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| Designer self-assembling peptide nanofiber biological materials.
June 4, 2010 at 2:04 PM
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| | Designer self-assembling peptide nanofiber biological materials. Chem Soc Rev. 2010 Jun 3; Authors: Hauser CA, Zhang S Scientists and bioengineers have dreamed of designing materials from the bottom up with the finest detail and ultimate control at the single molecular level. The discovery of a class of self-assembling peptides that spontaneously undergo self-organization into well-ordered structures opened a new avenue for molecular fabrication of biological materials. Since this discovery, diverse classes of short peptides have been invented with broad applications, including 3D tissue cell culture, reparative and regenerative medicine, tissue engineering, slow drug release and medical device development. Molecular design of new materials using short peptides is poised to become increasingly important in biomedical research, biomedical technology and medicine, and is covered in this tutorial review. PMID: 20520907 [PubMed - as supplied by publisher] | | |
| Functional Heterogeneity of Embryonic Stem Cells Revealed through Translational Amplification of an Early Endodermal Transcript.
June 4, 2010 at 2:04 PM
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| | Functional Heterogeneity of Embryonic Stem Cells Revealed through Translational Amplification of an Early Endodermal Transcript. PLoS Biol. 2010;8(5):e1000379 Authors: Canham MA, Sharov AA, Ko MS, Brickman JM ES cells are defined as self-renewing, pluripotent cell lines derived from early embryos. Cultures of ES cells are also characterized by the expression of certain markers thought to represent the pluripotent state. However, despite the widespread expression of key markers such as Oct4 and the appearance of a characteristic undifferentiated morphology, functional ES cells may represent only a small fraction of the cultures grown under self-renewing conditions. Thus phenotypically "undifferentiated" cells may consist of a heterogeneous population of functionally distinct cell types. Here we use a transgenic allele designed to detect low level transcription in the primitive endoderm lineage as a tool to identify an immediate early endoderm-like ES cell state. This reporter employs a tandem array of internal ribosomal entry sites to drive translation of an enhanced Yellow Fluorescent Protein (Venus) from the transcript that normally encodes for the early endodermal ma! rker Hex. Expression of this Venus transgene reports on single cells with low Hex transcript levels and reveals the existence of distinct populations of Oct4 positive undifferentiated ES cells. One of these cells types, characterized by both the expression of the Venus transgene and the ES cells marker SSEA-1 (V(+)S(+)), appears to represent an early step in primitive endoderm specification. We show that the fraction of cells present within this state is influenced by factors that both promote and suppress primitive endoderm differentiation, but conditions that support ES cell self-renewal prevent their progression into differentiation and support an equilibrium between this state and at least one other that resembles the Nanog positive inner cell mass of the mammalian blastocysts. Interestingly, while these subpopulations are equivalently and clonally interconvertible under self-renewing conditions, when induced to differentiate both in vivo and in vitro they exhibit diffe! rent behaviours. Most strikingly when introduced back into mor! ulae or blastocysts, the V(+)S(+) population is not effective at contributing to the epiblast and can contribute to the extra-embryonic visceral and parietal endoderm, while the V(-)S(+) population generates high contribution chimeras. Taken together our data support a model in which ES cell culture has trapped a set of interconvertible cell states reminiscent of the early stages in blastocyst differentiation that may exist only transiently in the early embryo. PMID: 20520791 [PubMed - in process] | | |
| Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": A transcriptional informatics analysis with validation.
June 4, 2010 at 2:04 PM
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| | Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": A transcriptional informatics analysis with validation. Cell Cycle. 2010 Jun 22;9(11) Authors: Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP Cav-1 (-/-) deficient stromal cells are a new genetic model for myofibroblasts and cancer-associated fibroblasts. Using an unbiased informatics analysis of the transcriptional profile of Cav-1 (-/-) deficient mesenchymal stromal cells, we have now identified many of the major signaling pathways that are activated by a loss of Cav-1, under conditions of metabolic restriction (with low glucose media). Our informatics analysis suggests that a loss of Cav-1 induces oxidative stress, which mimics a constitutive pseudo-hypoxic state, leading to (1) aerobic glycolysis and (2) inflammation in the tumor stromal microenvironment. This occurs via the activation of 2 major transcription factors, namely HIF (aerobic glycolysis) and NFkappaB (inflammation) in Cav-1 (-/-) stromal fibroblastic cells. Experimentally, we show that Cav-1 deficient stromal cells may possess defective mitochondria, due to the over-production of nitric oxide (NO), resulting in the tyrosine nitration of! the mitochondrial respiratory chain components (such as complex I). Elevated levels of nitro-tyrosine were observed both in Cav-1 (-/-) stromal cells, and via acute knock-down with siRNA targeting Cav-1. Finally, metabolic restriction with mitochondrial (complex I) and glycolysis inhibitors was synthetically lethal with a Cav-1 (-/-) deficiency in mice. As such, Cav-1 deficient mice show a dramatically reduced mitochondrial reserve capacity. Thus, a mitochondrial defect in Cav-1 deficient stromal cells could drive oxidative stress, leading to aerobic glycolysis, and inflammation, in the tumor microenvironment. These stromal alterations may underlie the molecular basis of the "Reverse Warburg Effect", and could provide the key to targeted anti-cancer therapies using metabolic inhibitors. In direct support of these findings, the transcriptional profile of Cav-1 (-/-) stromal cells overlaps significantly with Alzheimer's disease, which is characterized by oxidative stress, NO! over-production (peroxynitrite formation), inflammation, hypo! xia and mitochondrial dysfunction. We conclude that Cav-1 (-/-) deficient mice are a new whole-body animal model for an activated lethal tumor microenvironment, i.e., "tumor stroma" without the tumor. Since Cav-1 (-/-) mice are also an established animal model for profibrotic disease, our current results may have implications for understanding the pathogenesis of scleroderma (systemic sclerosis) and pulmonary fibrosis, which are also related to abnormal mesenchymal stem cell function. PMID: 20519932 [PubMed - as supplied by publisher] | | |
| Assessment of the human epidermal model LabCyte EPI-MODEL for In vitro skin corrosion testing according to the OECD test guideline 431.
June 4, 2010 at 2:04 PM
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| | Assessment of the human epidermal model LabCyte EPI-MODEL for In vitro skin corrosion testing according to the OECD test guideline 431. J Toxicol Sci. 2010;35(3):411-7 Authors: Katoh M, Hamajima F, Ogasawara T, Hata K A new OECD test guideline 431 (TG431) for in vitro skin corrosion tests using human reconstructed skin models was adopted by OECD in 2004. TG431 defines the criteria for the general function and performance of applicable skin models. In order to confirm that the new reconstructed human epidermal model, LabCyte EPI-MODEL is applicable for the skin corrosion test according to TG431, the predictability and repeatability of the model for the skin corrosion test was evaluated. The test was performed according to the test protocol described in TG431. Based on the knowledge that LabCyte EPI-MODEL is an epidermal model as well as EpiDerm, we decided to adopt the the Epiderm prediction model of skin corrosion for the LabCyte EPI-MODEL, using twenty test chemicals (10 corrosive chemicals and 10 non-corrosive chemicals) in the 1(st) stage. The prediction model results showed that the distinction of non-corrosion to corrosion corresponded perfectly. Therefore, it was judged t! hat the prediction model of EpiDerm could be applied to the LabCyte EPI-MODEL. In the 2(nd) stage, the repeatability of this test protocol with the LabCyte EPI-MODEL was examined using twelve chemicals (6 corrosive chemicals and 6 non-corrosive chemicals) that are described in TG431, and these results recognized a high repeatability and accurate predictability. It was concluded that LabCyte EPI-MODEL is applicable for the skin corrosive test protocol according to TG431. PMID: 20519850 [PubMed - in process] | | |
| A G-CSF functionalized scaffold for stem cells seeding: a differentiating device for cardiac purposes.
June 4, 2010 at 2:04 PM
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| | A G-CSF functionalized scaffold for stem cells seeding: a differentiating device for cardiac purposes. J Cell Mol Med. 2010 Jun 1; Authors: Spadaccio C, Rainer A, Trombetta M, Centola M, Lusini M, Chello M, Covino E, De Marco F, Coccia R, Toyoda Y, Genovese JA Abstract Myocardial infarction and its consequences represent one of the most demanding challenges in cell therapy and regenerative medicine. Transfer of skeletal myoblasts into decompensated hearts has been performed through intramyocardial injection. However, the achievement of both a cardiomyocyte differentiation and a precise integration of the injected cells into the myocardial wall, in order to augment synchronized contractility and avoid potentially life-threatening alterations in the electrical conduction of the heart, still remains a major target to be pursued. Recently, Granulocytes Colony-Stimulating Factor (G-CSF) fueled the interest of researchers for its direct effect on cardiomyocytes, inhibiting both apoptosis and remodelling in the failing heart and protecting from ventricular arrhythmias through the upregulation of Connexin 43 (Cx43). We propose a tissue engineering approach concerning the fabrication of an electrospun cardiac graft functionalize! d with G-CSF, in order to provide the correct signalling sequence to orientate myoblast differentiation and exert important systemic and local effects, positively modulating the infarction microenvironment. Poly-L-lactide electrospun scaffolds were seeded with C2C12 murine skeletal myoblast for 48 hours. Biological assays demonstrated the induction of Cx43 expression along with morphostructural changes resulting in cell elongation and appearance of cellular junctions resembling the usual cardiomyocyte arrangement at the ultrastructural level. The possibility of fabricating extracellular matrix-mimicking scaffolds able to promote myoblast precommitment towards myocardiocyte lineage and mitigate the hazardous environment of the damaged myocardium represents an interesting strategy in cardiac tissue engineering. PMID: 20518852 [PubMed - as supplied by publisher] | | |
| Very small embryonic-like stem cells for regenerative medicine: WO2010039241.
June 4, 2010 at 2:04 PM
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| | Very small embryonic-like stem cells for regenerative medicine: WO2010039241. Expert Opin Ther Pat. 2010 Jun 2; Authors: Taupin P Background: The application is in the field of stem cells and regenerative medicine. Objective: It aims at identifying and characterising a population of pluripotent stem cells present in adult tissues. Methods: Cells were isolated and purified using Fluorescence-Activated Cell Sorting and Direct ImageStream analysis from various adult and umbilical cord tissues of rodents and humans. Cells were propagated in the presence of trophic factors and feeder cell layers of C2C12 cells. Cells were characterised by electron microscopy and immunocytology. Results: A population of cells that do not express a panleukocytic antigen CD45 and are negative for other markers of haematopoietic lineages were isolated and purified. The isolated cells elicit morphological features of embryonic stem cells (ESCs). They express markers of pluripotent stem cells, such as Nanog, Oct-4 and SSEA-1. On culturing on feeder cell layers, the isolated and purified cells generate embryoid body-lik! e sphere. Conclusion: The identified and characterised cells elicit features of pluripotent stem cells and similarities with ESCs. They are termed very small embryonic-like stem cells (VSELs). The application claims the use of VSELs for cellular therapy and regenerative medicine. PMID: 20518618 [PubMed - as supplied by publisher] | | |
| Bladder regeneration by collagen scaffolds with collagen binding human basic fibroblast growth factor.
June 4, 2010 at 2:04 PM
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| | Bladder regeneration by collagen scaffolds with collagen binding human basic fibroblast growth factor. J Urol. 2010 Jun;183(6):2432-9 Authors: Chen W, Shi C, Yi S, Chen B, Zhang W, Fang Z, Wei Z, Jiang S, Sun X, Hou X, Xiao Z, Ye G, Dai J PURPOSE: Studies show that basic fibroblast growth factor can promote bladder regeneration. However, the lack of targeting delivery approaches limits its clinical application. We investigated a collagen based targeting system for bladder regeneration. A collagen binding domain was added to the native basic fibroblast growth factor N-terminal to allow it to bind to collagen. MATERIALS AND METHODS: Sprague-Dawley rats underwent partial cystectomy. Collagen scaffolds loaded with collagen binding domain basic fibroblast growth factor, native basic fibroblast growth factor or phosphate buffered saline were grafted to the remaining host bladders, respectively. At days 30 and 90 reconstructed bladders were evaluated by histological analysis and urodynamics. RESULTS: This targeting basic fibroblast growth factor delivery system induced satisfying bladder histological structures. It promoted more vascularization and smooth muscle cell ingrowth. Urodynamics revealed well ac! commodated bladder tissue with volume capacity and compliance. CONCLUSIONS: Results show that the targeting delivery system consisting of collagen binding domain basic fibroblast growth factor and collagen membranes induced better bladder regeneration at the injury site. Thus, this targeting delivery system may be an effective strategy for bladder regeneration with potential clinical applications. PMID: 20403614 [PubMed - indexed for MEDLINE] | | |
| Portal venous endothelium in developing human liver contains haematopoietic and epithelial progenitor cells.
June 4, 2010 at 2:04 PM
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| | Portal venous endothelium in developing human liver contains haematopoietic and epithelial progenitor cells. Exp Cell Res. 2010 May 15;316(9):1637-47 Authors: Terrace JD, Hay DC, Samuel K, Anderson RA, Currie IS, Parks RW, Forbes SJ, Ross JA Future treatments for chronic liver disease are likely to involve manipulation of liver progenitor cells (LPCs). In the human, data characterising the regenerative response is limited and the origin of adult LPCs is unknown. However, these remain critical factors in the design of cell-based liver therapies. The developing human liver provides an ideal model to study cell lineage derivation from progenitors and to understand how foetal haematopoiesis and liver development might explain the nature of the adult LPC population. In 1st trimester human liver, portal venous endothelium (PVE) expressed adult LPC markers and markers of haematopoietic progenitor cells (HPCs) shared with haemogenic endothelium found in the embryonic dorsal aorta. Sorted PVE cells were able to generate hepatoblast-like cells co-expressing CK18 and CK19 in addition to Dlk/pref-1, E-cadherin, albumin and fibrinogen in vitro. Furthermore, PVE cells could initiate haematopoiesis. These data sugge! st that PVE shares phenotypical and functional similarities both with adult LPCs and embryonic haemogenic endothelium. This indicates that a temporal relationship might exist between progenitor cells in foetal liver development and adult liver regeneration, which may involve progeny of PVE. PMID: 20211168 [PubMed - indexed for MEDLINE] | | |
| FGF but not EGF induces phosphorylation of the cAMP response element binding protein in olfactory mucosa-derived cell cultures.
June 4, 2010 at 2:04 PM
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| | FGF but not EGF induces phosphorylation of the cAMP response element binding protein in olfactory mucosa-derived cell cultures. Exp Cell Res. 2010 May 15;316(9):1489-99 Authors: Barraud P, He X, Zhao C, Caldwell MA, Franklin RJ The stem/progenitor cells of the olfactory epithelium are potentially useful cells for autologous cell-based therapy because of their relative accessibility compared to other sources of neural stem cells. However, they have very limited potential to self-renew in vitro under growth factor stimulation compared to central nervous system-derived stem/progenitor cells. Using a sphere-forming assay and immunocytochemistry to identify cells that contained phosphorylated cAMP response element binding protein (pCREB) as an indicator of cell responsiveness to growth factor activation, we found that olfactory-spheres primed with FGF2 responded to FGF2 and EGF stimulation. In contrast, olfactory-spheres primed with EGF failed to respond to FGF2 or EGF stimulation despite the detection of FGFR1 and EGFR and their transcripts. These data demonstrate that FGF2 but not EGF permit the maintenance of a subset of cells responsive to FGF2 and EGF, whereas EGF induces unresponsive to! either growth factor possibly via intrinsic mechanisms of regulation. PMID: 20211167 [PubMed - indexed for MEDLINE] | | |
| Donor compensation: an ethical imperative!
June 4, 2010 at 2:04 PM
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| | Donor compensation: an ethical imperative! Transplant Proc. 2010 Jan-Feb;42(1):124-5 Authors: Reichardt JO The number of living organ donors is increasing worldwide, but donor needs are widely neglected in support of anticommodification policies. This article argues that the warrant of donor autonomy during the decision process to donate is only one requirement of adequate donor care. Another is the donor's protection against the systematic and institutional exploitation of his altruistic dispositions. People with the disposition to support those, who are in desperate need, with a nonrenewable part of their own body, despite a small but unavoidable risk of death or health impairment, do not deserve to be additionally burdened with further disincentives, such as financial risks and uncompensated costs of donation. And although the borderline between a morally required disincentive removal and a more controversial net incentive to boost donation might be vague and open to discussion, to disadvantage living donors by design constitutes a serious barrier to the fairness of! living organ donation-a barrier that should be removed. PMID: 20172295 [PubMed - indexed for MEDLINE] | | |
| Morphological and mechanical characteristics of the reconstructed rat abdominal wall following use of a wet electrospun biodegradable polyurethane elastomer scaffold.
June 4, 2010 at 2:04 PM
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| | Morphological and mechanical characteristics of the reconstructed rat abdominal wall following use of a wet electrospun biodegradable polyurethane elastomer scaffold. Biomaterials. 2010 Apr;31(12):3253-65 Authors: Hashizume R, Fujimoto KL, Hong Y, Amoroso NJ, Tobita K, Miki T, Keller BB, Sacks MS, Wagner WR Although a variety of materials are currently used for abdominal wall repair, general complications encountered include herniation, infection, and mechanical mismatch with native tissue. An approach wherein a degradable synthetic material is ultimately replaced by tissue mechanically approximating the native state could obviate these complications. We report here on the generation of biodegradable scaffolds for abdominal wall replacement using a wet electrospinning technique in which fibers of a biodegradable elastomer, poly(ester urethane)urea (PEUU), were concurrently deposited with electrosprayed serum-based culture medium. Wet electrospun PEUU (wet ePEUU) was found to exhibit markedly different mechanical behavior and to possess an altered microstructure relative to dry processed ePEUU. In a rat model for abdominal wall replacement, wet ePEUU scaffolds (1x2.5 cm) provided a healing result that developed toward approximating physiologic mechanical behavior at 8! weeks. An extensive cellular infiltrate possessing contractile smooth muscle markers was observed together with extensive extracellular matrix (collagens, elastin) elaboration. Control implants of dry ePEUU and expanded polytetrafluoroethylene did not experience substantial cellular infiltration and did not take on the native mechanical anisotropy of the rat abdominal wall. These results illustrate the markedly different in vivo behavior observed with this newly reported wet electrospinning process, offering a potentially useful refinement of an increasingly common biomaterial processing technique. PMID: 20138661 [PubMed - indexed for MEDLINE] | | |
| The performance of bone marrow mesenchymal stem cell--implant complexes prepared by cell sheet engineering techniques.
June 4, 2010 at 2:04 PM
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| | The performance of bone marrow mesenchymal stem cell--implant complexes prepared by cell sheet engineering techniques. Biomaterials. 2010 Apr;31(12):3212-21 Authors: Zhou W, Han C, Song Y, Yan X, Li D, Chai Z, Feng Z, Dong Y, Li L, Xie X, Chen F, Zhao Y This study investigated the hypothesis that cell sheets composed of multilayered rabbit bone marrow derived mesenchymal stem cells (MSC) could be assembled with two kinds of implants (surface-modified titanium and zirconia) for the construction of a MSC-implant. The MSC sheets were harvested from culture flasks, wrapped around implants to construct the complexes, and then cultured in osteogenic medium. The layered cell sheets integrated well with implants and remained viable, with small mineralized nodules visible on the implant surfaces for up to four weeks after culture. Cells on the implants underwent classical in vitro osteogenic differentiation with an associated elevation of alkaline phosphatase activity and bone- and vascular-related protein expression. In vivo, two kinds of cell sheet-implant complexes were transplanted under the skin of SCID mice and cultured for eight weeks. For the MSC sheet titanium implant complex, histological examination revealed th! at new bone tissue that formed around implants followed a predominantly endochondral pathway, exhibiting histological markers of native bone; for the MSC sheet zirconia implant complex, however, intramembranous ossification appeared to occur on the surface of the zirconia implant, as observed with typical osteocytes embedded in dense matrix and accompanied by both microvessels and marrow cavities. These findings demonstrate that MSC-implants possessing osteogenic and vascularization abilities can be produced using cell sheet engineering techniques in conjunction with routine implant materials, which provide a novel technology to modify the implant surface. PMID: 20132981 [PubMed - indexed for MEDLINE] | | |
| The characterization and optimization of injectable silicone resin particles in conjunction with dermal fibroblasts and growth factors: an in vitro study.
June 4, 2010 at 2:04 PM
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| | The characterization and optimization of injectable silicone resin particles in conjunction with dermal fibroblasts and growth factors: an in vitro study. J Biomed Mater Res B Appl Biomater. 2010 Apr;93(1):227-35 Authors: Crews RM, Jennings JA, McCanless J, Cole JA, Bumgardner JD, Haggard WO Minimally invasive subdermal injection of liquid silicone has been used clinically to augment the soft tissue of the foot to mitigate high pressures that cause diabetic foot ulcers. However, implant migration has been a clinical issue. The objective of this study was to assess the effects of three specific concentrations of silicone resin particles (12 mum average diameter) in conjunction with either platelet-derived growth factor (PDGF-BB) or basic fibroblast growth factor (bFGF) on fibroblast cell proliferation, collagen synthesis, cell morphology, and migration through in vitro assays and a monolayer scratch wound model. PDGF and bFGF enhanced the proliferation of fibroblasts 5.7-fold and fivefold, respectively, while the addition of silicone particles had no significant effect on proliferation. Collagen production was increased approximately twofold with the addition of bFGF and the medium concentration of particles over bFGF without particles and the PDGF gro! ups. The addition of silicone particles had no significant effect on collagen production compared with control groups without particles. Fibroblast migration was enhanced by the addition of both PDGF and bFGF compared to controls, although slower scratch wound closure rates were observed in the presence of particles compared to controls without particles. Cell morphology suggested that particles induced cellular aggregation encircling silicone particles postwounding as well as migration into the wound area. These results suggest that silicone particles in combination with a growth factor might enhance fibroblast aggregation and implant stability, and could promote connective tissue ingrowth and implant encapsulation in the soft tissue of the diabetic foot. PMID: 20091922 [PubMed - indexed for MEDLINE] | | |
| In vivo outcomes of tissue-engineered osteochondral grafts.
June 4, 2010 at 2:04 PM
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| | In vivo outcomes of tissue-engineered osteochondral grafts. J Biomed Mater Res B Appl Biomater. 2010 Apr;93(1):164-74 Authors: Bal BS, Rahaman MN, Jayabalan P, Kuroki K, Cockrell MK, Yao JQ, Cook JL Tissue-engineered osteochondral grafts have been synthesized from a variety of materials, with some success at repairing chondral defects in animal models. We hypothesized that in tissue-engineered osteochondral grafts synthesized by bonding mesenchymal stem cell-loaded hydrogels to a porous material, the choice of the porous scaffold would affect graft healing to host bone, and the quality of cell restoration at the hyaline cartilage surface. Bone marrow-derived allogeneic mesenchymal stem cells were suspended in hydrogels that were attached to cylinders of porous tantalum metal, allograft bone, or a bioactive glass. The tissue-engineered osteochondral grafts, thus created were implanted into experimental defects in rabbit knees. Subchondral bone restoration, defect fill, bone ingrowth-implant integration, and articular tissue quality were compared between the three subchondral materials at 6 and 12 weeks. Bioactive glass and porous tantalum were superior to bone! allograft in integrating to adjacent host bone, regenerating hyaline-like tissue at the graft surface, and expressing type II collagen in the articular cartilage. PMID: 20091911 [PubMed - indexed for MEDLINE] | | |
| Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny.
June 4, 2010 at 2:04 PM
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| | Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny. Cardiovasc Res. 2010 Jun 1;86(3):506-15 Authors: Moonen JR, Krenning G, Brinker MG, Koerts JA, van Luyn MJ, Harmsen MC AIMS: Reciprocal plasticity exists between endothelial and mesenchymal lineages. For instance, mature endothelial cells adopt a smooth muscle-like phenotype through transforming growth factor beta-1 (TGFbeta1)-driven endothelial-to-mesenchymal transdifferentiation (EndMT). Peripheral blood contains circulating endothelial progenitor cells of which the endothelial colony-forming cells (ECFCs) harbour stem cell-like properties. Given the plasticity between endothelial and mesenchymal lineages and the stem cell-like properties of ECFCs, we hypothesized that ECFCs can give rise to smooth muscle-like progeny. METHODS AND RESULTS: ECFCs were stimulated with TGFbeta1, after which TGFbeta signalling cascades and their downstream effects were investigated. Indeed, EndMT of ECFCs resulted in smooth muscle-like progeniture. TGFbeta1-driven EndMT is mediated by ALK5 kinase activity, increased downstream Smad2 signalling, and reduced protein levels of inhibitor of DNA-binding ! protein 3. ECFCs lost expression of endothelial markers and endothelial anti-thrombogenic function. Simultaneously, mesenchymal marker expression was gained, cytoskeletal rearrangements occurred, and cells acquired a contractile phenotype. Transdifferentiated ECFCs were phenotypically stable and self-sustaining and, importantly, showed fibroblast growth factor-2 and angiopoietin-1-mediated pro-angiogenic paracrine properties. CONCLUSION: Our study is the first to demonstrate that ECFCs can give rise to smooth muscle-like progeny, with potential therapeutic benefits. These findings further illustrate that ECFCs are highly plastic, which by itself has implications for therapeutical use. PMID: 20083576 [PubMed - indexed for MEDLINE] | | |
| Bioinspired materials for controlling stem cell fate.
June 4, 2010 at 2:04 PM
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| | Bioinspired materials for controlling stem cell fate. Acc Chem Res. 2010 Mar 16;43(3):419-28 Authors: Fisher OZ, Khademhosseini A, Langer R, Peppas NA Although researchers currently have limited ability to mimic the natural stem cell microenvironment, recent work at the interface of stem biology and biomaterials science has demonstrated that control over stem cell behavior with artificial microenvironments is quite advanced. Embryonic and adult stem cells are potentially useful platforms for tissue regeneration, cell-based therapeutics, and disease-in-a-dish models for drug screening. The major challenge in this field is to reliably control stem cell behavior outside the body. Common biological control schemes often ignore physicochemical parameters that materials scientists and engineers commonly manipulate, such as substrate topography and mechanical and rheological properties. However, with appropriate attention to these parameters, researchers have designed novel synthetic microenvironments to control stem cell behavior in rather unnatural ways. In this Account, we review synthetic microenvironments that aim! to overcome the limitations of natural niches rather than to mimic them. A biomimetic stem cell control strategy is often limited by an incomplete understanding of the complex signaling pathways that drive stem cell behavior from early embryogenesis to late adulthood. The stem cell extracellular environment presents a miscellany of competing biological signals that keep the cell in a state of unstable equilibrium. Using synthetic polymers, researchers have designed synthetic microenvironments with an uncluttered array of cell signals, both specific and nonspecific, that are motivated by rather than modeled after biology. These have proven useful in maintaining cell potency, studying asymmetric cell division, and controlling cellular differentiation. We discuss recent research that highlights important biomaterials properties for controlling stem cell behavior, as well as advanced processes for selecting those materials, such as combinatorial and high-throughput screening. ! Much of this work has utilized micro- and nanoscale fabricatio! n tools for controlling material properties and generating diversity in both two and three dimensions. Because of their ease of synthesis and similarity to biological soft matter, hydrogels have become a biomaterial of choice for generating 3D microenvironments. In presenting these efforts within the framework of synthetic biology, we anticipate that future researchers may exploit synthetic polymers to create microenvironments that control stem cell behavior in clinically relevant ways. PMID: 20043634 [PubMed - indexed for MEDLINE] | | |
| Molecular and tissue responses in the healing of rat calvarial defects after local application of simvastatin combined with alpha tricalcium phosphate.
June 4, 2010 at 2:04 PM
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| | Molecular and tissue responses in the healing of rat calvarial defects after local application of simvastatin combined with alpha tricalcium phosphate. J Biomed Mater Res B Appl Biomater. 2010 Apr;93(1):65-73 Authors: Nyan M, Miyahara T, Noritake K, Hao J, Rodriguez R, Kuroda S, Kasugai S We have previously reported that healing of rat calvarial defects was enhanced by application of alpha tricalcium phosphate (alphaTCP) combined with simvastatin, a cholesterol synthesis inhibitor. The purpose of the present study was to investigate the cellular and molecular mechanisms in this phenomenon. Rat calvarial defects were grafted with alphaTCP with or without simvastatin or left untreated. Animals were sacrificed on 3, 7, 10, 14, and 21 days postoperatively and histological changes in the defect region were assessed. Gene expression patterns were examined by RT-PCR. Proliferation and migration of osteoprogenitor cells from the dura mater were increased in simvastatin group from day 3 to day 10 (p < 0.01). New bone formation was significantly increased in simvastatin group on day 14 and day 21 (p < 0.01). BMP-2 expression was significantly higher in simvastatin group on day 3 and day 14 (p < 0.05) and maintained until day 21. Increased upregulati! on of TGF-beta1 was also observed in the simvastatin group on day 7 (p < 0.05) which was maintained until day 14. These findings suggest that the proliferation and recruitment of osteoprogenitor cells were critical steps in early stage of bone healing and that these steps were enhanced by TGF-beta1 and BMP-2, which were stimulated by simvastatin. PMID: 20024970 [PubMed - indexed for MEDLINE] | | |
| Serum-free, xeno-free culture media maintain the proliferation rate and multipotentiality of adipose stem cells in vitro.
June 4, 2010 at 2:04 PM
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| | Serum-free, xeno-free culture media maintain the proliferation rate and multipotentiality of adipose stem cells in vitro. Cytotherapy. 2009;11(7):958-72 Authors: Lindroos B, Boucher S, Chase L, Kuokkanen H, Huhtala H, Haataja R, Vemuri M, Suuronen R, Miettinen S BACKGROUND AIMS: Human adipose stem cells (ASC) are an abundant, readily available population of multipotent progenitor cells that reside in adipose tissue. ASC have been shown to have therapeutic applicability in pre-clinical studies, but a standardized expansion method for clinical cell therapy has yet to be established. Isolated ASC are typically expanded in medium containing fetal bovine serum (FBS); however, sera and other culturing reagents of animal origin in clinical therapy pose numerous safety issues, including possible infections and severe immune reactions. METHODS: To identify optimal conditions for ex vivo expansion of ASC, the effects of seven serum-free (SF) and xeno-free (XF) media were investigated with both FBS and allogeneic human serum (alloHS; as a control media). Surface marker expression, proliferation, morphology and differentiation analyzes were utilized for investigating the effects of media on ASC. RESULTS: The proliferation and morphol! ogy analysis demonstrated significant differences between ASC cultured in SF/XF culture media compared with serum-containing culture media, with medium prototype StemPro MSC SFM XenoFree providing significantly higher proliferation rates than ASC cultured in media containing serum, while still maintaining the differentiation potential and surface marker expression profile characteristic of ASC. CONCLUSIONS: Looking forward, fully defined XF media formulations will provide the means for the development and approval of safer clinical cell therapy treatments. However, to fully recognize the capacity of these XF culture media, further pre-clinical safety and efficacy studies must be performed. PMID: 19903107 [PubMed - indexed for MEDLINE] | | |
| Constructive remodeling of biologic scaffolds is dependent on early exposure to physiologic bladder filling in a canine partial cystectomy model.
June 4, 2010 at 2:04 PM
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| | Constructive remodeling of biologic scaffolds is dependent on early exposure to physiologic bladder filling in a canine partial cystectomy model. J Surg Res. 2010 Jun 15;161(2):217-25 Authors: Boruch AV, Nieponice A, Qureshi IR, Gilbert TW, Badylak SF Biologic scaffolds composed of extracellular matrix (ECM) have been used to facilitate the constructive remodeling of several tissue types. Previous studies suggest that the ECM scaffold remodeling process is dependent on microenvironmental factors, including tissue-specific biomechanical loading. The objective of the present study was to evaluate the effects of long-term catheterization (LTC), with its associated inhibition of bladder filling and physiologic biomechanical loading, on ECM scaffold remodeling following partial cystectomy in a canine model. Reconstruction of the partial cystectomy site was performed using ECM scaffolds prepared from porcine small intestinal submucosa (SIS) or porcine urinary bladder matrix (UBM). Animals were randomly assigned to either a long-term catheterization (LTC) group (n=5, catheterized 28 d) or a short-term catheterization group (STC, n=5, catheterized 24 h), and scaffold remodeling was assessed by histologic methods at 4 a! nd 12 wk postoperatively. By 4 wk, animals in the STC group showed a well-developed and highly differentiated urothelium, a robust vascularization network, abundant smooth muscle actin (SMA), and smooth muscle myosin heavy chain (smMHC) expressing spindle-shaped cells, and many neuronal processes associated with newly formed arterioles. In contrast, at 4 wk the scaffolds in LTC animals were not epithelialized, and did not express neuronal markers. The scaffolds in the LTC group developed a dense granulation tissue containing SMA+, smMHC-, spindle-shaped cells that were morphologically and phenotypically consistent with myofibroblasts, but not smooth muscle cells. By 12 wk postoperatively, the ECM scaffolds in the STC animals showed a constructive remodeling response, with a differentiated urothelium and islands of smooth muscle cells within the remodeled scaffold. In contrast, at 12 wk the scaffolds in LTC animals had a remodeling response more consistent with fibrosis even! though catheters had been removed 8 wk earlier. These finding! s show t hat early exposure of site-appropriate mechanical loading (i.e., bladder filling) mediates a constructive remodeling response after ECM repair in a canine partial cystectomy model. PMID: 19577253 [PubMed - indexed for MEDLINE] | | |
| Analysis of neuropeptides in stretched skin.
June 4, 2010 at 2:04 PM
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| | Analysis of neuropeptides in stretched skin. Plast Reconstr Surg. 2009 Jul;124(1):102-13 Authors: Chin MS, Lancerotto L, Helm DL, Dastouri P, Prsa MJ, Ottensmeyer M, Akaishi S, Orgill DP, Ogawa R BACKGROUND: Mechanical forces modulate wound healing and scar formation through mechanotransduction. In response to mechanical stimulation, neuropeptides are released from peripheral terminals of primary afferent sensory neurons, influencing skin and immune cell functions and increasing vascular permeability, causing neurogenic inflammation. METHODS: A computer-controlled device was used to stretch murine skin. C57Bl6 mice (n = 26) were assigned to a cyclical square-wave tensile stimulation for 4 hours or continuous stimulation for 4 hours. Stretched skin was analyzed for expression of the neuropeptides, substance P and calcitonin gene-related peptide, their receptors (NK1R and calcitonin gene-related peptide receptor component protein), and growth factors (nerve growth factor, transforming growth factor beta1, vascular endothelial growth factor, and epidermal growth factor) using immunohistochemistry and real-time reverse-transcriptase polymerase chain reaction. ! RESULTS: Cyclical stimulation resulted in a significant increase in expression of neuropeptides and growth factors, whereas the corresponding peptide receptors were down-regulated. Transcription of neuropeptide mRNA was elevated in stretched skin, which proves that neuropeptides are released from not only peripheral terminals of nerve fibers but also resident skin cells. CONCLUSIONS: The authors' results suggest that skin stretching may alter cell physiology by stimulating neuropeptide expression, and that cyclical mechanical force may be more effectively stimulating mechanosensitive nociceptors or mechanoreceptors (mechanosensors) on cells. PMID: 19568049 [PubMed - indexed for MEDLINE] | | | | 
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