-adipocytes expanded in low-serum culture would be useful for adiposcience and pharmacological evaluations. PMID: 21143189 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Human dermal fibroblasts exhibit delayed adipogenic differentiation compared to mesenchymal stem cells. Stem Cells Dev. 2010 Dec 8; Authors: Jääger K, Neuman T Human dermal fibroblasts express mesenchymal stem cell (MSC) specific cell surface markers and differentiate into several cell types under appropriate conditions. Molecular mechanisms controlling the early stages of differentiation of dermal fibroblasts and MSCs isolated from different sources are not well studied. Here we have analyzed the cell type-specific changes of adipose tissue-derived mesenchymal stem cells (AdMSCs) and dermal fibroblasts (FBs) in the process of differentiation into adipocytes and osteoblasts. Analysis of gene expression in the course of adipogenic differentiation of AdMSCs and FBs isolated from the same individuals revealed a time lag in the induction of adipogenesis-related genes in FBs compared to AdMSCs, a phenomenon not described previously. Furthermore, preliminary evidence suggests that delayed adipogenesis of FBs is related to the delayed induction of preadipocyte transcription factor ZNF423 in FBs. These findings clearly show that AdMSCs and FBs have similar developmental potential but different molecular control mechanisms of initial stages of adipogenic differentiation. PMID: 21142453 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | A novel miniaturized multimodal bioreactor for continuous in situ assessment of bioartificial cardiac tissue during stimulation and maturation. Tissue Eng Part C Methods. 2010 Dec 8; Authors: Kensah G, Gruh I, Viering J, Schumann H, Dahlmann J, Meyer H, Skvorc D, Bär A, Akhyari P, Heisterkamp A, Haverich A, Martin U Stem cell based cardiac tissue engineering is a promising approach for regenerative therapy of the injured heart. At present, the small number of stem cell-derived cardiomyocytes that can be obtained using current culture and enrichment techniques represents one of the key limitations for the development of functional bioartificial cardiac tissue (BCT). We have addressed this problem by construction of a novel bioreactor with functional features of larger systems that enables the generation and in situ monitoring of miniaturized BCTs. BCTs were generated from rat cardiomyocytes in order to demonstrate advantages and usefulness of the bioreactor. Tissues showed spontaneous, synchronized contractions with cell orientation along the axis of strain. Cyclic stretch induced cardiomyocyte hypertrophy, demonstrated by a shift of myosin heavy chain expression from the alpha to beta isoform, together with elevated levels of atrial natriuretic factor. Stretch led to a moderate increase in systolic force (1.42 ± 0.09 mN vs. 0.96 ± 0.09 mN in controls), with significantly higher forces observed after β-adrenergic stimulation with noradrenalin (2.54 ± 0.11 mN). Combined mechanical and β-adrenergic stimulation had no synergistic effect. This study demonstrates for the first time that mechanical stimulation and direct real-time contraction force measurement can be combined into a single multi-modal bioreactor system, including electrical stimulation of excitable tissue, perfusion of the culture chamber and the possibility of (fluorescence) microscopic assessment during continuous cultivation. Thus, this bioreactor represents a valuable tool for monitoring tissue development and ultimately, the optimization of stem cell based tissue replacement strategies in regenerative medicine. PMID: 21142417 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Influence of Layer-by-Layer (LbL) Assembled CaCO(3)-Carriers on Macrophage Signaling Cascades. Biomacromolecules. 2010 Dec 13; Authors: Leßig J, Neu B, Reibetanz U Numerous drawbacks in the current medical treatment of chronic inflammations still require the design of sensitive and gentle methods without side effects. Layer-by-layer (LbL) coated microcarriers loaded with a cocktail of anti-inflammatory substances are supposed to be a new challenge for the medical treatment of immunoreactive cells such as macrophages and polymorphonuclear leukocytes (PMN). Nevertheless, microcarrier application requires biocompatibility of the system itself. Therefore, the aim of this study was to investigate microcarrier CaCO(3) systems LbL coated with biopolymers and a lipid bilayer, respectively, regarding the maintenance of the release of pro-inflammatory cytokines as TNFα and IL1β at normal levels. Only marginal increases after microcarrier interaction were allowed. The required microcarrier optimization results in the maximum use of a carrier/cell ratio of 1:1 for biopolymer-coated carriers and a carrier/cell ratio up to 5:1 for lipid-bilayer-coated carriers during the coincubation with macrophage-like cells. Low formation of reactive oxygen species (ROS) could not be maintained by either reduced carrier/cell ratios or by a surface lipid bilayer. PMID: 21142145 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Histone modifications in cancer biology and prognosis. Prog Drug Res. 2011;67:91-106 Authors: Kurdistani SK Cancer is a disease of genome sequence alterations as well as epigenetic changes. Epigenetics refers in part to the mechanisms by which histones affect various DNA-based processes, such as gene regulation. Histones are proteins around which the DNA wraps itself to form chromatin--the physiologically relevant form of the human genome. Histones are modified extensively by posttranslational modifications that alter chromatin structure and serve to recruit to or exclude protein complexes from DNA. Aberrations in histone modifications occur frequently in cancer including changes in their levels and distribution at gene promoters, gene coding regions, repetitive DNA sequences, and other genomic elements. Locus-specific alterations in histone modifications may have adverse effects on expression of nearby genes but so far have not been shown to have clinical utility. Cancer cells also exhibit alterations in global levels of specific histone modifications, generating an additional layer of epigenetic heterogeneity at the cellular level in tumor tissues. Unlike locus-specific changes, the cellular epigenetic heterogeneity can be used to define previously unrecognized subsets of cancer patients with distinct clinical outcomes. In general, increased prevalence of cells with lower global levels of histone modifications is prognostic of poorer clinical outcome such as increased risk of tumor recurrence and/or decreased survival probability. Prognostic utility of histone modifications has been demonstrated independently for multiple cancers including those of prostate, lung, kidney, breast, ovary, and pancreas, suggesting a fundamental association between global histone modification levels and tumor aggressiveness, regardless of cancer tissue of origin. Cellular levels of histone modifications may also predict response to certain chemotherapeutic agents, serving as predictive biomarkers that could inform clinical decisions on choice and course of therapy. The challenge before us is to understand how global levels of histone modifications are established and maintained and what their mechanistic links are to the cancer clinical behavior. PMID: 21141726 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | [Regenerative medicine and stem cells of corneal epithelium]. Nippon Ganka Gakkai Zasshi. 2010 Nov;114(11):968-75 Authors: Yokoo S Stem cells supply differentiated cells that compose the body organs. Stem cell research is increasing and their use in regenerative medicine is drawing a lot of attention. In ophthalmology, regenerative medicine of the corneal epithelium is already practiced by clinicians, and there is constant improvement in the culture methods. Research leading to the isolation of corneal epithelial stem cells, a kind of adult stem cell whose existence has been suggested, is done using various methods such as flow cytometry and selective culture methods. In this review, regenerative medicine of the corneal epithelium, stem cell isolation and culture methods are explained; and our new discoveries of stem cells' features such as their high adhesive ability is explained. PMID: 21141076 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |  | |  | |  |
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