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| Electrospun Alginate Nanofibers with Controlled Cell Adhesion for Tissue Engineering.
June 10, 2010 at 6:05 AM
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| | Electrospun Alginate Nanofibers with Controlled Cell Adhesion for Tissue Engineering. Macromol Biosci. 2010 Jun 9; Authors: Jeong SI, Krebs MD, Bonino CA, Khan SA, Alsberg E Alginate, a natural polysaccharide that has shown great potential as a cell scaffold for the regeneration of many tissues, has only been nominally explored as an electrospun biomaterial due to cytotoxic chemicals that have typically been used during nanofiber formation and crosslinking. Alginate cannot be electrospun by itself and is often co-spun with poly(ethylene oxide) (PEO). In this work, a cell adhesive peptide (GRGDSP) modified alginate (RA) and unmodified alginate (UA) were blended with PEO at different concentrations and blending ratios, and then electrospun to prepare uniform nanofibers. The ability of electrospun RA scaffolds to support human dermal fibroblast cell attachment, spreading, and subsequent proliferation was greatly enhanced on the adhesion ligand-modified nanofibers, demonstrating the promise of this electrospun polysaccharide material with defined nanoscale architecture and cell adhesive properties for tissue regeneration applications. PMID: 20533533 [PubMed - as supplied by publisher] | | |
| LPA rescues ER stress-associated apoptosis in hypoxia and serum deprivation-stimulated mesenchymal stem cells.
June 10, 2010 at 6:05 AM
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| | LPA rescues ER stress-associated apoptosis in hypoxia and serum deprivation-stimulated mesenchymal stem cells. J Cell Biochem. 2010 Jun 7; Authors: Li Z, Wei H, Liu X, Hu S, Cong X, Chen X Poor viability of transplanted mesenchymal stem cells (MSCs) in the infracted heart has limited their therapeutic efficacy in cardiac repair after myocardial infarction. We previously demonstrated that hypoxia and serum deprivation (hypoxia/SD) induced mitochondria-dependent apoptosis in MSCs, while lysophosphatidic acid (LPA) could almost completely block this apoptotic process. However, the role of endoplasmic reticulum (ER) stress and its upstream signaling events in hypoxia/SD-induced MSC apoptosis remain largely unknown. Here we found that hypoxia/SD-induced MSC apoptosis was associated with ER stress, as shown by the induction of CHOP expression and procaspase-12 cleavage, while the effects were abrogated by LPA treatment, suggesting ER stress is also a target of LPA. Furthermore, hypoxia/SD induced p38 activation, inhibition of which resulted in decreases of apoptotic cells, procaspase-12 cleavage and mitochondrial cytochrome c release that function in parallel in MSC apoptosis. Unexpectedly, p38 inhibition enhanced hypoxia/SD-induced CHOP expression. Interestingly, p38 activation, a common process mediating various biological effects of LPA, was inhibited by LPA in this study, and the regulation of p38 pathway by LPA was dependent on LPA(1/3)/Gi/ERK1/2 pathway-mediated MKP-1 induction but independent of PI3K/Akt pathway. Collectively, our findings indicate that ER stress is a target of LPA to antagonize hypoxia/SD-induced MSC apoptosis, and the modulation of mitochondrial and ER stress-associated apoptotic pathways by LPA is at least partly dependent on LPA(1/3)/Gi/ERK/MKP-1 pathway-mediated p38 inhibition. This study may provide new anti-apoptotic targets for elevating the viability of MSCs for therapeutic potential of cardiac repair. J. Cell. Biochem. (c) 2010 Wiley-Liss, Inc. PMID: 20533299 [PubMed - as supplied by publisher] | | |
| Different assembly of type IV collagen on hydrophilic and hydrophobic substrata alters endothelial cells interaction.
June 10, 2010 at 6:05 AM
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| | Different assembly of type IV collagen on hydrophilic and hydrophobic substrata alters endothelial cells interaction. Eur Cell Mater. 2010;19:262-272 Authors: Coelho NM, González-GarcÃa C, Planell JA, Salmerón-Sánchez M, Altankov G Considering the structural role of type IV collagen (Col IV) in the assembly of the basement membrane (BM) and the perspective of mimicking its organization for vascular tissue engineering purposes, we studied the adsorption pattern of this protein on model hydrophilic (clean glass) and hydrophobic trichloro(octadecyl)silane (ODS) surfaces known to strongly affect the behavior of other matrix proteins. The amount of fluorescently labeled Col IV was quantified showing saturation of the surface for concentration of the adsorbing solution of about 50mug/ml, but with approximately twice more adsorbed protein on ODS. AFM studies revealed a fine - nearly single molecular size - network arrangement of Col IV on hydrophilic glass, which turns into a prominent and growing polygonal network consisting of molecular aggregates on hydrophobic ODS. The protein layer forms within minutes in a concentration-dependent manner. We further found that human umbilical vein endothelial cells (HUVEC) attach less efficiently to the aggregated Col IV (on ODS), as judged by the significantly altered cell spreading, focal adhesions formation and the development of actin cytoskeleton. Conversely, the immunofluorescence studies for integrins revealed that the fine Col IV network formed on hydrophilic substrata is better recognized by the cells via both alpha1 and alpha2 heterodimers which support cellular interaction, apart from these on hydrophobic ODS where almost no clustering of integrins was observed. PMID: 20533192 [PubMed - as supplied by publisher] | | |
| Preparation and physical properties of a novel biocompatible porcine corneal acellularized matrix.
June 10, 2010 at 6:05 AM
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| | Preparation and physical properties of a novel biocompatible porcine corneal acellularized matrix. In Vitro Cell Dev Biol Anim. 2010 Jun 9; Authors: Shao Y, Quyang L, Zhou Y, Tang J, Tan Y, Liu Q, Lin Z, Yin T, Qiu F, Liu Z This study was to investigate the stability, physico-mechanical property and biocompatibility of porcine corneal acellularized matrix (PCAM) that was prepared using human sera treatment to decellularize corneas. The stability (the rate of biodegradation) and physico-mechanical property (water uptake, density, and porosity) of PCAM were not compromised, compared with porcine fresh cornea matrix (PFCM, p > 0.05). The contact and extract cytotoxicity tests with human corneal epithelial cells and human keratocytes showed that PCAM has a good biocompatibility ex vivo and no cytotoxic effect. These results present the ability to create safety scaffolds that function as cornea grafts and provide a novel experimental approach for the study of cornea tissue engineering using acellular porcine cornea. PMID: 20532994 [PubMed - as supplied by publisher] | | |
| Transplantation of Umbilical Cord Blood Stem Cells for Treating Spinal Cord Injury.
June 10, 2010 at 6:05 AM
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| | Transplantation of Umbilical Cord Blood Stem Cells for Treating Spinal Cord Injury. Stem Cell Rev. 2010 Jun 8; Authors: Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug's downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI. PMID: 20532836 [PubMed - as supplied by publisher] | | |
| The fabrication of PLGA microvessel scaffolds with nano-patterned inner walls.
June 10, 2010 at 6:05 AM
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| | The fabrication of PLGA microvessel scaffolds with nano-patterned inner walls. Biomed Microdevices. 2010 Jun 8; Authors: Wang GJ, Lin YC, Hsu SH Poly (lactic-co-glycolic acid) (PLGA) is one of the most commonly used biodegradable, biocompatible materials. Nanostructured PLGA has immense potential for application in tissue engineering. In this article we discuss a novel approach for the fabrication of PLGA microvessel scaffolds with nanostructured inner walls. In this novel nano-patterning approach, the thermal reflow technique is first adapted to fabricate a semi-cylindrical photoresist master mold. A thin film of titanium and a thin film of aluminum are sputtered in sequence on the semi-cylindrical microvessel network. Aluminum foil anodization is then executed to transform the aluminum thin film into a porous anodic aluminum oxide (AAO) film. During the casting process a PLGA solution is cast on the AAO film to build up semi-cylindrical PLGA microstructures with nanostructured inner walls after which inductive coupled plasma (ICP) is implemented to assist bonding of the two PLGA structures. The result is the building of a network of microchannels with nano-patterned inner walls. Bovine endothelial cells (BECs) are carefully cultured in the scaffold via semi-dynamic seeding for 7 days. Observations show that the BECs grew more separately in a nano-patterned microvessel scaffold than they did in a smooth surface scaffold. PMID: 20532635 [PubMed - as supplied by publisher] | | |
| Molecular genetic and bile acid profiles in 2 Japanese patients with 3beta-hydroxy-delta5-C27-steroid dehydrogenase/isomerase deficiency.
June 10, 2010 at 6:05 AM
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| | Molecular genetic and bile acid profiles in 2 Japanese patients with 3beta-hydroxy-delta5-C27-steroid dehydrogenase/isomerase deficiency. Pediatr Res. 2010 Jun 7; Authors: Mizuochi T, Kimura A, Ueki I, Takahashi T, Hashimoto T, Takao A, Seki Y, Takei H, Nittono H, Kurosawa T, Matsuishi T We report definitive diagnosis and effective chenodeoxycholic acid treatment of 2 Japanese children with 3beta-hydroxy-Delta-C27-steroid dehydrogenase/isomerase deficiency. Findings of cholestasis with normal serum gamma-glutamyltransferase activity and total bile acid concentration indicated the need for definitive bile acid analysis. Large amounts of 3beta-hydroxy-Delta-bile acids were detected by gas chromatography-mass spectrometry. HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patients and their parents identified 4 novel mutations of the HSD3B7 gene in the patients. One had a homozygous mutation, 314delA; the other had compound heterozygous mutations: V132F, T149I, and 973_974insCCTGC. Interestingly, the second patient's mother had V132F and T149I mutations in 1 allele. Excessive 3beta-hydroxy-Delta-bile acids such as 3beta,7alpha-dihydroxy- and 3beta,7alpha,12alpha-trihydroxy-5-cholenoic acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3beta-hydroxy-5-cholenoic acid. Liver dysfunction in both patients decreased with ursodeoxycholic acid treatment, but unusual bile acids still were detected. Normalization of the patients' liver function and improvement of bile acid profiles occurred with chenodeoxycholic acid treatment. Thus, we found mutations in the HSD3B7 gene accounting for autosomal recessive neonatal cholestasis caused by 3beta-hydroxy-Delta-C27-steroid dehydrogenase/isomerase deficiency. Early neonatal diagnosis permits initiation of chenodeoxycholic acid treatment at this critical time, before the late cholestatic stage. ABBREVIATIONS:: PMID: 20531254 [PubMed - as supplied by publisher] | | |
| Efficient Cell-Seeding into Scaffolds Improves Bone Formation.
June 10, 2010 at 6:05 AM
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| | Efficient Cell-Seeding into Scaffolds Improves Bone Formation. J Dent Res. 2010 Jun 8; Authors: Hasegawa T, Miwa M, Sakai Y, Niikura T, Lee SY, Oe K, Iwakura T, Kurosaka M, Komori T Bone marrow stromal cells (BMSCs)/beta-tricalcium phosphate (beta-TCP) composites have attracted a great deal of attention in bone tissue engineering. If more effective bone regeneration is to be achieved, efficient cell-seeding systems need to be clarified. In this study, we investigated the number of cells contained in composites, and the in vitro/vivo osteogenic differentiation capacity of composites using 4 conventional systems of seeding rat BMSCs into beta-TCP: soak, low-pressure, pipette, and syringe systems. The highest number of cells was contained in the composites from the syringe group. Moreover, after two-week osteogenic induction in vitro, the composites in the syringe group exhibited the highest osteogenic potential, which continued at 8 weeks after subcutaneous implantation in vivo. Our results indicated that efficient and appropriate cell-seeding could improve in vitro/vivo bone formation in composites and thus make a potential clinical contribution to successful bone tissue engineering. Abbreviations: BMSCs, bone marrow stromal cells; beta-TCP, beta-tricalcium phosphate; S-D, Sprague-Dawley; kPa, kilopascal; ALP, alkaline phosphatase; N, Newton; DNA, deoxyribonucleic acid; OCN, osteocalcin; ANOVA, analysis of variance; PLSD, protected least-significant difference; and HE, hematoxylin and eosin. PMID: 20530727 [PubMed - as supplied by publisher] | | |
| Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells?
June 10, 2010 at 6:05 AM
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| | Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells? Clin Cancer Res. 2010 Jun 8; Authors: Takahashi-Yanaga F, Kahn M The Wnt signaling pathways have been conserved throughout evolution and regulate cell proliferation, morphology, motility, and fate during embryonic development. These pathways also play important roles throughout adult life to maintain homeostasis of tissues including skin, blood, intestine, and brain by regulating somatic stem cells and their niches. Aberrant regulation of the Wnt pathway leads to neoplastic proliferation in these same tissues. It has been suggested that Wnt signaling is also involved in the regulation of cancer stem cells (CSC), because there are many similarities in the signaling pathways that regulate normal adult stem cells and CSC. In this Perspective, we have focused on the Wnt/beta-catenin signaling pathway, which is the most intensively studied and best characterized Wnt signaling pathway. We provide an overview on the function of the Wnt/beta-catenin signaling pathway in CSC, and the possibility of the development of novel therapeutics to target this pathway. Clin Cancer Res; 16(12); 3153-62. (c)2010 AACR. PMID: 20530697 [PubMed - as supplied by publisher] | | |
| Angiopoietin-2 Regulates Gene Expression in TIE2-Expressing Monocytes and Augments Their Inherent Proangiogenic Functions.
June 10, 2010 at 6:05 AM
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| | Angiopoietin-2 Regulates Gene Expression in TIE2-Expressing Monocytes and Augments Their Inherent Proangiogenic Functions. Cancer Res. 2010 Jun 8; Authors: Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y, Lewis CE TIE2-expressing monocytes/macrophages (TEM) are a highly proangiogenic subset of myeloid cells in tumors. Here, we show that circulating human TEMs are already preprogrammed in the circulation to be more angiogenic and express higher levels of such proangiogenic genes as matrix metalloproteinase-9 (MMP-9), VEGFA, COX-2, and WNT5A than TIE2(-) monocytes. Additionally, angiopoietin-2 (ANG-2) markedly enhanced the proangiogenic activity of TEMs and increased their expression of two proangiogenic enzymes: thymidine phosphorylase (TP) and cathepsin B (CTSB). Three "alternatively activated" (or M2-like) macrophage markers were also upregulated by ANG-2 in TEMs: interleukin-10, mannose receptor (MRC1), and CCL17. To investigate the effects of ANG-2 on the phenotype and function of TEMs in tumors, we used a double-transgenic (DT) mouse model in which ANG-2 was specifically overexpressed by endothelial cells. Syngeneic tumors grown in these ANG-2 DT mice were more vascularized and contained greater numbers of TEMs than those in wild-type (WT) mice. In both tumor types, expression of MMP-9 and MRC1 was mainly restricted to tumor TEMs rather than TIE2(-) macrophages. Furthermore, tumor TEMs expressed higher levels of MRC1, TP, and CTSB in ANG-2 DT tumors than WT tumors. Taken together, our data show that although circulating TEMs are innately proangiogenic, exposure to tumor-derived ANG-2 stimulates these cells to exhibit a broader, tumor-promoting phenotype. As such, the ANG-2-TEM axis may represent a new target for antiangiogenic cancer therapies. Cancer Res; 70(13); OF1-11. (c)2010 AACR. PMID: 20530679 [PubMed - as supplied by publisher] | | |
| Effects of Ionizing Radiation on Self-Renewal and Pluripotency of Human Embryonic Stem Cells.
June 10, 2010 at 6:05 AM
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| | Effects of Ionizing Radiation on Self-Renewal and Pluripotency of Human Embryonic Stem Cells. Cancer Res. 2010 Jun 8; Authors: Wilson KD, Sun N, Huang M, Zhang WY, Lee AS, Li Z, Wang SX, Wu JC Human embryonic stem cells (hESC) present a novel platform for in vitro investigation of the early embryonic cellular response to ionizing radiation. Thus far, no study has analyzed the genome-wide transcriptional response to ionizing radiation in hESCs, nor has any study assessed their ability to form teratomas, the definitive test of pluripotency. In this study, we use microarrays to analyze the global gene expression changes in hESCs after low-dose (0.4 Gy), medium-dose (2 Gy), and high-dose (4 Gy) irradiation. We identify genes and pathways at each radiation dose that are involved in cell death, p53 signaling, cell cycling, cancer, embryonic and organ development, and others. Using Gene Set Enrichment Analysis, we also show that the expression of a comprehensive set of core embryonic transcription factors is not altered by radiation at any dose. Transplantation of irradiated hESCs to immune-deficient mice results in teratoma formation from hESCs irradiated at all doses, definitive proof of pluripotency. Further, using a bioluminescence imaging technique, we have found that irradiation causes hESCs to initially die after transplantation, but the surviving cells quickly recover by 2 weeks to levels similar to control. To conclude, we show that similar to somatic cells, irradiated hESCs suffer significant death and apoptosis after irradiation. However, they continue to remain pluripotent and are able to form all three embryonic germ layers. Studies such as this will help define the limits for radiation exposure for pregnant women and also radiotracer reporter probes for tracking cellular regenerative therapies. Cancer Res; 70(13); OF1-10. (c)2010 AACR. PMID: 20530673 [PubMed - as supplied by publisher] | | |
| Keratinocyte growth factor phage model peptides can promote epidermal cell proliferation without tumorigenic effect.
June 10, 2010 at 6:05 AM
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| | Keratinocyte growth factor phage model peptides can promote epidermal cell proliferation without tumorigenic effect. Chin Med J (Engl). 2010 May;123(9):1195-200 Authors: Zong XL, Jiang DY, Wang JC, Liu JL, Liu ZZ, Cai JL BACKGROUND: Keratinocyte growth factor (KGF) significantly influences epithelial wound healing. The aim of this study was to isolate KGF phage model peptides from a phage display 7-mer peptide library to evaluate their effect on promoting epidermal cell proliferation. METHODS: A phage display 7-mer peptide library was screened using monoclonal anti-human KGF antibody as the target. Enzyme linked immunosorbent assay (ELISA) was performed to select monoclonal phages with good binding activity. DNA sequencing was done to find the similarities of model peptides. Three-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, immunofluorescence assay and quantitative real-time PCR analysis were employed to evaluate the effect of the phage model peptides on epidermal cells. RESULTS: Thirty-three out of fifty-eight (56.9%) of the isolated monoclonal phages exhibited high binding activity by ELISA. Ten of fifteen obtained phage model peptides were similar to KGF or epidermal growth factor (EGF). MTT assay data showed that four (No. 1 - 4) of the ten phage model peptides could promote epidermal cell proliferation. The expression of keratinocyte growth factor receptor (KGFR) mRNA in the KGF control group and the two phage model peptide groups (No. 1 and No. 2) increased. Expression of c-Fos mRNA and c-Jun mRNA in the KGF control group increased, but did not increase in the four phage model peptide groups (No.1 - 4). CONCLUSION: Four phage model peptides isolated from the phage display 7-mer peptide library can safely promote epidermal cell proliferation without tumorigenic effect. PMID: 20529562 [PubMed - in process] | | |
| Mesenchymal stem cells immunosuppressive properties: is it specific to bone marrow-derived cells?
June 10, 2010 at 6:05 AM
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| | Mesenchymal stem cells immunosuppressive properties: is it specific to bone marrow-derived cells? Stem Cell Res Ther. 2010 Jun 8;1(2):15 Authors: Jorgensen C ABSTRACT: Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs have paracrine effects, including immunomodulation that occurs through the secretion of soluble mediators, including nitric oxide or interleukin-6, transforming growth factor-beta, human leukocyte antigen G5, and prostaglandin E2. MSCs in the bone marrow are in close contact with T and B cells and regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. All of these biological effects are probably shared by all stromal cells, including fibroblasts and stem cells isolated from exfoliated deciduous teeth. The therapeutical implications are discussed. PMID: 20529386 [PubMed - as supplied by publisher] | | |
| Smart biomaterials - regulating cell behavior through signaling molecules.
June 10, 2010 at 6:05 AM
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| | Smart biomaterials - regulating cell behavior through signaling molecules. BMC Biol. 2010;8(1):59 Authors: Mieszawska AJ, Kaplan DL ABSTRACT : Important advances in the field of tissue engineering are arising from increased interest in novel biomaterial designs with bioactive components that directly influence cell behavior. Following the recent work of Mitchell and co-workers published in BMC Biology, we review how spatial and temporal control of signaling molecules in a matrix material regulates cellular responses for tissue-specific applications.See research article http://www.biomedcentral.com/1741-7007/8/57. PMID: 20529238 [PubMed - in process] | | |
| Human Umbilical Cord Blood as an Emerging Stem Cell Therapy for Diabetes Mellitus.
June 10, 2010 at 6:05 AM
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| | Human Umbilical Cord Blood as an Emerging Stem Cell Therapy for Diabetes Mellitus. Curr Stem Cell Res Ther. 2010 Jun 9; Authors: Reddi AS, Kuppasani K, Ende N Cellular therapy for patients with diabetes is receiving great attention among scientists and clinicians. Bone marrow is considered one of the rich sources of stem cells. However, the limited availability of bone marrow donors precludes its use for all the suitable patients. Human umbilical cord blood (HUCB) is being increasingly used as an alternative source of stem cells for cell-based therapy for malignant and nonmalignant diseases. HUCB is preferred to bone marrow because of its easy availability, low potential for graft-versus-host disease and tumorigenicity as well as infectious complications. Furthermore, no immunosuppression is required. In vitro and in vivo studies have shown that HUCB-derived stem cells can differentiate into insulin-secreting beta-cells. Administration of HUCB cells has been shown to improve blood glucose levels in diabetic animals. The first use of autologous HUCB transfusion in type 1 diabetic children is showing promise in reducing the daily requirement of insulin dose and the maintenance of near normoglycemia over a short period of time. The time has come for more clinical trials using autologous and allogenic cord blood transfusion to treat diabetes mellitus. PMID: 20528762 [PubMed - as supplied by publisher] | | |
| Therapeutic Window, a Critical Developmental Stage for Stem Cell Therapies.
June 10, 2010 at 6:05 AM
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| | Therapeutic Window, a Critical Developmental Stage for Stem Cell Therapies. Curr Stem Cell Res Ther. 2010 Jun 9; Authors: Li SC, Han YP, Dethlefs BA, Loudon WG In children, cancers are the deadliest of diseases and second only to accidents as the leading cause of death. The deadliest of the brain cancers are the malignant gliomas. Approximately two-thirds of children can survive less malignant types of brain cancers, however, in approximately 67% of these survivors recurs under the current regimes of surgery followed by administration of high doses toxic drugs and exposure to high doses of radiation. Even more distressing is that fortunate survivors are generally left with life-long cognitive disabilities. A new medical approach is desperately needed. Stem cells, with their natural ability to seek out brain tumors, could be used to accurately deliver therapy directly to the cancer sparing normal tissues for suppression of tumor growth. Despite exciting initial reports, clinical potency of stem cell therapy in animal brain tumor models has to date proven disappointing. Attempts to extrapolate the animal study results to humans are stymied by the fact that stem cells are heterogeneous, resulting in differences in their efficacy. Indeed, therapeutic success relies on an effective strategy to select for a stem cell sub-population within some particular stage of the development at which they are competitive and capable of targeting brain tumors. To improve this during developmental path, concept of a 'therapeutic window' is proposed. The "therapeutic window" for stem cells or more specifically a "biochemical therapeutic window" can be determined from biochemical assays and a "biological therapeutic window" from biological assays or even a molecular window for genetic description. Taken together, we can use selective processes to generate more effective stem cells to treat cancers as is clearly needed today. PMID: 20528752 [PubMed - as supplied by publisher] | | |
| Strategies for regeneration of heart muscle.
June 10, 2010 at 6:05 AM
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| | Strategies for regeneration of heart muscle. Crit Rev Eukaryot Gene Expr. 2010;20(1):35-50 Authors: Guyette JP, Cohen IS, Gaudette GR Regenerative medicine has emerged to the forefront of cardiac research, marrying discoveries in both basic science and engineering to develop viable therapeutic approaches for treating the diseased heart. Signifi cant advancements in gene therapy, stem cell biology, and cardiomyoplasty provide new optimism for regenerating damaged myocardium. Exciting new strategies for endogenous and exogenous regeneration have been proposed. However, questions remain as to whether these approaches can provide enough new myocyte mass to sufficiently restore mechanical function to the heart. In this article, we consider the mechanisms of endogenous cardiomyocyte regeneration and exogenous cell differentiation (with respect to myoblasts, stem cells, and induced pluripotent cells being researched for cell therapies). We begin by reviewing some of the cues that are being harnessed in strategies of gene/cell therapy for regenerating myocardium. We also consider some of the technical challenges that remain in determining new myocyte generation, tracking delivered cells in vivo, and correlating new myocyte contractility with cardiac function. Strategies for regenerating the heart are being realized as both animal and clinical trials suggest that these new approaches provide short-term improvement of cardiac function. However, a more complete understanding of the underlying mechanisms and applications is necessary to sustain longer-term therapeutic success. PMID: 20528736 [PubMed - in process] | | |
| Secreted frizzled related protein 4 reduces fibrosis scar size and ameliorates cardiac function after ischemic injury.
June 10, 2010 at 6:05 AM
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| | Secreted frizzled related protein 4 reduces fibrosis scar size and ameliorates cardiac function after ischemic injury. Tissue Eng Part A. 2010 Jun 9; Authors: Matsushima K, Suyama T, Takenaka C, Nishishita N, Ikeda K, Ikada Y, Sawa Y, Jakt LM, Mori H, Kawamata S Abstract The expression of the Wnt modulator secreted frizzled related protein 4 (Sfrp4) is up-regulated after heart ischemic injury. We show that intra-muscular administration of recombinant Sfrp4 to rat heart ischemic injury and recanalization models prevents further deterioration of cardiac function after the ischemic injury. The effect of Sfrp4 persisted for at least 20 weeks when Sfrp4 was administered in a slow release system (Sfrp4-polyhedra) to both acute and subacute ischemic models. The histology of the dissected heart showed that the cardiac wall was thicker and the area of acellular scarring was smaller in Sfrp4-treated hearts compared to controls. Increased amounts of both the inactive serine 9-phosphorylated form of GSK-3betaand the active form of beta-catenin were observed by immunohistology 3 days after LAD ligation in control, but not Sfrp4-treated hearts. All together, we show that administration of Sfrp4 interferes with canonical Wnt signaling that could mediate the formation of acellular scar and consequently contributes to the prevention of aggravation of cardiac function. Key words: beta-catenin, Sfrp4, GSK-3 beta, myocardial infarction, polyhedra, fibrous scar. PMID: 20528676 [PubMed - as supplied by publisher] | | |
| A preexisting microvascular network benefits in vivo revascularization of a microvascularized tissue-engineered skin substitute.
June 10, 2010 at 6:05 AM
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| | A preexisting microvascular network benefits in vivo revascularization of a microvascularized tissue-engineered skin substitute. Tissue Eng Part A. 2010 Jun 9; Authors: Gibot L, Galbraith T, Huot J, Auger FA Delayed or absence of vascularization is one of the major reasons for skin engraftment failure in patients with extensive burns. For such trauma victims, the best alternative to a split-thickness graft would be wound coverage with an autologous in vitro reconstructed skin (RS) combining dermis and epidermis with an appropriate microvascularization. We have developed a microvascularized reconstructed skin (ERS) based on our self-assembly approach, which is generated from autologous cultured cells without any exogenous angiogenic growth factor or scaffold. After transplantation in athymic mice, an early inosculation between the graft and host vasculatures occurred within 4 days. We also concurrently detected an active invasion of the dermis by host capillaries sprouting from the wound bed. Thus, the microvascular network constructed in vitro within our 3D skin substitute did not only develop functional anastomoses with the host's blood vessels but also promoted a rapid, complete and optimal vascularization of the implanted tissues by exerting an angiogenic effect compared to control RS. Our model may bring about interesting possibilities for regenerative medicine by leading to faster vascularization in clinical applications. In addition, the ERS can be a useful in vitro angiogenesis model. PMID: 20528673 [PubMed - as supplied by publisher] | | |
| Efficient Myogenic Differentiation of Murine Dermal Sca-1 (-) Cells via Initial Aggregation Culture.
June 10, 2010 at 6:05 AM
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| | Efficient Myogenic Differentiation of Murine Dermal Sca-1 (-) Cells via Initial Aggregation Culture. Tissue Eng Part A. 2010 Jun 9; Authors: Wakabayashi M, Ito Y, Hamazaki TS, Okochi H Stem cells from various organs have been shown to regenerate muscle cells. Among them, skin-derived cells are promising because of their easy accessibility. We separated murine dermal cells into Sca-1 (+) and (-) fractions and investigated which of them could differentiate into muscle cells. After the cells were aggregated for 4 days and cultured on a collagen type I coated plate for 7-10 days, the Sca-1 (-) fraction had expanded into many myoblastic cells, but the Sca-1 (+) fraction had not. Initial commitment to the myogenic lineage appeared to start during the aggregation. Sca-1 (-) cells proliferated exponentially and maintained their ability to differentiate into skeletal muscle cells within 7-10 days. About 60% of the cells showed positive staining for skeletal fast myosin heavy chain. Transplantation experiments revealed that the myoblastic cells arising after several passages were successfully engrafted into damaged host muscle. In conclusion, we have found that murine dermal Sca-1 (-) cells differentiate into muscle cells in vitro and in vivo after using an initial aggregation procedure. Their high differentiation efficiency and proliferation ability will offer substantial advantages for stem cell research. PMID: 20528672 [PubMed - as supplied by publisher] | | |
| Xenogeneic extracellular matrix as an inductive scaffold for regeneration of a functioning musculotendinous junction.
June 10, 2010 at 6:05 AM
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| | Xenogeneic extracellular matrix as an inductive scaffold for regeneration of a functioning musculotendinous junction. Tissue Eng Part A. 2010 Jun 9; Authors: Turner NJ, Yates AJ, Weber DJ, Qureshi IR, Beer Stolz D, Gilbert TW, Badylak SF The prevailing dogma in tissue engineering is cell-centric. One shortcoming of this approach is the failure to provide the implanted cells with a suitable in vivo microenvironment that promotes tissue reconstruction. Extracellular matrix (ECM)-based scaffolds provide a 3-dimensional microenvironment that can promote constructive and functional tissue remodeling rather than inflammation and scarring even in the absence of any implanted cells. The objective of this study was to determine the ability of an ECM-based scaffold to facilitate functional restoration of the distal gastrocnemius musculotendinous junction in a canine model following complete resection of the tissue. Within 6 months, vascularized, innervated skeletal muscle which was similar to normal muscle tissue had formed at the ECM-scaffold implantation site. This neo-tissue generated 48% of the contractile force of contralateral musculotendinous junction and represents the first report of de-novo formation of contractile, vascularized and innervated skeletal muscle in-situ following significant tissue loss. PMID: 20528669 [PubMed - as supplied by publisher] | | |
| Controlled cell seeding methodologies: a first step towards clinically relevant bone tissue engineering strategies.
June 10, 2010 at 6:05 AM
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| | Controlled cell seeding methodologies: a first step towards clinically relevant bone tissue engineering strategies. Tissue Eng Part C Methods. 2010 Jun 9; Authors: Impens SL, Chen Y, Mullens S, Luyten FP, Schrooten J The repair of large and complex bone defects could be helped by a cell based bone tissue engineering (TE) strategy. A reliable and consistent cell seeding methodology is a mandatory step in bringing bone TE into the clinic. However, optimization of the cell seeding step is only relevant when it can be reliably evaluated. The cell seeding efficiency (CSE) plays a fundamental role herein. Results showed that cell lysis and the definition used to determine the CSE, played a key role in quantifying the CSE. The definition of CSE should therefore be consistent and unambiguous. The study of the influence of five drop seeding related parameters within the studied test conditions showed that (i) the cell density and (ii) the seeding vessel did not significantly affect the CSE, whereas (iii) the volume of seeding medium to free scaffold volume ratio (MFR), (iv) the seeding time and (v) the scaffold morphology did. Prolonging the incubation time increased the CSE, up to a plateau value at 4 hours, while increasing the MFR or permeability by changing the morphology of the scaffolds significantly reduced the CSE. These results confirm that cell seeding optimization is needed and that an evidence based selection of the seeding conditions is favored. PMID: 20528665 [PubMed - as supplied by publisher] | | |
| Simple modular bioreactors for tissue engineering: a system for characterization of oxygen gradients, hMSC differentiation, and pre-vascularization.
June 10, 2010 at 6:05 AM
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| | Simple modular bioreactors for tissue engineering: a system for characterization of oxygen gradients, hMSC differentiation, and pre-vascularization. Tissue Eng Part C Methods. 2010 Jun 9; Authors: Lovett M, Rockwood DN, Baryshyan A, Kaplan DL Large-scale tissue engineering is limited by nutrient perfusion and mass transport limitations, especially oxygen diffusion, which restrict construct development to smaller than clinically relevant dimensions and limit the ability for in vivo integration. The goal of this work was to develop a modular approach to tissue engineering, where scaffold and tissue size, transport issues, and surgical implantation in vivo are considered from the outset. Human mesenchymal stem cells (hMSCs) were used as the model cell type, as their differentiation has been studied for several different cell lineages and often with conflicting results. Changes in the expression profiles of hMSCs differentiated under varied oxygen tensions are presented, demonstrating tissue-specific oxygen requirements for both adipogenic (20% O2) and chondrogenic (5% O2) differentiation. Oxygen and nutrient transport were enhanced by developing a bioreactor system for perfusing hMSC-seeded collagen gels using porous silk tubes, resulting in enhanced oxygen transport and cell viability within the gels. These systems are simple to use and scaled for versatility, to allow for the systematic study of relationships between cell content, oxygen and cell function. The data may be combined with oxygen transport modeling to derive minimally-sized modular units for construction of clinically-relevant tissue engineered constructs, a generic strategy that may be employed for vascularized target tissues. PMID: 20528664 [PubMed - as supplied by publisher] | | |
| Solving cell infiltration limitations of electrospun nanofiber meshes for tissue engineering applications.
June 10, 2010 at 6:05 AM
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| | Solving cell infiltration limitations of electrospun nanofiber meshes for tissue engineering applications. Nanomedicine (Lond). 2010 Jun;5(4):539-554 Authors: Guimarães A, Martins A, Pinho ED, Faria S, Reis RL, Neves NM Aim: Utilize the dual composition strategy to increase the pore size and solve the low cell infiltration capacity on random nanofiber meshes, an intrinsic limitation of electrospun scaffolds for tissue engineering applications. Materials & methods: Polycaprolactone and poly(ethylene oxide) solutions were electrospun simultaneously to obtain a dual composition nanofiber mesh. Selective dissolution of the poly(ethylene oxide) nanofiber fraction was performed. The biologic performance of these enhanced pore size nanofibrous structures was assessed with human osteoblastic cells. Results: The electrospun nanofiber meshes, after the poly(ethylene oxide) dissolution, showed statistically significant larger pore sizes when compared with polycaprolactone nanofiber meshes with a similar polycaprolactone volume fraction. This was also confirmed by interferometric optical profilometry. Using scanning electron microscopy and laser scanning confocal microscopy, it was observed that osteoblastic cells could penetrate into the nanofibrous structure and migrate into the opposite and unseeded side of the mesh. Conclusion: An electrospun mesh was created with sufficient pore size to allow cell infiltration into its structure, thus resulting in a fully populated construct appropriate for 3D tissue engineering applications. PMID: 20528450 [PubMed - as supplied by publisher] | | |
| In vivo evaluation of mixtures of uncultured freshly-isolated adipose-derived stem cells and demineralized bone matrix for bone regeneration in a rat critically-sized calvarial defect model.
June 10, 2010 at 6:05 AM
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| | In vivo evaluation of mixtures of uncultured freshly-isolated adipose-derived stem cells and demineralized bone matrix for bone regeneration in a rat critically-sized calvarial defect model. Stem Cells Dev. 2010 Jun 7; Authors: Rhee SC, Ji YH, Dhong ES, Park SH, Yoon ES Background: Although many studies have suggested that human adipose tissue contains pluripotent stem cells, a few reports are available on Stromal Vascular Fraction (SVF). In the present study, we evaluated the bone formation capacities of SVF. We implanted uncultured freshly-isolated adipose-derived stem cells com-bined with demineralized bone matrix to induce bone regeneration in a critically-sized rat calvarial defect model. Materials and Methods: We used demineralized bone matrix (DBX(R)) and/or P (L/DL) LA [Poly (70L-lactide-co-30DL-lactide) Co Polymer P (L/DL) LA] as a scaffold. Fifty white rats were randomized to 5 dif-ferent groups (n=10): 1) Control, 2) Group DBM, 3) Group DBM+SVF, 4) Group DBM+PLA, 5) Group DBM+PLA+SVF. After acquiring SVF, an 8-mm critically-sized calvarial defect was made in each rat. Spe-cimens were harvested at 8 weeks post-implantation and evaluated radiographically and histologically. New bone formation was qualified by H&E staining and by anti-osteocalcin antibody (OC4-30) immunostaining of calvarial sections. Amounts of mineralization were determined by radiodensitometric analysis. Results: In gross appearance, Group DBM+SVF and Group DBM+PLA+SVF showed more abundant bone formation than the other groups. Radiodensitometric evaluations revealed that significant inter-group differ-ences were observed according to the Kruskal-Wallis (Rank) test (p= 0.030<0.05). The five groups show dif-ferent amounts of filling of bone defects (Control group: 13.48%, Group DBM: 39.94% Group DBM+SVF: 57.69%, Group DBM+PLA: 24.86%, Group DBM+PLA+SVF: 42.75%). Histological evaluation revealed there was abundant new bone formation in Group DBM+SVF and Group DBM+PLA+SVF. Conclusions: It was found that undifferentiated adipose-derived stem cells in the form of SVF induced new bone formation in rat calvarial defects. Accordingly, SVF offers a practical, promising candidate for regenera-tive tissue engineering or cell-based therapy. PMID: 20528145 [PubMed - as supplied by publisher] | | |
| MR-based attenuation correction for hybrid PET-MR brain imaging systems using deformable image registration.
June 10, 2010 at 6:05 AM
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| | MR-based attenuation correction for hybrid PET-MR brain imaging systems using deformable image registration. Med Phys. 2010 May;37(5):2101-9 Authors: Schreibmann E, Nye JA, Schuster DM, Martin DR, Votaw J, Fox T PURPOSE: Realization of combined positron emission tomography (PET)--magnetic resonance (MR) scanners has the potential to significantly change healthcare and revolutionize clinical practice as it allows, simultaneously, visualization of molecular imaging and anatomical imaging. PET-MR, acquired in one imaging study, will likely become the advanced imaging modality of choice for neurological studies, certain forms of cancer, stroke, and the emerging study of stem cell therapy. A challenge toward the implementation and operation of combined PET-MR scanners is that attenuation corrections maps are not directly available due to space and cost constraints. This article presents a method to obtain accurate patient-specific PET attenuation coefficients maps in head imaging by warping an atlas computed tomography (CT) data set to the patient-specific MR data set using a deformable registration model. METHODS: A multimodality optical flow deformable model has been developed that establishes a voxel-to-voxel correspondence between the CT atlas and patient MR images. Once the mapping is established, the atlas is warped with the deformation field obtained by the registration to create a simulated CT image study that matches the patient anatomy, which could be used for attenuation correction. RESULTS: To evaluate the accuracy of the deformable-based attenuation correction, 17 clinical brain tumor cases were studied using acquired MR-CT images. A simulated CT was compared to the patient's true CT to assess geometrical accuracy of the deformation module as well as voxel-to-voxel comparison of Hounsfield units (HUs). In all cases, mapping from the atlas CT to the individual MR was achieved with geometrical accuracy as judged using quantitative inspection tools. The mean distance between simulated and true CT external contour and bony anatomy was 1.26 and 2.15 mm, respectively. In terms of HU unit comparison, the mean voxel-to-voxel difference was less than 2 HU for all cases. CONCLUSIONS: Attenuation correction for hybrid PET-MR scanners was easily achieved by individualizing an atlas CT to the MR data set using a deformable model without requiring user interaction. The method provided clinical accuracy while eliminating the need for an additional CT scan for PET attenuation correction. PMID: 20527543 [PubMed - in process] | | |
| lacZ as a genetic reporter for real-time MRI.
June 10, 2010 at 6:05 AM
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| | lacZ as a genetic reporter for real-time MRI. Magn Reson Med. 2010 Mar;63(3):745-53 Authors: Bengtsson NE, Brown G, Scott EW, Walter GA Molecular imaging based on MRI is currently hampered by the lack of genetic reporters for in vivo imaging. We determined that the commercially available substrate S-Gal can be used to detect genetically engineered beta-galactosidase expressing cells by MRI. The effect and specificity of the reaction between beta-galactosidase and S-Gal on MRI contrast were determined both in vitro and in vivo. beta-galactosidase activity in the presence of S-Gal resulted in enhanced T(2) and T*(2) MR-contrast, which was amplified with increasing magnetic field strengths (4.7-17.6 T) in phantom studies. Using both lacZ(+) transgenic animals and lacZ(+) tissue transplants, we were able to detect labeled cells in live animals in real time. Similar to phantom studies, detection of the labeled cells/tissues in vivo was enhanced at high magnetic fields. These results demonstrate that the genetic reporter, lacZ, can be used as an in vivo marker gene using high-field-strength MRI. PMID: 20146234 [PubMed - indexed for MEDLINE] | | |
| Functional properties of cartilaginous tissues engineered from infrapatellar fat pad-derived mesenchymal stem cells.
June 10, 2010 at 6:05 AM
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| | Functional properties of cartilaginous tissues engineered from infrapatellar fat pad-derived mesenchymal stem cells. J Biomech. 2010 Mar 22;43(5):920-6 Authors: Buckley CT, Vinardell T, Thorpe SD, Haugh MG, Jones E, McGonagle D, Kelly DJ Articular cartilage has a poor intrinsic capacity for self-repair. The advent of autologous chondrocyte implantation has provided a feasible method to treat cartilage defects. However, the associated drawbacks with the isolation and expansion of chondrocytes from autologous tissue has prompted research into alternative cell sources such as mesenchymal stem cells (MSCs) which have been found to exist in the bone marrow as well as other joint tissues such as the infrapatellar fat pad (IFP), synovium and within the synovial fluid itself. In this work we assessed the chondrogenic potential of IFP-derived porcine cells over a 6 week period in agarose hydrogel culture in terms of mechanical properties, biochemical content and histology. It was found that IFP cells underwent robust chondrogenesis as assessed by glycosaminoglycan (1.47+/-0.22% w/w) and collagen (1.44+/-0.22% w/w) accumulation after 42 days of culture. The 1Hz dynamic modulus of the engineered tissue at this time point was 272.8 kPa (+/-46.8). The removal of TGF-beta3 from culture after 21 days was shown to have a significant effect on both the mechanical properties and biochemical content of IFP constructs after 42 days, with minimal increases occurring from day 21 to day 42 without continued supplementation of TGF-beta3. These findings further strengthen the case that the IFP may be a promising cell source for putative cartilage repair strategies. PMID: 20005518 [PubMed - indexed for MEDLINE] | | |
| Directing bone marrow-derived stromal cell function with mechanics.
June 10, 2010 at 6:05 AM
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| | Directing bone marrow-derived stromal cell function with mechanics. J Biomech. 2010 Mar 22;43(5):807-17 Authors: Potier E, Noailly J, Ito K Because bone marrow-derived stromal cells (BMSCs) are able to generate many cell types, they are envisioned as source of regenerative cells to repair numerous tissues, including bone, cartilage, and ligaments. Success of BMSC-based therapies, however, relies on a number of methodological improvements, among which better understanding and control of the BMSC differentiation pathways. Since many years, the biochemical environment is known to govern BMSC differentiation, but more recent evidences show that the biomechanical environment is also directing cell functions. Using in vitro systems that aim to reproduce selected components of the in vivo mechanical environment, it was demonstrated that mechanical loadings can affect BMSC proliferation and improve the osteogenic, chondrogenic, or myogenic phenotype of BMSCs. These effects, however, seem to be modulated by parameters other than mechanics, such as substrate nature or soluble biochemical environment. This paper reviews and discusses recent experimental data showing that despite some knowledge limitation, mechanical stimulation already constitutes an additional and efficient tool to drive BMSC differentiation. PMID: 19962149 [PubMed - indexed for MEDLINE] | | | | 
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