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Cells, Volume 5, Issue 4 (December 2016) – 10 articles

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1061 KiB  
Review
Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery
by Masaki Hosoya and Katherine Czysz
Cells 2016, 5(4), 46; https://doi.org/10.3390/cells5040046 - 21 Dec 2016
Cited by 22 | Viewed by 7512
Abstract
Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) [...] Read more.
Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro. The availability of human iPS cell-derived cells, particularly as an alternative for difficult-to-access tissues and organs, is increasing steadily; however, their use in the field of translational medicine remains challenging. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator with which to evaluate pharmacological and toxicological effects in both the preclinical and clinical settings. In general, during the preclinical stage of the drug development process, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. This review provides an overview of current strategies for human iPS cell-based drug discovery from the perspective of translational research, and discusses the importance of early consideration of clinically relevant biomarkers. Full article
(This article belongs to the Special Issue Ten Years of iPSCs: Current Status and Future Perspectives)
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3608 KiB  
Article
Random Splicing of Several Exons Caused by a Single Base Change in the Target Exon of CRISPR/Cas9 Mediated Gene Knockout
by Marcel Kapahnke, Antje Banning and Ritva Tikkanen
Cells 2016, 5(4), 45; https://doi.org/10.3390/cells5040045 - 14 Dec 2016
Cited by 47 | Viewed by 9311
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)-associated sequence 9 (CRISPR/Cas9) system is widely used for genome editing purposes as it facilitates an efficient knockout of a specific gene in, e.g. cultured cells. Targeted double-strand breaks are introduced to the target sequence of [...] Read more.
The clustered regularly interspaced short palindromic repeats (CRISPR)-associated sequence 9 (CRISPR/Cas9) system is widely used for genome editing purposes as it facilitates an efficient knockout of a specific gene in, e.g. cultured cells. Targeted double-strand breaks are introduced to the target sequence of the guide RNAs, which activates the cellular DNA repair mechanism for non-homologous-end-joining, resulting in unprecise repair and introduction of small deletions or insertions. Due to this, sequence alterations in the coding region of the target gene frequently cause frame-shift mutations, facilitating degradation of the mRNA. We here show that such CRISPR/Cas9-mediated alterations in the target exon may also result in altered splicing of the respective pre-mRNA, most likely due to mutations of splice-regulatory sequences. Using the human FLOT-1 gene as an example, we demonstrate that such altered splicing products also give rise to aberrant protein products. These may potentially function as dominant-negative proteins and thus interfere with the interpretation of the data generated with these cell lines. Since most researchers only control the consequences of CRISPR knockout at genomic and protein level, our data should encourage to also check the alterations at the mRNA level. Full article
(This article belongs to the Special Issue Signal Transduction 2016)
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911 KiB  
Review
Potential of Induced Pluripotent Stem Cells (iPSCs) for Treating Age-Related Macular Degeneration (AMD)
by Mark Fields, Hui Cai, Jie Gong and Lucian Del Priore
Cells 2016, 5(4), 44; https://doi.org/10.3390/cells5040044 - 8 Dec 2016
Cited by 25 | Viewed by 8238
Abstract
The field of stem cell biology has rapidly evolved in the last few decades. In the area of regenerative medicine, clinical applications using stem cells hold the potential to be a powerful tool in the treatment of a wide variety of diseases, in [...] Read more.
The field of stem cell biology has rapidly evolved in the last few decades. In the area of regenerative medicine, clinical applications using stem cells hold the potential to be a powerful tool in the treatment of a wide variety of diseases, in particular, disorders of the eye. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising technologies that can potentially provide an unlimited source of cells for cell replacement therapy in the treatment of retinal degenerative disorders such as age-related macular degeneration (AMD), Stargardt disease, and other disorders. ESCs and iPSCs have been used to generate retinal pigment epithelium (RPE) cells and their functional behavior has been tested in vitro and in vivo in animal models. Additionally, iPSC-derived RPE cells provide an autologous source of cells for therapeutic use, as well as allow for novel approaches in disease modeling and drug development platforms. Clinical trials are currently testing the safety and efficacy of these cells in patients with AMD. In this review, the current status of iPSC disease modeling of AMD is discussed, as well as the challenges and potential of this technology as a viable option for cell replacement therapy in retinal degeneration. Full article
(This article belongs to the Special Issue Ten Years of iPSCs: Current Status and Future Perspectives)
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2479 KiB  
Review
Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer
by Justine H. Dewald, Florent Colomb, Marie Bobowski-Gerard, Sophie Groux-Degroote and Philippe Delannoy
Cells 2016, 5(4), 43; https://doi.org/10.3390/cells5040043 - 29 Nov 2016
Cited by 62 | Viewed by 9738
Abstract
Glycosylation is one of the most important modifications of proteins and lipids, and cell surface glycoconjugates are thought to play important roles in a variety of biological functions including cell-cell and cell-substrate interactions, bacterial adhesion, cell immunogenicity and cell signaling. Alterations of glycosylation [...] Read more.
Glycosylation is one of the most important modifications of proteins and lipids, and cell surface glycoconjugates are thought to play important roles in a variety of biological functions including cell-cell and cell-substrate interactions, bacterial adhesion, cell immunogenicity and cell signaling. Alterations of glycosylation are observed in number of diseases such as cancer and chronic inflammation. In that context, pro-inflammatory cytokines have been shown to modulate cell surface glycosylation by regulating the expression of glycosyltransferases involved in the biosynthesis of carbohydrate chains. These changes in cell surface glycosylation are also known to regulate cell signaling and could contribute to disease pathogenesis. This review summarizes our current knowledge of the glycosylation changes induced by pro-inflammatory cytokines, with a particular focus on cancer and cystic fibrosis, and their consequences on cell interactions and signaling. Full article
(This article belongs to the Special Issue Signal Transduction 2016)
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537 KiB  
Review
The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions
by Alexander V. Sirotkin
Cells 2016, 5(4), 42; https://doi.org/10.3390/cells5040042 - 24 Nov 2016
Cited by 30 | Viewed by 5352
Abstract
The present short review demonstrates the involvement of sirtuins (SIRTs) in the control of ovarian functions at various regulatory levels. External and endocrine factors can affect female reproduction via SIRTs-mammalian target of rapamycin (mTOR) system, which, via hormones and growth factors, can in [...] Read more.
The present short review demonstrates the involvement of sirtuins (SIRTs) in the control of ovarian functions at various regulatory levels. External and endocrine factors can affect female reproduction via SIRTs-mammalian target of rapamycin (mTOR) system, which, via hormones and growth factors, can in turn regulate basic ovarian functions (proliferation, apoptosis, secretory activity of ovarian cells, their response to upstream hormonal regulators, ovarian folliculo- and oogenesis, and fecundity). SIRTs and SIRTs-related signaling molecules and drugs regulating mTOR can be used for characterization, prediction, and regulation of ovarian functions, as well as for diagnostics and treatment of ovarian disorders. Full article
(This article belongs to the Special Issue Sirtuins in Aging and Diseases)
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2694 KiB  
Article
Prelamin A Accumulation Attenuates Rac1 Activity and Increases the Intrinsic Migrational Persistence of Aged Vascular Smooth Muscle Cells
by Lauren J. Porter, Mark R. Holt, Daniel Soong, Catherine M. Shanahan and Derek T. Warren
Cells 2016, 5(4), 41; https://doi.org/10.3390/cells5040041 - 15 Nov 2016
Cited by 12 | Viewed by 6149
Abstract
Vascular smooth muscle cell (VSMC) motility is essential during both physiological and pathological vessel remodeling. Although ageing has emerged as a major risk factor in the development of cardiovascular disease, our understanding of the impact of ageing on VSMC motility remains limited. Prelamin [...] Read more.
Vascular smooth muscle cell (VSMC) motility is essential during both physiological and pathological vessel remodeling. Although ageing has emerged as a major risk factor in the development of cardiovascular disease, our understanding of the impact of ageing on VSMC motility remains limited. Prelamin A accumulation is known to drive VSMC ageing and we show that presenescent VSMCs, that have accumulated prelamin A, display increased focal adhesion dynamics, augmented migrational velocity/persistence and attenuated Rac1 activity. Importantly, prelamin A accumulation in proliferative VSMCs, induced by depletion of the prelamin A processing enzyme FACE1, recapitulated the focal adhesion, migrational persistence and Rac1 phenotypes observed in presenescent VSMCs. Moreover, lamin A/C-depleted VSMCs also display reduced Rac1 activity, suggesting that prelamin A influences Rac1 activity by interfering with lamin A/C function at the nuclear envelope. Taken together, these data demonstrate that lamin A/C maintains Rac1 activity in VSMCs and prelamin A disrupts lamin A/C function to reduce Rac1 activity and induce migrational persistence during VSMC ageing. Full article
(This article belongs to the Collection Lamins and Laminopathies)
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2772 KiB  
Review
Airway Epithelial Cell Cilia and Obstructive Lung Disease
by Asma Yaghi and Myrna B. Dolovich
Cells 2016, 5(4), 40; https://doi.org/10.3390/cells5040040 - 11 Nov 2016
Cited by 105 | Viewed by 16072
Abstract
Airway epithelium is the first line of defense against exposure of the airway and lung to various inflammatory stimuli. Ciliary beating of airway epithelial cells constitutes an important part of the mucociliary transport apparatus. To be effective in transporting secretions out of the [...] Read more.
Airway epithelium is the first line of defense against exposure of the airway and lung to various inflammatory stimuli. Ciliary beating of airway epithelial cells constitutes an important part of the mucociliary transport apparatus. To be effective in transporting secretions out of the lung, the mucociliary transport apparatus must exhibit a cohesive beating of all ciliated epithelial cells that line the upper and lower respiratory tract. Cilia function can be modulated by exposures to endogenous and exogenous factors and by the viscosity of the mucus lining the epithelium. Cilia function is impaired in lung diseases such as COPD and asthma, and pharmacologic agents can modulate cilia function and mucus viscosity. Cilia beating is reduced in COPD, however, more research is needed to determine the structural-functional regulation of ciliary beating via all signaling pathways and how this might relate to the initiation or progression of obstructive lung diseases. Additionally, genotypes and how these can influence phenotypes and epithelial cell cilia function and structure should be taken into consideration in future investigations. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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5291 KiB  
Review
Self-Organization of Stem Cell Colonies and of Early Mammalian Embryos: Recent Experiments Shed New Light on the Role of Autonomy vs. External Instructions in Basic Body Plan Development
by Hans-Werner Denker
Cells 2016, 5(4), 39; https://doi.org/10.3390/cells5040039 - 25 Oct 2016
Cited by 10 | Viewed by 5662
Abstract
Organoids”, i.e., complex structures that can develop when pluripotent or multipotent stem cells are maintained in three-dimensional cultures, have become a new area of interest in stem cell research. Hopes have grown that when focussing experimentally on the mechanisms behind this [...] Read more.
Organoids”, i.e., complex structures that can develop when pluripotent or multipotent stem cells are maintained in three-dimensional cultures, have become a new area of interest in stem cell research. Hopes have grown that when focussing experimentally on the mechanisms behind this type of in vitro morphogenesis, research aiming at tissue and organ replacements can be boosted. Processes leading to the formation of organoids in vitro are now often addressed as self-organization, a term referring to the formation of complex tissue architecture in groups of cells without depending on specific instruction provided by other cells or tissues. The present article focuses on recent reports using the term self-organization in the context of studies on embryogenesis, specifically addressing pattern formation processes in human blastocysts attaching in vitro, or in colonies of pluripotent stem cells (“gastruloids”). These morphogenetic processes are of particular interest because, during development in vivo, they lead to basic body plan formation and individuation. Since improved methodologies like those employed by the cited authors became available, early embryonic pattern formation/self-organization appears to evolve now as a research topic of its own. This review discusses concepts concerning the involved mechanisms, focussing on autonomy of basic body plan development vs. dependence on external signals, as possibly provided by implantation in the uterus, and it addresses biological differences between an early mammalian embryo, e.g., a morula, and a cluster of pluripotent stem cells. It is concluded that, apart from being of considerable biological interest, the described type of research needs to be contemplated carefully with regard to ethical implications when performed with human cells. Full article
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1909 KiB  
Article
Segmental Aging Underlies the Development of a Parkinson Phenotype in the AS/AGU Rat
by Sohair M. Khojah, Anthony P. Payne, Dagmara McGuinness and Paul G. Shiels
Cells 2016, 5(4), 38; https://doi.org/10.3390/cells5040038 - 17 Oct 2016
Cited by 11 | Viewed by 5688
Abstract
There is a paucity of information on the molecular biology of aging processes in the brain. We have used biomarkers of aging (SA β-Gal, p16Ink4a, Sirt5, Sirt6, and Sirt7) to demonstrate the presence of an accelerated aging phenotype across different brain [...] Read more.
There is a paucity of information on the molecular biology of aging processes in the brain. We have used biomarkers of aging (SA β-Gal, p16Ink4a, Sirt5, Sirt6, and Sirt7) to demonstrate the presence of an accelerated aging phenotype across different brain regions in the AS/AGU rat, a spontaneous Parkinsonian mutant of PKCγ derived from a parental AS strain. P16INK4a expression was significantly higher in AS/AGU animals compared to age-matched AS controls (p < 0.001) and displayed segmental expression across various brain regions. The age-related expression of sirtuins similarly showed differences between strains and between brain regions. Our data clearly show segmental aging processes within the rat brain, and that these are accelerated in the AS/AGU mutant. The accelerated aging, Parkinsonian phenotype, and disruption to dopamine signalling in the basal ganglia in AS/AGU rats, suggests that this rat strain represents a useful model for studies of development and progression of Parkinson’s disease in the context of biological aging and may offer unique mechanistic insights into the biology of aging. Full article
(This article belongs to the Special Issue Sirtuins in Aging and Diseases)
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583 KiB  
Review
Implications and Assessment of the Elastic Behavior of Lamins in Laminopathies
by Subarna Dutta, Maitree Bhattacharyya and Kaushik Sengupta
Cells 2016, 5(4), 37; https://doi.org/10.3390/cells5040037 - 14 Oct 2016
Cited by 6 | Viewed by 5210
Abstract
Lamins are mechanosensitive and elastic components of the nuclear lamina that respond to external mechanical cues by altering gene regulation in a feedback mechanism. Numerous mutations in A-type lamins cause a plethora of diverse diseases collectively termed as laminopathies, the majority of which [...] Read more.
Lamins are mechanosensitive and elastic components of the nuclear lamina that respond to external mechanical cues by altering gene regulation in a feedback mechanism. Numerous mutations in A-type lamins cause a plethora of diverse diseases collectively termed as laminopathies, the majority of which are characterized by irregularly shaped, fragile, and plastic nuclei. These nuclei are challenged to normal mechanotransduction and lead to disease phenotypes. Here, we review our current understanding of the nucleocytoskeleton coupling in mechanotransduction mediated by lamins. We also present an up-to-date understanding of the methods used to determine laminar elasticity both at the bulk and single molecule level. Full article
(This article belongs to the Collection Lamins and Laminopathies)
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