|  |  |  | | | | | TE-RegenMed-StemCell feed | | | | | | | | | | | | | | | | | | | Bioactive Electrospun Scaffolds Delivering Growth Factors and Genes for Tissue Engineering Applications. Pharm Res. 2010 Nov 19; Authors: Ji W, Sun Y, Yang F, van den Beucken JJ, Fan M, Chen Z, Jansen JA A biomaterial scaffold is one of the key factors for successful tissue engineering. In recent years, an increasing tendency has been observed toward the combination of scaffolds and biomolecules, e.g. growth factors and therapeutic genes, to achieve bioactive scaffolds, which not only provide physical support but also express biological signals to modulate tissue regeneration. Huge efforts have been made on the exploration of strategies to prepare bioactive scaffolds. Within the past five years, electrospun scaffolds have gained an exponentially increasing popularity in this area because of their ultrathin fiber diameter and large surface-volume ratio, which is favored for biomolecule delivery. This paper reviews current techniques that can be used to prepare bioactive electrospun scaffolds, including physical adsorption, blend electrospinning, coaxial electrospinning, and covalent immobilization. In addition, this paper also analyzes the existing challenges (i.e., protein instability, low gene transfection efficiency, and difficulties in accurate kinetics prediction) to achieve biomolecule release from electrospun scaffolds, which necessitate further research to fully exploit the biomedical applications of these bioactive scaffolds. PMID: 21088985 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | PTHrP Overexpression Partially Inhibits a Mechanical Strain-Induced Arthritic Phenotype in Chondrocytes. Osteoarthritis Cartilage. 2010 Nov 15; Authors: Wang D, Taboas JM, Tuan RS OBJECTIVE: Cell-based tissue engineering strategies are currently in clinical use and continue to be developed at a rapid pace for the repair of cartilage defects. Regardless of the repair methodology, chondrocytes within newly regenerated cartilage remain susceptible to the abnormal inflammatory and mechanical environments that underlie osteoarthritic disease, likely compromising the implant's integration, function, and longevity. The present study investigates the use of parathyroid hormone-related peptide (PTHrP) overexpression for chondroprotection. DESIGN: Bovine articular chondrocytes were transfected with human PTHrP (hPTHrP) constructs (1-141 or 1-173) and subjected to injurious cyclic tensile strain (CTS; 0.5Hz and 16% elongation) for 48hours. mRNA expression of matrix remodeling, inflammatory signaling, hypertrophic, and apoptotic genes were examined with real-time reverse transcription polymerase chain reaction. Nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production were measured using the Griess assay and enzyme immunoassay, respectively. RESULTS: CTS induced an arthritic phenotype in articular chondrocytes as indicated by increased gene expression of collagenases and aggrecanases and increased production of NO and PGE(2). Additionally, CTS increased collagen type X (Col10a1) mRNA expression, whereas overexpression of either hPTHrP isoform inhibited CTS-induced Col10a1 gene expression. However, hPTHrP 1-141 augmented CTS-induced NO and PGE(2) production, and neither hPTHrP isoform had any significant effect on apoptotic genes. CONCLUSIONS: Our results suggest that chondrocytes overexpressing PTHrP resist mechanical strain-induced hypertrophic-like changes. Therapeutic PTHrP gene transfer may be considered for chondroprotection applications in newly regenerated cartilage. PMID: 21087676 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Migration of dorsal aorta mesenchymal stem cells induced by mouse embryonic circulation. Dev Dyn. 2010 Nov 18; Authors: Yan XL, Lan Y, Wang XY, He WY, Yao HY, Chen DB, Xiong JX, Gao J, Li Z, Yang G, Li XS, Liu YL, Zhang JY, Liu B, Mao N Mesenchymal stem cells (MSCs) represent powerful tools for regenerative medicine for their differentiation and migration capacity. However, ontogeny and migration of MSCs in mammalian mid-gestation conceptus is poorly understood. We identified canonical MSCs in the mouse embryonic day (E) 11.5 dorsal aorta (DA). They possessed homogenous immunophenotype (CD45(-)CD31(-)Flk-1(-)CD44(+)CD29(+)), expressed perivascular markers (α-SMA(+)NG2(+)PDGFRβ(+)PDGFRα(+)), and had tri-lineage differentiation potential (osteoblasts, adipocytes, and chondrocytes). Of interest, MSCs were also detected in E12.5-E13.5 embryonic circulation, 24 hr later than in DA, suggesting migration like hematopoietic stem cells. Functionally, E12.5 embryonic blood could trigger efficient migration of DA-MSCs through platelet-derived growth factor (PDGF) receptor-, transforming growth factor-beta receptor-, but not basic fibroblast growth factor receptor-mediated signaling. Moreover, downstream JNK and AKT signaling pathway played important roles in embryonic blood- or PDGF-mediated migration of DA-derived MSCs. Taken together, these results revealed that clonal MSCs developed in the mouse DA. More importantly, the embryonic circulation, in addition to its conventional transporting roles, could modulate migration of MSC during early embryogenesis. Developmental Dynamics, 2011. © 2010 Wiley-Liss, Inc. PMID: 21089075 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Generation of Pig iPS Cells: A Model for Cell Therapy. J Cardiovasc Transl Res. 2010 Nov 19; Authors: Montserrat N, Bahima EG, Batlle L, Häfner S, Rodrigues AM, González F, Belmonte JC Reprogramming of pig somatic cells to induced pluripotent stem cells provides a tremendous advance in the field of regenerative medicine since the pig represents an ideal large animal model for the preclinical testing of emerging cell therapies. However, the current generation of pig-induced pluripotent stem cells (piPSCs) require the use of time-consuming and laborious retroviral or lentiviral transduction approaches, in order to ectopically express the pluripotency-associated transcription factors Oct4, Sox2, Klf4 and c-Myc, in the presence of feeder cells. Here, we describe a simple method to produce piPSC with a single transfection of a CAG-driven polycistronic plasmid expressing Oct4, Sox2, Klf4, c-Myc and a green fluorescent protein (GFP) reporter gene, in gelatine-coated plates, with or without feeder cells. In our system, the derivation of piPSCs from adult pig ear fibroblasts on a gelatine coating showed a higher efficiency and rate of reprogramming when compared with three consecutive retroviral transductions of a similar polycistronic construct. Our piPSCs expressed the classical embryonic stem cell markers, exhibit a stable karyotype and formed teratomas. Moreover, we also developed a simple method to generate in vitro spontaneous beating cardiomiocyte-like cells from piPSCs. Overall, our preliminary results set the bases for the massive production of xeno-free and integration-free piPSCs and provide a powerful tool for the preclinical application of iPSC technology in a large animal setting. PMID: 21088946 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Myocyte Turnover in the Aging Human Heart. Circ Res. 2010 Nov 18; Authors: Kajstura J, Gurusamy N, Ogórek B, Goichberg P, Clavo-Rondon C, Hosoda T, D'Amario D, Bardelli S, Beltrami AP, Cesselli D, Bussani R, Del Monte F, Quaini F, Rota M, Beltrami CA, Buchholz BA, Leri A, Anversa P Rationale: The turnover of cardiomyocytes in the aging female and male heart is currently unknown, emphasizing the need to define human myocardial biology. Objective: The effects of age and gender on the magnitude of myocyte regeneration and the origin of newly formed cardiomyocytes were determined. Methods and Results: The interaction of myocyte replacement, cellular senescence, growth inhibition, and apoptosis was measured in normal female (n=32) and male (n=42) human hearts collected from patients 19 to 104 years of age who died from causes other than cardiovascular diseases. A progressive loss of telomeric DNA in human cardiac stem cells (hCSCs) occurs with aging and the newly formed cardiomyocytes inherit short telomeres and rapidly reach the senescent phenotype. Our data provide novel information on the superior ability of the female heart to sustain the multiple variables associated with the development of the senescent myopathy. At all ages, the female heart is equipped with a larger pool of functionally competent hCSCs and younger myocytes than the male myocardium. The replicative potential is higher and telomeres are longer in female hCSCs than in male hCSCs. In the female heart, myocyte turnover occurs at a rate of 10%, 14%, and 40% per year at 20, 60, and 100 years of age, respectively. Corresponding values in the male heart are 7%, 12%, and 32% per year, documenting that cardiomyogenesis involves a large and progressively increasing number of parenchymal cells with aging. From 20 to 100 years of age, the myocyte compartment is replaced 15 times in women and 11 times in men. Conclusions: The human heart is a highly dynamic organ regulated by a pool of resident hCSCs that modulate cardiac homeostasis and condition organ aging. PMID: 21088285 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | A Western-Type Diet Accelerates Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer. Am J Pathol. 2010 Nov 18; Authors: Llaverias G, Danilo C, Wang Y, Witkiewicz AK, Daumer K, Lisanti MP, Frank PG Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model. Consumption of a Western-type diet-that is, enriched in both fat and cholesterol-accelerated prostate tumor incidence and tumor burden compared to mice fed a control chow diet. Furthermore, we also show that this diet increased the extent and the histological grade of prostate tumors. These findings were confirmed by the presence of increased levels of protein markers of advanced tumors in prostates obtained from animals fed a Western-type diet compared to those obtained from control animals. Increased lung metastases in animals fed a Western-type diet were also observed. In addition, we found that with a Western diet, animals bearing tumors presented with reduced plasma cholesterol levels compared with animals fed a control diet. Finally, we show that tumors obtained from animals fed a Western-type diet displayed increased expression of the high-density lipoprotein receptor SR-BI and increased angiogenesis. Taken together, our data suggest that dietary fat and cholesterol play an important role in the development of prostate cancer. PMID: 21088217 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Another possible cell source for cardiac regenerative medicine: Reprogramming adult fibroblasts to cardiomyocytes and endothelial progenitor cells. Med Hypotheses. 2010 Nov 17; Authors: Xie X, Sun A, Huang Z, Zhu W, Wang S, Zou Y, Ge J Ischemic heart disease (IHD) is a significant burden to healthcare systems in the world despite substantial advances in risk modification, pharmacological therapy and revascularization therapy. Stem cell therapy is emerging as a novel therapeutic paradigm for myocardial repair. Several cell types including embryonic stem cells, adult stem cells and induced pluripotent stem (iPS) cells have been used for the treatment of ischemic heart disease. But all these engrafted cells must be systematically or locally administered after being expanded in vitro, the rare differentiation into cardiomyocytes and low cellular survival of engrafted cells also limited the efficacy of stem cell therapy. Recent research indicated that it was feasible to reprogramme one mature cell type into another cell type directly by introducing several transcription factors, which was called transdifferentiation. We speculate that cell reprogramming might provide potential new cell sources for therapeutic cardiac regeneration. For these reasons, we hypothesize that converting cardiac fibroblasts to cardiomyocytes and endothelial progenitor cells (EPCs) either in vivo or in vitro might be a possible way for future therapeutic cardiac regeneration. Furthermore we also analyzed the possible difficulties we might face on way to realize this hypothesis. PMID: 21087827 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Selective follicular targeting by modification of the particle sizes. J Control Release. 2010 Nov 15; Authors: Patzelt A, Richter H, Knorr F, Schäfer U, Lehr CM, Dähne L, Sterry W, Lademann J Hair follicles represent interesting target sites for topically applied substances such as topical vaccinations or agents used in the field of regenerative medicine. In recent years, it could be shown that particles penetrate very effectively into the hair follicles. In the present study, the influence of particle size on the follicular penetration depths was examined. The penetration depths of two different types of particles sized 122 to 1000 nm in size were determined in vitro on porcine skin. The results revealed that the particles of medium size (643 and 646 nm, respectively) penetrated deeper into the porcine hair follicles than smaller or larger particles. Conclusion: It was concluded that by varying the particle size, different sites within the porcine hair follicle can be targeted selectively. For the human terminal hair follicle, the situation can be expected to be similar due to a similar size ratio of the hair follicles. PMID: 21087645 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Hematopoietic differentiation from human ESCs as a model for developmental studies and future clinical translations. FEBS J. 2010 Oct 21; Authors: Moreno-Gimeno I, Ledran MH, Lako M Human embryonic stem cells (hESCs) and induced pluripotent stem cells are excellent models for the study of embryonic hematopoiesis in vitro, aiding the design of new differentiation models that may be applicable to cell-replacement therapies. Adult and fetal hematopoietic stem cells are currently being used in biomedical applications; however, the latest advances in regenerative medicine and stem cell biology suggest that hESC-derived hematopoietic stem cells are an outstanding tool for enhancing immunotherapy and treatments for blood disorders and cancer, for example. In this review, we compare various methods used for inducing in vitro hematopoietic differentiation from hESCs, based on co-culture with stromal cells or formation of embryoid bodies, and analyse their ability to give rise to hematopoietic precursors, with emphasis on their engraftment potential as a measure of their functionality in vivo. PMID: 21087454 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Scalable production of cardiomyocytes derived from induced pluripotent stem (iPS) cells without c-Myc. Tissue Eng Part A. 2010 Nov 19; Authors: Zwi L, Mizrahi I, Arbel G, Gepstein A, Gepstein L Cardiomyocytes derived from induced pluripotent stem (iPS) cells hold great promise for basic and translational cardiovascular research. For the successful implementation of this unique technology, however, it is essential to establish efficient, reproducible, and safe strategies to produce cardiomyocytes in a scalable manner. The aim of the current study was to establish scalable bioprocess that allows direct embryoid bodies (EBs) formation for the differentiation of iPS cells (generated without the oncogene c-Myc) into cardiomyocytes. The cardiomyocytes' structural, molecular and functional properties were then compared to ones derived by the well-established static culture system. Similar gene expression patterns were observed in both differentiation systems with the sequential expression of mesoderm markers, cardiac transcription factors, and cardiomyocyte structural genes. Cells in the contracting EBs were stained positively for cardiac troponin-I, sarcomeric alpha-actinin, cardiac troponin-T and connexin-43. Electrophysiological measurements using multielectrode array (MEA) recordings demonstrated that the bioreactor-derived cardiomyocytes were functionally similar to static derived cardiomyocytes and responded appropriately to different drugs, including adrenergic and muscarinic agonists (isoproterenol and carbamylcholine, respectively) and the gap junction uncoupler heptanol. Our study describes, for the first time, a strategy for scalable differentiation of c-Myc-free iPS cells into cardiomyocytes with the appropriate molecular, structural, and functional properties. The result of this study should have important implications for several cardiovascular research areas and specifically for the emerging field of regenerative medicine. PMID: 21087204 [PubMed - as supplied by publisher] | | | | | | | | | |  | |  | |  |
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