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Divergent reprogramming routes lead to alternative stem-cell states
Tonge, Peter D.,Corso, Andrew J.,Monetti, Claudio,Hussein, Samer M. I.,Puri, Mira C.,Michael, Iacovos P.,Li, Mira,Lee, Dong-Sung,Mar, Jessica C.,Cloonan, Nicole,Wood, David L.,Gauthier, Maely E.,Korn, Nature Publishing Group, a division of Macmillan P 2014 Nature Vol.516 No.7530
Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states.
Maintaining Professionalism in Semi-Professional Sport: Are We Asking too Much?
Deborah Agnew,Pip Henderson,Andrew Marks,Carl Woods 글로벌지식마케팅경영학회 2019 Journal of Global Sport Management Vol.4 No.1
How integrity is understood depends on the context. This paper explores the idea of integrity of sport, specifically the sub-elite South Australian National Football League competition. This mixed-methods study utilized both surveys and interviews to understand the issues that threaten the integrity of the South Australian competition. Threats emerged regarding financial remuneration, competition fairness and demands for semi-professional athletes. Athletes competing at sub-elite levels are expected to uphold the same standards as those competing in the national elite competition without the same financial remuneration. This potentially motivates players to leave the sub-elite competition in favor of lower leagues where there are fewer commitments and higher pay. Sub-elite footballers also engage in some high-risk behaviors, which can undermine the community’s trust in the sport, thereby threating its integrity. Further research regarding the integrity of football supporters is warranted to maintain the integrity of the overall competition.
Joan Oliva,Fawzia Bardag-Gorce,Andrew Wood,Hiroyuki Sota,Yutaka Niihara 한국조직공학과 재생의학회 2015 조직공학과 재생의학 Vol.12 No.5
Autologous stem cell transplantation for eye diseases is immunologically preferable to avoid allograft rejection. However, the fate of the grafted cells has never been studied. Here, we propose to use 19F-perfluorocarbon magnetic resonance imaging tracer agent, to label cell sheet in vitro. This labeling enables non-invasive visualization of possible migration of grafted cells. Oral mucosal epithelial cells were isolated from rabbit oral mucosal epithelium and were cultivated in a thermo-responsive surface to engineer a multilayer cell sheet. Different concentrations of 19F-perfluorocarbon were added to the cell sheet culture media, one or two times. Cells were analyzed in a 7 T nuclear magnetic resonance to determine the labeling efficiency. We found that 10 mg/mL and two incubations with 19F-perfluorocarbon were the optimal condition for labeling. H&E and immunocytochemistry showed that labeling did not affect the expression of cell sheets specific markers (CK4, CK13, connexin43, E-cadherin). Furthermore, no significant effects were observed on the number of cells and the cell viability, making 19F-perfluorocarbon suitable for cell tracking, with no side effects.
Chen Ziming,Li Mengyuan,Chen Peilin,Tai Andrew,Li Jiayue,Bassonga Euphemie Landao,Gao Junjie,Liu Delin,Wood David,Kennedy Brendan F.,Zheng Qiujian,Zheng Ming H. 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-
Tendinopathy is one of the most common musculoskeletal diseases, and mechanical overload is considered its primary cause. However, the underlying mechanism through which mechanical overload induces tendinopathy has not been determined. In this study, we identified for the first time that tendon cells can release extracellular mitochondria (ExtraMito) particles, a subtype of medium extracellular particles (mEPs), into the environment through a process regulated by mechanical loading. RNA sequencing systematically revealed that oxygen-related reactions, extracellular particles, and inflammation were present in diseased human tendons, suggesting that these factors play a role in the pathogenesis of tendinopathy. We simulated the disease condition by imposing a 9% strain overload on three-dimensional mouse tendon constructs in our cyclic uniaxial stretching bioreactor. The three-dimensional mouse tendon constructs under normal loading with 6% strain exhibited an extended mitochondrial network, as observed through live-cell confocal laser scanning microscopy. In contrast, mechanical overload led to a fragmented mitochondrial network. Our microscopic and immunoblot results demonstrated that mechanical loading induced tendon cells to release ExtraMito particles. Furthermore, we showed that mEPs released from tendon cells overloaded with a 9% strain (mEP9%) induced macrophage chemotaxis and increased the production of proinflammatory cytokines, including IL-6, CXCL1, and IL-18, from macrophages compared to mEP0%, mEP3%, and mEP6%. Partial depletion of the ExtraMito particles from mEP9% by magnetic-activated cell sorting significantly reduced macrophage chemotaxis. N-acetyl-L-cysteine treatment preserved the mitochondrial network in overloaded tendon cells, diminishing overload-induced macrophage chemotaxis toward mEP9%. These findings revealed a novel mechanism of tendinopathy; in an overloaded environment, ExtraMito particles convey mechanical response signals from tendon cells to the immune microenvironment, culminating in tendinopathy.
Microarray Analysis of Oral Mucosal Epithelial Cell Sheet
Fawzia Bardag-Gorce,Joan Oliva,Hope Niihara,Andrew Makalinao,Sean Sabino,Derek Pan,Jacquelyn Thropay,Hiroyuki Sota,Yutaka Niihara,Andrew Wood 한국조직공학과 재생의학회 2013 조직공학과 재생의학 Vol.10 No.6
Corneal epithelium regeneration using autologous oral mucosal epithelial cell sheet is a successful new approach in corneal therapy. In the present study, gene expression profiling was performed to characterize engi-neered cell sheets. Cell sheets were obtained by culturing isolated rabbit oral mucosal epithelial cells on a thermo-responsive cultureware (UpCell®, CellSeed Inc. Japan). H&E staining of cell sheets showed a multistratified epi-thelium, similar to corneal epithelium. DeltaN-p63 stained positive in the basal cells, indicating that cell sheets have renewal capacity. Microarray analysis of these cell sheets showed that only 160 genes out of 43,000 rabbit probes listed on the microarray chip were identified. We first identified the extracellular matrix group of genes and found that matrix metalloproteinase MMP-1, MMP-3 and MMP-12, known to promote angiogenesis, were down regu-lated, while MMP-13 and collagen type VIII alpha 1 (COL8A1), proteins involved in wound healing, were up reg-ulated. Tissue inhibitors of metalloproteinase TIMP-1 and TIMP-3, anti-angiogenic factors, were also identified. Gap junction protein A7 (GJA7 or Connexin 45) was found up regulated, indicating that cell sheets have developed well preserved cell-cell interactions. Alcohol dehydrogenase 5 (ADH class III) and aldehyde dehydrogenase (ALDH1A1), involved in protecting the cornea against oxidative stress induced by UV radiation, were also found up regulated. In conclusion, microarray analysis has led us to identify new target molecules and their subsequent biochemical analysis indicated how the composite cell sheets are advantageous to the original isolated cells in terms of the integrity and potency of corneal epithelial grafts without any scaffolds.
Feeder Cells Free Rabbit Oral Mucosa Epithelial Cell Sheet Engineering
Joan Oliva,Ken Ochiai,Arjie Florentino,Fawzia Bardag-Gorce,Andrew Wood,Yutaka Niihara 한국조직공학과 재생의학회 2018 조직공학과 재생의학 Vol.15 No.3
The optimal cell culture method of autologous oral mucosal epithelial cell sheet is not well established for a safe transplantation on to the patients’ ocular surface. Animal serum and 3T3 mouse feeder cells are currently being used to stimulate the growth of the epithelial cells. However, the use of animal compounds can have potential side effects for the patient after transplantation of the engineered cell sheet. In the present study, we focused on engineering a rabbit oral mucosal epithelial cell sheet without 3T3 mouse feeder cells using a mix of Dulbecco’s Modified Eagle Medium/Bronchial Epithelial Cell Growth Medium culture media (DMEM/BEGM). Autologous oral mucosal epithelial cell sheets, engineered with DMEM/BEGM feeder cell free culture media, were compared to those cultured in presence of serum and feeder cells. Using a DMEM/BEGM mix culture media, feeder cell free culture condition, autologous oral mucosal epithelial cells reached confluence and formed a multilayered sheet. The phenotype of engineered cell sheets cultured with DMEM/BEGM were characterized and compared to those cultured with serum and feeder. Hematoxylin and eosin staining showed the formation of a similar stratified multilayer cell sheets, in both culture conditions. The expression of deltaN-p63, ABCG2, PCNA, E-cadherin, Beta-catenin, CK3, CK4, CK13, Muc5AC, was similar in both culture conditions. We demonstrated that rabbit autologous oral mucosal epithelial cell sheet can be engineered, in feeder cell free conditions. The use of the DMEM/BEGM culture media to engineer culture autologous oral mucosa epithelial cell sheet will help to identify key factors involved in the growth and differentiation of oral mucosal epithelial cells.
Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees
Jun, Goo,Manning, Alisa,Almeida, Marcio,Zawistowski, Matthew,Wood, Andrew R.,Teslovich, Tanya M.,Fuchsberger, Christian,Feng, Shuang,Cingolani, Pablo,Gaulton, Kyle J.,Dyer, Thomas,Blackwell, Thomas W. National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.2
<P>A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant c/s-expression quantitative trait loci that could not be detected in population studies, validating our approach. Flowever, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.</P>
Sputum Inflammatory Mediators Are Increased in Aspergillus fumigatus Culture-Positive Asthmatics
Michael A Ghebre,Dhananjay Desai,Amisha Singapuri,Joanne Woods,Laura Rapley,Suzanne Cohen,Athula Herath,Andrew J Wardlaw,Catherine H Pashley,Richard May,Chris E Brightling 대한천식알레르기학회 2017 Allergy, Asthma & Immunology Research Vol.9 No.2
Aspergillus fumigatus sensitization and culture in asthma are associated with disease severity and lung function impairment, but their relationship with airway inflammation is poorly understood. We investigated the profile of 24 sputum inflammatory mediators in A. fumigatus culture-positive or-negative moderate-to-severe asthmatics. Fifty-two subjects were recruited from a single center. A. fumigatus was cultured from 19 asthmatics. Asthma control, symptom score, lung function, and sputum cell count were not significantly different between the asthmatics with and without a positive A. fumigatus culture. All of the sputum mediators were numerically increased in subjects with a positive versus negative sputum A. fumigatus culture. Sputum TNF-R2 was significantly elevated (P=0.03) and the mediator that best distinguished A. fumigatus culture-positive from culturenegative subjects (receiver-operator characteristic area under the curve 0.66 [95% CI: 0.51 to 0.82, P=0.045]). A. fumigates-positive culture in moderate- to-severe asthma is associated with increased inflammatory sputum mediators.