|  |  |  | | | | | TE-RegenMed-StemCell feed | | | | | | | | | | | | | | | | | | | Identification and frequency of CCR5Δ32/Δ32 HIV-resistant cord blood units from Houston area hospitals. HIV Med. 2011 Mar 6; Authors: Gonzalez G, Park S, Chen D, Armitage S, Shpall E, Behringer R OBJECTIVES: The use of umbilical cord blood (CB) that is genetically resistant to HIV infection has been proposed as a novel stem cell therapy for the treatment of patients with AIDS. These genetically unique CB units (CBUs) should be present in public CB banks at a predicted frequency. METHODS: The chemokine (C-C motif) receptor 5 (CCR5) genotypes of CBUs donated to the M. D. Anderson CB Bank by four Houston area hospitals were determined by polymerase chain reaction (PCR) and DNA sequencing. RESULTS: The frequency of CCR5Δ32/Δ32 CBUs was consistent with the frequency of the CCR5Δ32 allele in human populations, and was apparently dependent on the ethnic population of the parents of the newborns from whom the CBUs were collected. CONCLUSIONS: Routine genotyping to identify HIV-resistant CBUs could create a bank of CB-derived stem/progenitor cells with which to treat HIV infection. PMID: 21375684 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Gene Therapy as a Novel Pharmaceutical Intervention for Stroke. Curr Pharm Des. 2011 Mar 4; Authors: Ooboshi H Cerebrovascular disease is the leading cause of death and disability in Japan and most Western countries. Gene transfer techniques may be applicable to the treatment of serious types of stroke, since several experimental studies have revealed the usefulness of gene therapy in the protection of neurons, reduction of infarct size and improvement of function. Prevention of vasospasm after subarachnoid hemorrhage is one of the best candidates for vascular gene therapy. Ischemia-induced apoptosis, inflammation, and derangement of neurovascular units can be targeted by the gene transfer approach. Recent studies have shown that promotion of neurogenesis and functional recovery may also be achieved by this strategy. Furthermore, a combination of stem cell therapy with gene transfer methods may be feasible. This review describes novel approaches for the treatment of stroke using gene transfer techniques. PMID: 21375487 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Intramyocardial bone marrow stem cell transplantation during coronary artery bypass surgery: A meta-analysis. J Thorac Cardiovasc Surg. 2011 Mar 2; Authors: Donndorf P, Kundt G, Kaminski A, Yerebakan C, Liebold A, Steinhoff G, Glass A OBJECTIVE: Experimental and clinical studies have suggested that intramyocardial bone marrow stem cell transplantation combined with coronary artery bypass grafting might improve left ventricular function in the setting of chronic ischemic heart disease. We therefore conducted a systematic review and meta-analysis of available publications regarding the efficacy and safety of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting. METHODS: The databases PUBMED, MEDLINE, Cochrane Controlled Trials Register, and ClinicalTrials.gov (all from their inception to May 2009) were searched for randomized controlled trials and cohort studies of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting to treat ischemic heart disease. Six studies were included. RESULTS: Compared with control groups, the bone marrow stem cell transplantation group showed a significant improvement of left ventricular ejection fraction from baseline to follow-up (5.40%; 95% confidence interval, 1.36-9.44; P = .009). Moreover, the overall change of left ventricular end-diastolic volume from baseline to follow-up favored the bone marrow stem cell therapy group (9.55 mL; 95% confidence interval, -2.82 to 21.92; P = .13). Major adverse cardiovascular events, including ventricular arrhythmia and the composite of other cardiovascular events, were not significantly different between the bone marrow stem cell therapy group and controls (relative risk for ventricular arrhythmia = 0.951; 95% confidence interval, 0.389-2.325; P = .913; relative risk for cardiovascular event = 1.134; 95% confidence interval, 0.28-4.6; P = .86). CONCLUSIONS: Clinical evidence suggests that intramyocardial bone marrow stem cell transplantation in combination with coronary artery bypass grafting is associated with improvements of functional parameters in patients with chronic ischemic heart disease. Furthermore, surgical intramyocardial bone marrow stem cell transplantation seems to be safe. PMID: 21376346 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | X-chromosome epigenetic reprogramming in pluripotent stem cells via noncoding genes. Semin Cell Dev Biol. 2011 Mar 2; Authors: Kim DH, Jeon Y, Anguera MC, Lee JT Acquisition of the pluripotent state coincides with epigenetic reprogramming of the X-chromosome. Female embryonic stem cells are characterized by the presence of two active X-chromosomes, cell differentiation by inactivation of one of the two Xs, and induced pluripotent stem cells by reactivation of the inactivated X-chromosome in the originating somatic cell. The tight linkage between X- and stem cell reprogramming occurs through pluripotency factors acting on noncoding genes of the X-inactivation center. This review article will discuss the latest advances in our understanding at the molecular level. Mouse embryonic stem cells provide a standard for defining the pluripotent ground state, which is characterized by low levels of the noncoding Xist RNA and the absence of heterochromatin marks on the X-chromosome. Human pluripotent stem cells, however, exhibit X-chromosome epigenetic instability that may have implications for their use in regenerative medicine. XIST RNA and heterochromatin marks on the X-chromosome indicate whether human pluripotent stem cells are developmentally 'naïve', with characteristics of the pluripotent ground state. X-chromosome status and determination thereof via noncoding RNA expression thus provide valuable benchmarks of the epigenetic quality of pluripotent stem cells, an important consideration given their enormous potential for stem cell therapy. PMID: 21376830 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | The California stem cell agency appears ready to partner with the AlphaMed Press of North Carolina to start a new scientific journal dealing with stem cell research and efforts to translate the findings into clinical treatments.
CIRM's venture into publishing comes amid a proliferation of new journals devoted to stem cell research.
CIRM plans to commit $600,000 over a three-year period to | | | | | | | | | | | | | | | | | | | | | | | | | Electroporation-mediated transfer of Runx2 and Osterix genes to enhance osteogenesis of adipose stem cells. Biomaterials. 2011 Jan;32(3):760-8 Authors: Lee JS, Lee JM, Im GI In the present study, we tested the hypothesis that electroporation-mediated transfer of Runx2, Osterix, or both genes enhances the in vitro and in vivo osteogenesis from adipose stem cells (ASCs). ASCs were transfected with Runx2, Osterix, or both genes using electroporation, and further cultured in monolayer or in PLGA scaffold under osteogenic medium for 14 days, then analyzed for in vitro osteogenic differentiation. Transfected ASC-PLGA scaffold hybrids were also implanted on nude mice to test for in vivo ectopic bone formation. Runx2 and Osterix genes were strongly expressed in ASCs transfected with each gene on day 7, decreasing rapidly on day 14. Runx2 protein was strongly expressed in ASCs transfected with the Runx2 gene, while Osterix protein was strongly expressed in ASCs transfected with either or both Runx2 and Osterix genes. Overexpression of Runx2 and Osterix significantly increased the gene expression of osteogenic differentiation markers (alkaline phosphatase [ALP], osteocalcin [OCN], type I collagen [COL1A1], and bone sialoprotein [BSP]) in ASCs. Transfection of Runx2 and Osterix genes enhanced the protein expression of OCN, type I collagen, and BSP, as demonstrated by Western blot analysis, and ALP activity as well as enhancing mineralization in the monolayer culture and ASC-PLGA scaffold hybrids. Runx2- or Osterix-transfected ASC-PLGA scaffold hybrids promoted bone formation in nude mice after 6 weeks of in vivo implantation. PMID: 20947160 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Oxidative stress induces senescence in human mesenchymal stem cells. Exp Cell Res. 2011 Mar 1; Authors: Brandl A, Meier M, Bechmann V, Angele P Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. Their regenerative potential is impaired by cellular senescence. The effects of oxidative stress on MSCs are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of MSCs, subject to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by rtPCR. Sub-lethal doses of oxidative stress reduced proliferation rates and induced senescent-morphological features and senescence-associated β-galactosidase positivity. Prolonged low dose treatment with hydrogen peroxide had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. Following acute oxidant insult p21 was up-regulated prior to returning to initial levels. TRF1 was significantly reduced, TRF2 showed a slight up-regulation. SIRT1 and XRCC5 were up-regulated after oxidant insult and expression levels increased in ageing cells. Compared to fibroblasts and chondrocytes, MSCs showed an increased tolerance to oxidative stress regarding proliferation, telomere biology and gene expression with an impaired stress tolerance in aged cells. PMID: 21376036 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Regeneration of full-thickness abdominal wall defects in rats using collagen scaffolds loaded with collagen-binding basic fibroblast growth factor. Biomaterials. 2011 Jan;32(3):753-9 Authors: Shi C, Chen W, Zhao Y, Chen B, Xiao Z, Wei Z, Hou X, Tang J, Wang Z, Dai J Biomaterials are increasingly used in the repair of tissue defects. The aim of the present study was to evaluate a new composite biomaterial for reconstruction of a 2 × 2.5 cm full-thickness abdominal wall defect. In this study, the collagen membrane was activated with the engineered human basic fibroblast growth factor (bFGF). To enhance the binding of bFGF to collagen membranes, a specific peptide of collagen-binding domain (CBD) was fused to the N-terminal of bFGF. After implantation, little adhesion was caused in collagen/CBD-bFGF, collagen/NAT-bFGF and collagen/PBS groups. Moreover, collagen/CBD-bFGF group could effectively promote the vascularization at 30 d after surgery and significantly accelerate the integration of myofibers into the collagen material at 90 d after surgery compared to the other two groups. Due to the replacement of the myofibers in materials, the mechanical strength of implanted biomaterials in collagen/CBD-bFGF group was also greater than the other two groups at 90 d after surgery. Thus, the collagen/CBD-bFGF composite biomaterial was promising for the treatment of full-thickness abdominal wall defect. PMID: 20937527 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Pocket epithelium in the pathological setting for HMGB1 release. J Dent Res. 2011 Feb;90(2):235-40 Authors: Ebe N, Hara-Yokoyama M, Iwasaki K, Iseki S, Okuhara S, Podyma-Inoue KA, Terasawa K, Watanabe A, Akizuki T, Watanabe H, Yanagishita M, Izumi Y High-mobility group box-1 (HMGB1) protein acts as a transcription factor in the nucleus and also as a pro-inflammatory cytokine when released into extracellular fluids. The presence of higher levels of HMGB1 is reported in the gingival crevicular fluid from periodontal patients. Since the proliferation of bacteria within the periodontal pocket is closely involved in the exacerbation of periodontal disease, it is hypothesized that the periodontal pocket causes the release of HMGB1. Immunohistochemical staining of inflamed gingiva revealed that HMGB1 is exclusively dislocated from the nucleus to the cytoplasm in the pocket epithelium, whereas it is mainly present in the nucleus in the gingival epithelium. Butyric acid, an extracellular metabolite from periodontopathic bacteria populating the periodontal pocket, induced the passive release of HMGB1 as a result of eliciting necrosis in the human gingival epithelial cell line. Thus, the periodontal epithelium may provide a unique pathological setting for HMGB1 release by bacterial insult. PMID: 21149855 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Quantitative Structure-Cytotoxicity Relationship of Newly Synthesised Trihaloacetylazulenes Determined by a Semi-Empirical Molecular-Orbital Method (PM5). Anticancer Res. 2011 Feb;31(2):515-20 Authors: Ishihara M, Wakabayashi H, Motohashi N, Sakagami H In order to extend the search for tumour-targeting compounds, this study performed a quantitative structure-activity relationship (QSAR) analysis of 26 newly synthesised trihaloacetylazulenes. PMID: 21378332 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | Performance of biodegradable microcapsules of poly(butylene succinate), poly(butylene succinate-co-adipate) and poly(butylene terephthalate-co-adipate) as drug encapsulation systems. Colloids Surf B Biointerfaces. 2011 Mar 2; Authors: Brunner CT, Baran ET, Pinho ED, Reis RL, Neves NM Poly(butylene succinate) (PBSu), poly(butylene succinate-co-adipate) (PBSA) and poly(butylene terephthalate-co-adipate) (PBTA) microcapsules were prepared by the double emulsion/solvent evaporation method. The effect of polymer and poly(vinyl alcohol) (PVA) concentration on the microcapsule morphologies, drug encapsulation efficiency (EE) and drug loading (DL) of bovine serum albumin (BSA) and all-trans retinoic acid (atRA) were all investigated. As a result, the sizes of PBSu, PBSA and PBTA microcapsules were increased significantly by varying polymer concentrations from 6 to 9%. atRA was encapsulated into the microcapsules with an high level of approximately 95% EE. The highest EE and DL of BSA were observed at 1% polymer concentration in values of 60 and 37%, respectively. 4% PVA was found as the optimum concentration and resulted in 75% EE and 14% DL of BSA. The BSA release from the capsules of PBSA was the longest, with 10% release in the first day and a steady release of 17% until the end of day 28. The release of atRA from PBSu microcapsules showed a zero-order profile for 2 weeks, keeping a steady release rate during 4 weeks with a 9% cumulative release. Similarly, the PBSA microcapsules showed a prolonged and a steady release of atRA during 6 weeks with 12% release. In the case of PBTA microcapsules, after a burst release of 10% in the first day, showed a parabolic release profile of atRA during 42 days, releasing 36% of atRA. PMID: 21376545 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Bioengineered periodontal tissue formed on titanium dental implants. J Dent Res. 2011 Feb;90(2):251-6 Authors: Lin Y, Gallucci GO, Buser D, Bosshardt D, Belser UC, Yelick PC The ability to use autologous dental progenitor cells (DPCs) to form organized periodontal tissues on titanium implants would be a significant improvement over current implant therapies. Based on prior experimental results, we hypothesized that rat periodontal ligament (PDL)-derived DPCs can be used to bioengineer PDL tissues on titanium implants in a novel, in vivo rat maxillary molar implant model. Analyses of recovered implants revealed organized PDL tissues surrounding titanium implant surfaces in PDL-cell-seeded, and not in unseeded control, implants. Rat PDL DPCs also exhibited differentiative potential characteristic of stem cells. These proof-of-principle findings suggest that PDL DPCs can organize periodontal tissues in the jaw, at the site of previously lost teeth, indicating that this method holds potential as an alternative approach to osseointegrated dental implants. Further refinement of this approach will facilitate the development of clinically relevant methods for autologous PDL regeneration on titanium implants in humans. PMID: 21149858 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | MicroRNA 21 regulates the proliferation of human adipose tissue-derived mesenchymal stem cells and high-fat diet-induced obesity alters microRNA 21. J Cell Physiol. 2011 Mar 4; Authors: Kim YJ, Hwang SH, Cho HH, Shin KK, Bae YC, Jung JS A better understanding of the molecular mechanisms that govern human adipose tissue-derived mesenchymal stem cells (hASCs) differentiation could provide new insights into a number of diseases including obesity. Our previous study demonstrated that microRNA-21 (miR-21) controls the adipogenic differentiation of hASCs. In this study, we determined the expression of miR-21 in white adipose tissues in a high-fat diet (HFD)-induced obesity mouse model to examine the relationship between miR-21 and obesity and the effect of miR-21 on hASCs proliferation. Our study showed biphasic changes of miR-21 expression and a correlation between miR-21 level and adipocyte number in the epididymal fat of HFD mice. Overexpression of miR-21 decreased cell proliferation, whereas inhibiting miR-21 with 2'-O-methyl-antisense RNA increased it. Overexpression of miR-21 decreased both protein and mRNA levels of STAT3, whereas inhibiting miR-21 with 2'-O-methyl-antisense RNA increased these levels. The activity of a luciferase construct containing the miR-21 target site from the STAT3 3'UTR was lower in LV-miR21-infected hASCs than in LV-miLacZ infected cells. RNA interference-mediated downregulation of STAT3 decreased cell proliferation without affecting adipogenic differentiation. These findings provide the evidence of the correlation between miR-21 level and adipocyte number in the white adipose tissue of HFD-induced obese mice, which provides new insights into the mechanisms of obesity. J. Cell. Physiol. © 2011 Wiley-Liss, Inc. PMID: 21381024 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Magnetically-directed self-assembly of electrospun superparamagnetic fibrous bundles to form three-dimensional tissues with a highly ordered architecture. Tissue Eng Part C Methods. 2011 Mar 4; Authors: Lee WY, Cheng WY, Yeh YC, Lai CH, Hwang SM, Hsiao CW, Huang CW, Chen MC, Sung HW Engineering three-dimensional (3D) cell-dense tissues with a well-organized structure remains a challenge in tissue engineering. In this study, highly oriented fibrous bundles, consisted of composite fibers of poly(L-lactide-co-glycolide)/superparamagnetic iron oxide nanoparticles, were fabricated using an electrospinning technique. The magnetic properties of the fabricated fibrous bundles were examined by a vibrating sample magnetometer and a superconducting quantum interference device; the results demonstrate that the fabricated fibrous bundles revealed superparamagnetic behavior without magnetic hysteresis. After seeding C2C12 myoblasts on the fibrous bundles, cells were grown along the direction of the underlying fibers (cell rods), an aligned pattern similar to those in native skeletal muscle tissues. When treated with the differentiation medium, myoblasts were fused together and formed multinucleated myotubes. As soon as applying an external magnetic field, the cell rods can spontaneously response to the magnetic control and self-assemble into 3D tissues with a highly ordered architecture. These findings demonstrate that the magnetically susceptible fibrous bundles not only can serve as a functional unit providing the topographic cue for cell orientation, but also can be magnetically manipulated for the creation of 3D cell-dense constructs. This technique may be applied to various cell types and scaffold configurations, thus advancing the design of engineered tissues that more closely replicate native tissues. PMID: 21375393 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | A Whole Organ Regenerative Medicine Approach for Liver Replacement. Tissue Eng Part C Methods. 2011 Mar 4; Authors: Badylak SF, Zhang L, Medberry CJ, Fukumitsu K, Faulk D, Jiang H, Reing JE, Gramignoli R, Komori J, Ross M, Nagaya M, Lagasse E, Beer Stolz D, Strom S, Fox IJ BACKGROUND & AIMS: The therapy of choice for end-stage liver disease is whole organ liver transplantation but this option is limited by a shortage of donor organs. Cell-based therapies and hepatic tissue engineering have been considered as alternatives to liver transplantation but neither have proven effective to date. A regenerative medicine approach for liver replacement has recently been described that includes the use of a 3-dimensional organ scaffold prepared by decellularization of xenogeneic liver. The present study investigates a new, minimally disruptive method for whole organ liver decellularization and three different cell reseeding strategies to engineer functional liver tissue. METHODS: A combination of enzymatic, detergent and mechanical methods are used to remove all cells from isolated rat livers. Whole organ perfusion is used in a customized organ chamber and the decellularized livers are examined by morphologic, biochemical and immunolabeling techniques for preservation of the native matrix architecture and composition. Three different methods for hepatocyte seeding of the resultant three dimensional liver scaffolds are evaluated to maximize cell survival and function: 1) direct parenchymal injection, 2) multi-step infusion or 3) continuous perfusion. RESULTS: The decellularization process preserves the three-dimensional macrostructure, the ultrastructure, the composition of the extracellular matrix components, the native microvascular network of the liver and the bile drainage system, and up to 50% of growth factor content. The three-dimensional liver matrix reseeded with the multistep infusion of hepatocytes generated approximately 90% of cell engraftment and supported liver-specific functional capacities of the engrafted cells including albumin production, urea metabolism, and cytochrome P450 induction. CONCLUSIONS: Whole organ liver decellularization is possible with maintenance of structure and composition suitable to support functional hepatocytes. PMID: 21375407 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The promotion of cartilage defect repair using adenovirus mediated Sox9 gene transfer of rabbit bone marrow mesenchymal stem cells. Biomaterials. 2011 Mar 4; Authors: Cao L, Yang F, Liu G, Yu D, Li H, Fan Q, Gan Y, Tang T, Dai K Although Sox9 is essential for chondrogenic differentiation and matrix production, its application in cartilage tissue engineering has been rarely reported. In this study, the chondrogenic effect of Sox9 on bone marrow mesenchymal stem cells (BMSCs) in vitro and its application in articular cartilage repair in vivo were evaluated. Rabbit BMSCs were transduced with adenoviral vector containing Sox9. Toluidine blue, safranin O staining and real-time PCR were performed to check chondrogenic differentiation. The results showed that Sox9 could induce chondrogenesis of BMSCs both in monolayer and on PGA scaffold effectively. The rabbit model with full-thickness cartilage defects was established and then repaired by PGA scaffold and rabbit BMSCs with or without Sox9 transduction. HE, safranin O staining and immunohistochemistry were used to assess the repair of defects by the complex. Better repair, including more newly-formed cartilage tissue and hyaline cartilage-specific extracellular matrix and greater expression of several chondrogenesis marker genes were observed in PGA scaffold and BMSCs with Sox9 transduction, compared to that without transduction. Our findings defined the important role of Sox9 in the repair of cartilage defects in vivo and provided evidence that Sox9 had the potential and advantage in the application of tissue engineering. PMID: 21377725 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Promoted dermis healing from full-thickness skin defect by porous silk fibroin scaffolds (PSFSs). Biomed Mater Eng. 2010;20(5):295-308 Authors: Guan G, Bai L, Zuo B, Li M, Wu Z, Li Y, Wang L Studies on skin substitutes and dermal scaffolds have been extensively carried out in the past several decades and some commercial products derived from collagen and polymers have been in marketing. Yet little research on silk fibroin based dermal scaffolds and products has been reported so far. In the present study, therefore, porous silk fibroin scaffolds (PSFSs) have been prepared by freeze drying method. The effects of PSFSs on skin recovery from full thickness defect have been examined by histological evaluation with respect to neovascularization, dermal regeneration and infiltration of inflammatory cells. In addition, tissue compatibility between PSFSs and polyvinyl alcohol (PVA) sponges (as control) has been semiquantitatively compared by scoring method. The results showed that at day 18 after implantation, new tissues formed in PSFSs whose structure was almost equal to normal skin structure where proportional distribution of functional blood vessels could be found. Furthermore, infiltration of inflammatory cells in PSFSs disappeared within 7 days. By contrast, a variety of interstices, fibrous encapsulization and moderate infiltration of inflammatory cells could be found in PVA sponges at day 18 after implantation. In summary, PSFSs has significantly promoted the skin recovery from full thickness defect, showing fibroin's outstanding tissue compatibility. PMID: 21084741 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Electrospun sulfated silk fibroin nanofibrous scaffolds for vascular tissue engineering. Biomaterials. 2011 Mar 2; Authors: Liu H, Li X, Zhou G, Fan H, Fan Y One of the major downfalls of tissue-engineered small-diameter vascular grafts is the inability to obtain a confluent endothelium on the lumenal surface. Loosely attached endothelial cells (ECs) are easily separated from the vessel wall when exposed to the in vivo vascular system. Thus any denuded areas on the lumenal surface of vascular grafts may lead to thrombus formation via platelet deposition and activation. If the denuded areas could express anticoagulant activity until the endothelial cell lining is fully achieved, it may greatly improve the chances of successful vascular reconstruction. In this study, we fabricate sulfated silk fibroin nanofibrous scaffolds (S-silk scaffolds) and assess the anticoagulant activity and cytocompatibility of S-silk scaffolds in vitro in order to improve the antithrombogenicity and get some insights into its potential use for vascular tissue engineering. Sulfated silk fibroin was prepared by reaction with chlorosulphonic acid in pyridine, and then was developed to form an S-silk scaffold by electrospinning technique. FTIR analyses identified the successful incorporation of sulfate groups in silk fibroin molecules. It was found that the anticoagulant activity of S-silk scaffolds was significantly enhanced compared with silk fibroin nanofibrous scaffolds (Silk scaffolds). Vascular cells, including ECs and smooth muscle cells (SMCs), demonstrated strong attachment to S-silk scaffolds and proliferated well with higher expression of some phenotype-related marker genes and proteins. Overall, the data in this study suggest the suitability of S-silk scaffolds used along with vascular cells for the development of tissue-engineered vascular grafts. PMID: 21376391 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Synthesis and biological activities of a library of glycosaminoglycans mimetic oligosaccharides. Biomaterials. 2011 Jan;32(3):769-76 Authors: Ikeda Y, Charef S, Ouidja MO, Barbier-Chassefière V, Sineriz F, Duchesnay A, Narasimprakash H, Martelly I, Kern P, Barritault D, Petit E, Papy-Garcia D Biologically active oligosaccharides related to glycosaminoglycans are accumulating increased attention because of their therapeutic potential and for their value in mechanistic studies. Heparan mimetics (HMs) are a family of dextran based polymer known to mimic the properties of glycosaminoglycans, and particularly those of heparan sulfates, as to interact with heparin binding proteins. HMs have shown to stimulate tissue repair in various animal models. Here, we use different methods to depolymerize HMs in order to produce a library of related oligosaccharides and study their biological activities. Since HMs were resistant to endoglycanases activities, depolymerization was achieved by chemical approaches. In vitro biological studies showed that HM oligosaccharides can differentially potentiate FGF-2 mitogenic and antithrombotic activities. In vivo, a selected oligosaccharide (H-dp12) showed to be able to regenerate tissue almost as well as the related polymeric product. The very low anticoagulant activity and high biological activity of low mass oligosaccharides give to these products a new therapeutic potential. PMID: 20947159 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Inverted colloidal crystal scaffolds with laminin-derived peptides for neuronal differentiation of bone marrow stromal cells. Biomaterials. 2011 Jan;32(3):819-31 Authors: Kuo YC, Chiu KH This study presents the effect of pore regularity on the preservation and differentiation of bone marrow stromal cells (BMSCs). Scaffolds with interconnected pores of inverted colloidal crystal (ICC) geometry were prepared by infiltrating chitosan-gelatin gels into the interstices of self-assembled microspheres, which were later dissolved with a solvent. In addition, the pore surfaces were grafted with two laminin-derived peptides (LDP). The experimental results revealed that the number of BMSCs in ICC scaffolds could increase 2.7-fold after cultivation over 7 days. Moreover, the distribution of cultured BMSCs in ICC scaffolds was quite uniform as compared with freeform scaffolds. ICC scaffolds could preserve 63% phenotypic BMSCs in average and freeform scaffolds 56%. The grafted LDP enhanced the adhesion efficiency of BMSCs in ICC scaffolds (about 70-75%) and produced NeuN-positive cells. A further induction with neuron growth factor could guide the differentiation of BMSCs toward mature neurons in LDP-grafted ICC scaffolds. The controlled topography of ICC structure and surface LDP can be promising in the cultivation of BMSCs and neural regeneration. PMID: 20974492 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | [Biomaterials and vascular grafts]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2010 Dec;27(6):1420-4 Authors: Xiang P, Li M The latest articles concerning the vascular grafts made of biomaterials were retrieved and the data on application of electrospun biopolymer in small diameter vascular tissue engineering scaffolds were comprehensively analyzed. The biomaterials, including natural vascular, decellularized scaffolds and biopolymer in the field of vascular grafts were studied. But natural vascular grafts and decellularized scaffolds can not meet the requirements of small diameter vascular graft because of inadequate sources and potential immunogenicity, respectively. The small diameter vascular scaffolds prepared by electrospinning of biopolymer can optimally simulate the blood vessel structure and properties, and hence can present a better approach to acquiring small diameter vascular tissue engineering scaffolds. PMID: 21375008 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | The regeneration of transected sciatic nerves of adult rats using chitosan nerve conduits seeded with bone marrow stromal cell-derived Schwann cells. Biomaterials. 2011 Jan;32(3):787-96 Authors: Ao Q, Fung CK, Tsui AY, Cai S, Zuo HC, Chan YS, Shum DK Autologous nerve grafts have been the 'gold standard' for treatment of peripheral nerve defects that exceed the critical gap length. To address issues of limited availability of donor nerves and donor site morbidity, we have fabricated chitosan conduits and seeded them with bone marrow stromal cell (BMSC)-derived Schwann cells as an alternative. The derived Schwann cells used were checked for fate commitment. The conduits were tested for efficacy in bridging the critical gap length of 12 mm in sciatic nerves of adult rats. By three months post-operation, mid-shank circumference, nerve conduction velocity, average regenerated myelin area, and myelinated axon count, in nerves bridged with BMSC-derived Schwann cells were similar to those treated with sciatic nerve-derived Schwann cells (p > 0.05) but significantly higher than those bridged with PBS-filled conduits (p < 0.05). Evidence is thus provided in support of the use of chitosan conduits seeded with BMSC-derived Schwann cells to treat critical defects in peripheral nerves. This provides the basis to pursue BMSC as an autologous source of Schwann cells for transplantation therapy in larger animal species. PMID: 20950852 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Development of rabbit meniscus acellular matrix. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2011 Feb 10;33(1):62-5 Authors: Yu Z, Yu Jie L, Jing Xiang H, Bin D Objective To prepare a rabbit meniscus acellular matrix scaffold and explore the histomorphological and biomechanical properties of the scaffold. Methods Rabbit meniscuses were collected and acellularized using a modified eight-step detergent process with hydrogen peroxide, distilled water, Triton X-100, and sodium deoxycholate. Its color and texture were observed. Histomorphological assessment was performed using routine hematoxylin-eosin stain, toluidine blue stain, Saffron stain, Hoechst-33258 stain, and immunohistochemical staining of collagen I. The ultrastructure of the specimens was observed with inverted phase contrast microscopy. Transient recovery rate of deformation, maximal recovery rate of deformation, and maximal compressive strength were tested to determine the biomechanical properties of the scaffold. Results The processed meniscus was milk-white in color with loose structure. It histologically appeared cell-free, stained positively for collagen I, and had abundant micropores according to phase-contrast microscopy. The transient recovery rate of deformation was (76.65∓4.61)%, the maximal recovery rate of deformation was 100%, and the maximal compressive strength was (4.51∓0.69) N when the specimens were compressed 40%. Conclusions The rabbit meniscus acellular matrix scaffold, with numerous micropores, is easy to be recovered from deformation and suitable for the adhesiveness and growth of breeding cells. This scaffold can be used as an ideal implant for future tissue engineering of the meniscus. PMID: 21375940 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | SEM stereo imaging for 3D visualization and analysis of cells in tissue engineered constructs. Technical Note. Tissue Eng Part C Methods. 2011 Mar 4; Authors: Cuijpers VM, Walboomers XF, Jansen J In tissue engineering research, various 3D techniques are available to study cell morphology, biomaterials and their relations. To overcome disadvantages of frequently used imaging techniques, in the current study stereo imaging SEM is proposed. First, the 3D SEM application was validated using a series of standardized microspheres. Thereafter, MC-3T3 cell morphology was visualized and cell parameters as cell height were quantified on titanium and calcium-phosphate materials using 3D reconstruction software. Besides 3D visualization of the cells, quantitative assessment showed significant substrate-dependency of cell spreading in time. Such quantification of cell spreading kinetics can be used for optimization of tissue engineering scaffold surface properties. However, further standardization of SEM image acquisition and 3D SEM software settings are still essential for 3D cell analysis. PMID: 21375392 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Cytocompatibility study of a natural biomaterial crosslinker-Genipin with therapeutic model cells. J Biomed Mater Res B Appl Biomater. 2011 Apr;97(1):58-65 Authors: Wang C, Lau TT, Loh WL, Su K, Wang DA Genipin has been widely used as a natural crosslinker to substitute chemical crosslinkers such as glutaraldehyde to crosslink various biomaterials like gelatin, collagen, and chitosan. However, there are contradicting views on the cytotoxicity and safety of genipin in tissue engineering. Therefore in this study, we aimed to evaluate the toxicity of genipin on skeletal tissues cells-osteoblasts and chondrocytes as they are also representatives of typical anchorage-dependent cells (ADCs) and nontypical ADCs. Results suggest that genipin toxicity is dose dependent and acute but not time dependent on both osteoblasts and chondrocytes. In particular, chondrocytes exhibit substantial alterations in the gene expression when exposed to Maximum nontoxic concentration (MaxNC) of genipin but there were no significant changes in the genes tested in osteoblasts. Since osteoblasts are typical ADCs, cellular focal adhesion assessment was carried out with F-actin being more contracted and unorganized when exposed to minimum toxic concentration (MinTC) of genipin. The mechanisms involved in cell deaths in both cell types are believed to be similar and hence using osteoblast as the model, cells were stained positive for Annexin-V and Reactive oxygen species (ROS) level were elevated at MinTC of genipin. Collectively, genipin induced cell apoptosis via ROS production, and apparently, gene expressions could also be altered at MaxNC. For this reason, we recommend the dose of genipin to be controlled within 0.5 mM. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater , 2011. PMID: 21381191 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | A Whole Organ Regenerative Medicine Approach for Liver Replacement. Tissue Eng Part C Methods. 2011 Mar 4; Authors: Badylak SF, Zhang L, Medberry CJ, Fukumitsu K, Faulk D, Jiang H, Reing JE, Gramignoli R, Komori J, Ross M, Nagaya M, Lagasse E, Beer Stolz D, Strom S, Fox IJ BACKGROUND & AIMS: The therapy of choice for end-stage liver disease is whole organ liver transplantation but this option is limited by a shortage of donor organs. Cell-based therapies and hepatic tissue engineering have been considered as alternatives to liver transplantation but neither have proven effective to date. A regenerative medicine approach for liver replacement has recently been described that includes the use of a 3-dimensional organ scaffold prepared by decellularization of xenogeneic liver. The present study investigates a new, minimally disruptive method for whole organ liver decellularization and three different cell reseeding strategies to engineer functional liver tissue. METHODS: A combination of enzymatic, detergent and mechanical methods are used to remove all cells from isolated rat livers. Whole organ perfusion is used in a customized organ chamber and the decellularized livers are examined by morphologic, biochemical and immunolabeling techniques for preservation of the native matrix architecture and composition. Three different methods for hepatocyte seeding of the resultant three dimensional liver scaffolds are evaluated to maximize cell survival and function: 1) direct parenchymal injection, 2) multi-step infusion or 3) continuous perfusion. RESULTS: The decellularization process preserves the three-dimensional macrostructure, the ultrastructure, the composition of the extracellular matrix components, the native microvascular network of the liver and the bile drainage system, and up to 50% of growth factor content. The three-dimensional liver matrix reseeded with the multistep infusion of hepatocytes generated approximately 90% of cell engraftment and supported liver-specific functional capacities of the engrafted cells including albumin production, urea metabolism, and cytochrome P450 induction. CONCLUSIONS: Whole organ liver decellularization is possible with maintenance of structure and composition suitable to support functional hepatocytes. PMID: 21375407 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Performance of biodegradable microcapsules of poly(butylene succinate), poly(butylene succinate-co-adipate) and poly(butylene terephthalate-co-adipate) as drug encapsulation systems. Colloids Surf B Biointerfaces. 2011 Mar 2; Authors: Brunner CT, Baran ET, Pinho ED, Reis RL, Neves NM Poly(butylene succinate) (PBSu), poly(butylene succinate-co-adipate) (PBSA) and poly(butylene terephthalate-co-adipate) (PBTA) microcapsules were prepared by the double emulsion/solvent evaporation method. The effect of polymer and poly(vinyl alcohol) (PVA) concentration on the microcapsule morphologies, drug encapsulation efficiency (EE) and drug loading (DL) of bovine serum albumin (BSA) and all-trans retinoic acid (atRA) were all investigated. As a result, the sizes of PBSu, PBSA and PBTA microcapsules were increased significantly by varying polymer concentrations from 6 to 9%. atRA was encapsulated into the microcapsules with an high level of approximately 95% EE. The highest EE and DL of BSA were observed at 1% polymer concentration in values of 60 and 37%, respectively. 4% PVA was found as the optimum concentration and resulted in 75% EE and 14% DL of BSA. The BSA release from the capsules of PBSA was the longest, with 10% release in the first day and a steady release of 17% until the end of day 28. The release of atRA from PBSu microcapsules showed a zero-order profile for 2 weeks, keeping a steady release rate during 4 weeks with a 9% cumulative release. Similarly, the PBSA microcapsules showed a prolonged and a steady release of atRA during 6 weeks with 12% release. In the case of PBTA microcapsules, after a burst release of 10% in the first day, showed a parabolic release profile of atRA during 42 days, releasing 36% of atRA. PMID: 21376545 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | A collagen-poly(lactic acid-co-ɛ-caprolactone) hybrid scaffold for bladder tissue regeneration. Biomaterials. 2011 Mar 3; Authors: Engelhardt EM, Micol LA, Houis S, Wurm FM, Hilborn J, Hubbell JA, Frey P Scaffold materials should favor cell attachment and proliferation, and provide designable 3D structures with appropriate mechanical strength. Collagen matrices have proven to be beneficial scaffolds for tissue regeneration. However, apart from small intestinal submucosa, they offer a limited mechanical strength even if crosslinking can enhance their mechanical properties. A more cell-friendly way to increase material strength is to combine synthetic polymer meshes with plastic compressed collagen gels. This work describes the potential of plastic compressed collagen-poly(lactic acid-co-ɛ-caprolactone) (PLAC) hybrids as scaffolds for bladder tissue regeneration. Human bladder smooth muscle and urothelial cells were cultured on and inside collagen-PLAC hybrids in vitro. Scaffolds were analyzed by electron microscopy, histology, immunohistochemistry, and AlamarBlue assay. Both cell types proliferated in and on the hybrid, forming dense cell layers on top after two weeks. Furthermore, hybrids were implanted subcutaneously in the backs of nude mice. Host cell infiltration, scaffold degradation, and the presence of the seeded bladder cells were analyzed. Hybrids showed a lower inflammatory reaction in vivo than PLAC meshes alone, and first signs of polymer degradation were visible at six months. Collagen-PLAC hybrids have potential for bladder tissue regeneration, as they show efficient cell seeding, proliferation, and good mechanical properties. PMID: 21377203 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Cardiomyopathy of Aging in the Mammalian Heart is Characterized by Myocardial Hypertrophy, Fibrosis and a Predisposition Towards Cardiomyocyte Apoptosis and Autophagy. Exp Gerontol. 2011 Mar 3; Authors: Boyle AJ, Shih H, Hwang J, Ye J, Lee B, Zhang Y, Kwon D, Jun K, Zheng D, Sievers R, Angeli F, Yeghiazarians Y, Lee R Aging is associated with an increased incidence of heart failure, but the existence of an age-related cardiomyopathy remains controversial. Differences in strain, age and technique of measuring cardiac function differ between experiments, confounding the interpretation of these studies. Additionally, the structural and genetic profile at the onset of heart failure has not been extensively studied. We therefore performed serial echocardiography, which allows repeated assessment of left ventricular (LV) function, on a cohort of the same mice every 3 months as they aged and demonstrated that LV systolic dysfunction becomes apparent at 18 months of age. These aging animals had left ventricular hypertrophy and fibrosis, but did not have inducible ventricular tachyarrhythmias. Gene expression profiling of left ventricular tissue demonstrated 40 differentially expressed probesets and 36 differentially expressed gene ontology terms, largely related to inflammation and immunity. At this early stage of cardiac dysfunction, we observed increased cardiomyocyte expression of the pro-apoptotic activated caspase-3, but no actual increase in apoptosis. The aging hearts also have higher levels of anti-apoptotic and autophagic factors, which may have rendered protection from apoptosis. In conclusion, we describe the functional, structural and genetic changes in murine hearts as they first develop cardiomyopathy of aging. PMID: 21377520 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | X-chromosome epigenetic reprogramming in pluripotent stem cells via noncoding genes. Semin Cell Dev Biol. 2011 Mar 2; Authors: Kim DH, Jeon Y, Anguera MC, Lee JT Acquisition of the pluripotent state coincides with epigenetic reprogramming of the X-chromosome. Female embryonic stem cells are characterized by the presence of two active X-chromosomes, cell differentiation by inactivation of one of the two Xs, and induced pluripotent stem cells by reactivation of the inactivated X-chromosome in the originating somatic cell. The tight linkage between X- and stem cell reprogramming occurs through pluripotency factors acting on noncoding genes of the X-inactivation center. This review article will discuss the latest advances in our understanding at the molecular level. Mouse embryonic stem cells provide a standard for defining the pluripotent ground state, which is characterized by low levels of the noncoding Xist RNA and the absence of heterochromatin marks on the X-chromosome. Human pluripotent stem cells, however, exhibit X-chromosome epigenetic instability that may have implications for their use in regenerative medicine. XIST RNA and heterochromatin marks on the X-chromosome indicate whether human pluripotent stem cells are developmentally 'naïve', with characteristics of the pluripotent ground state. X-chromosome status and determination thereof via noncoding RNA expression thus provide valuable benchmarks of the epigenetic quality of pluripotent stem cells, an important consideration given their enormous potential for stem cell therapy. PMID: 21376830 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Viability and proliferation potential of adipose-derived stem cells following labeling with a positron-emitting radiotracer. Eur J Nucl Med Mol Imaging. 2011 Mar 5; Authors: Elhami E, Goertzen AL, Xiang B, Deng J, Stillwell C, Mzengeza S, Arora RC, Freed D, Tian G PURPOSE: Adipose-derived stem cells (ASCs) have promising potential in regenerative medicine and cell therapy. Our objective is to examine the biological function of the labeled stem cells following labeling with a readily available positron emission tomography (PET) tracer, (18)F-fluoro-2-deoxy-D: -glucose (FDG). In this work we characterize labeling efficiency through assessment of FDG uptake and retention by the ASCs and the effect of FDG on cell viability, proliferation, transdifferentiation, and cell function in vitro using rat ASCs. METHODS: Samples of 10(5) ASCs (from visceral fat tissue) were labeled with concentrations of FDG (1-55 Bq/cell) in 0.75 ml culture medium. Label uptake and retention, as a function of labeling time, FDG concentration, and efflux period were measured to determine optimum cell labeling conditions. Cell viability, proliferation, DNA structure damage, cell differentiation, and other cell functions were examined. Non-labeled ASC samples were used as a control for all experimental groups. Labeled ASCs were injected via tail vein in several healthy rats and initial cell biodistribution was assessed. RESULTS: Our results showed that FDG uptake and retention by the stem cells did not depend on FDG concentration but on labeling and efflux periods and glucose content of the labeling and efflux media. Cell viability, transdifferentiation, and cell function were not greatly affected. DNA damage due to FDG radioactivity was acute, but reversible; cells managed to repair the damage and continue with cell cycles. Over all, FDG (up to 25 Bq/cell) did not impose severe cytotoxicity in rat ASCs. Initial biodistribution of the FDG-labeled ASCs was 80% + retention in the lungs. In the delayed whole-body images (2-3 h postinjection) there was some activity distribution resembling typical FDG uptake patterns. CONCLUSION: For in vivo cell tracking studies with PET tracers, the parameter of interest is the amount of radiotracer that is present in the cells being labeled and consequent biological effects. From our study we developed a labeling protocol for labeling ASCs with a readily available PET tracer, FDG. Our results indicate that ASCs can be safely labeled with FDG concentration up to 25 Bq/cell, without compromising their biological function. A labeling period of 90 min in glucose-free medium and efflux of 60 min in complete media resulted in optimum label retention, i.e., 60% + by the stem cells. The initial biodistribution of the implanted FDG-labeled stem cells can be monitored using microPET imaging. PMID: 21380591 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Adipose-derived Stromal/Stem Cells (ASC) in Regenerative Medicine: Pharmaceutical Applications. Curr Pharm Des. 2011 Mar 7; Authors: Gimble JM, Nuttall ME Information relating to the biology, culture expansion, and mechanisms relating to adipose-derived cells has advanced significantly in the past decade. Both the heterogeneous stromal vascular fraction (SVF) and more homogeneous adipose-derived stem cells (ASC) offer unique opportunities as novel cell-based therapeutics and as traditional pharmaceutical discovery tools. This review highlights the cytokine secretory functions of ASC and SVF cells as well as their potential use as immunomodulators and gene delivery vehicles. These functions make it feasible to exploit adipose-derived cells in the treatment of ischemic, musculoskeletal, and oncological disorders. With appropriate commercial development and in vivo validation, ASC and SVF cells will have a significant therapeutic impact in the future. PMID: 21375497 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Labeling of Primary Human Hepatocytes With Micron-Sized Iron Oxide Particles in Suspension Culture Suitable for Large-Scale Preparation. Artif Organs. 2011 Mar 6; Authors: Kammer NN, Billecke N, Morgul MH, Adonopoulou MK, Mogl M, Huang MD, Florek S, Schmitt KR, Raschzok N, Sauer IM Labeling of hepatocytes with micron-sized iron oxide particles (MPIOs) enables cell detection using clinical magnetic resonance equipment. For clinical applications, large numbers of cells must be labeled in a simple and rapid manner and have to be applied in suspension. However, all existing protocols are based on adhesion culture labeling with subsequent resuspension, only suitable for small experimental settings. The aim of this study was to investigate the feasibility of preparing MPIO-labeled primary human hepatocytes in a temporary suspension culture. Human hepatocytes were isolated from 16 donors and labeled with MPIOs in suspension, using the Rotary Cell Culture System. Particle incorporation was investigated by light and electron microscopy. Cells were compared with adhesion culture-labeled and subsequently enzymatically resuspended cells. During a period of 5 days, hepatocyte-specific parameters of cell damage (aspartate aminotransferase and alanine aminotransferase) and metabolic activity (urea and albumin) were analyzed (n = 7). Suspension cultures showed a higher outcome in cell recovery compared with the conventional labeling method. When incubated with 180 particles/viable cell for 4 h, the mean particle uptake was 28.8 particles/cell at a labeling efficiency of 95.1%. Labeling in suspension had no adverse effects on cell integrity or metabolic activity. We conclude that labeling of human hepatocytes in suspension is feasible and simple and may serve future large-scale processing of cells. PMID: 21375547 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Body composition changes and inhibition of fat development in vivo implicates androgen in regulation of stem cell lineage allocation. J Cell Biochem. 2011 Mar 4; Authors: Semirale AA, Zhang X, Wiren KM Androgens regulate body composition in youth and declining testosterone that occurs with aging is associated with muscle wasting, increased fat mass and osteopenia. Transgenic mice with targeted androgen receptor (AR) overexpression in mesenchymal stem cells (MSC) were generated to explore the role of androgen signaling in the regulation of body composition. Transgenic males, but not females, were shorter and have reduced body weight and visceral fat accumulation. Dual energy x-ray absorptiometry (DXA) revealed significant reductions in fat mass with a reciprocal increase in lean mass, yet no difference in food consumption or locomotor activity was observed. Adipose tissue weight was normal in brown fat but reduced in both gonadal and perirenal depots, and reduced hyperplasia was observed with smaller adipocyte size in visceral and subcutaneous white adipose tissue. Although serum leptin, adiponectin, triglyceride, and insulin levels were no different between the genotypes, intraperitoneal glucose tolerance testing showed improved glucose clearance in transgenic males. High levels of the AR transgene are detected in MSCs but not in mature fat tissue. Reduced fibroblast colony forming units indicate fewer progenitor cells resident in the marrow in vivo. Precocious expression of GLUT4, PPARγ and C/EBPα was observed in proliferating precursor cultures from transgenic mice compared to controls. In more mature cultures, there was little difference between the genotypes. We propose a mechanism where enhanced androgen sensitivity can alter lineage commitment in vivo to reduce progenitor number and fat development, while increasing the expression of key factors to promote smaller adipocytes with improved glucose clearance. J. Cell. Biochem. © 2011 Wiley-Liss, Inc. PMID: 21381083 [PubMed - as supplied by publisher] | | | | | | | | | |  | |  | |  |
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