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- Volume 18, Issue 13, 2012
Current Pharmaceutical Design - Volume 18, Issue 13, 2012
Volume 18, Issue 13, 2012
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Editorial [Hot Topic: Stem Cells and Tissue Regeneration (Executive Guest Editor: Roberta Di Pietro)]
More LessMankind has been always fascinated by the promise of longevity, immortality and rejuvenation. Both in Greek and in Roman mythology the difference between eternal life and eternal youth is a recurrent theme and paradigmatic is the story of Tithonos, the lover of Eos, Titan of the dawn, who obtained from Zeus the boon of immortality without eternal youth. For the first time in human history science is gaining tools to slow down, stop or even reverse biological ageing. Although life is regenerative by definition, not all the tissues possess the same regenerative potential and also those that regenerate well succumb to the ravages of ageing. The discovery of stem cells and recent advances in cellular and molecular biology have led to the development of novel therapeutic strategies aimed at the regeneration of many tissues that were injured by age, trauma or disease. For many years, bone marrow-derived stem cells were the primary source of stem cells for tissue engineering applications whereas recently more accessible sources have been identified and exploited. The emerging field of regenerative medicine started as an interdisciplinary approach to heal tissue defects and relied on the doctrine of cells, biomaterial scaffolds and signalling molecules. Although we are now at a stage in which engineering a complex tissue is no longer an unachievable goal, several issues still remain to be answered before stem cell application in clinical settings. We believe that an understanding of the molecules and processes that enable stem cells to initiate self-renewal and to divide, proliferate and then differentiate to rejuvenate damaged tissues might be the key to regenerative medicine and an eventual cure for many diseases. Thus, in the attempt to give a useful contribution to translational medicine approaches, the present hot topic issue has been organized in a first part including reviews focused on aspects of stem cell biology and basic research and a second part including reviews dealing with the most advanced stem cell-based therapeutic applications. The opening paper entitled “The architectural organization of human stem cell cycle regulatory machinery” by Gary S. Stein et al. is an outstanding review on the present state of knowledge on the nuclear architecture of human embryonic stem cells [1]. The authors clearly illustrate the differences between human embryonic stem cells and somatic cells in cell cycle control mechanisms and, particularly, in histone regulatory element components localization. The minimal organization of regulatory machinery in nuclei of pluripotent stem cells is underlined as an advantage to identify crucial components of the nuclear environment to apply to a broader context of regenerative medicine and drug design. In the following article “Chromatin modification and senescence” Giovanni Di Bernardo and the group of Umberto Galderisi, President of the Italian Society of Stem Cell Research (SCR Italy), efficiently summarize the complex issue of epigenetic changes occurring during the lifespan of a cell and, consequently, of the whole individual [2]. Particular attention is paid to different chromatin remodelling factors responsible for the unique chromatin organization of undifferentiated stem cells. Moreover, chromatin changes hallmark of normal or premature ageing are clearly described throughout the paper. The theme of ageing and senescence is continued with the review “Stem cell ageing and apoptosis” authored by Stefania Fulle et al. [3]. This is a clear and extensive overview of the current knowledge on the ageing process of stem cells and on the signalling pathways leading to programmed cell death. An ample section of the review is dedicated to haematopoietic stem cells, as a model of replicative ageing, and to satellite stem cells, as a model of chronological ageing. The authors conclude remarking that in spite of the huge number of studies and reports on stem cell ageing a more precise mechanistic understanding of stem cell behaviour is needed before this knowledge can be translated into human anti-ageing therapies. Among the recently discovered molecules able to influence stem cell function and biological processes, Stefania Crippa and the group of Maurilio Sampaolesi analyze the “Role of miRNAs in muscle stem cell biology: proliferation, differentiation and death” in an updated and comprehensive review [4]. Besides providing extensive information on miRNA biogenesis and degradation, the authors underscore novel and intriguing mechanisms regulating the fate of mesodermal stem cells (cardiac/skeletal muscle switch) suggesting that this transition may be due to the impaired expression of specific miRNAs in certain degenerative cardiac disorders.....
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The Architectural Organization of Human Stem Cell Cycle Regulatory Machinery
Two striking features of human embryonic stem cells that support biological activity are an abbreviated cell cycle and reduced complexity to nuclear organization. The potential implications for rapid proliferation of human embryonic stem cells within the context of sustaining pluripotency, suppressing phenotypic gene expression and linkage to simplicity in the architectural compartmentalization of regulatory machinery in nuclear microenvironments is explored. Characterization of the molecular and architectural commitment steps that license human embryonic stem cells to initiate histone gene expression is providing understanding of the principal regulatory mechanisms that control the G1/S phase transition in primitive pluripotent cells. From both fundamental regulatory and clinical perspectives, further understanding of the pluripotent cell cycle in relation to compartmentalization of regulatory machinery in nuclear microenvironments is relevant to applications of stem cells for regenerative medicine and new dimensions to therapy where traditional drug discovery strategies have been minimally effective.
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Chromatin Modification and Senescence
Authors: Giovanni Di Bernardo, Marilena Cipollaro and Umberto GalderisiCells are the fundamental structure composing our bodies and hence cellular decline (called senescence) contributes to ageing. Endogenous and exogenous stresses may induce cellular senescence. Stressors are mainly macromolecule damage events, which include: shortening of chromosome telomeres; non-telomeric DNA damage; excessive mitogenic signals, which may cause DNA damage; and non-genotoxic stress, such as perturbations to chromatin organization. For many years the analysis of chromatin perturbation as a leading event in triggering senescence has been overlooked. Now, it is well recognized that chromatin DNA packaging is not immune to the ravages of time. All eukaryotes experience changes in chromatin organization and gene-expression patterns as they age. This can be due to perturbation in the function of chromatin modifiers. In this review we will discuss the role in the senescence process of the different types of chromatin modifiers, such as the ATP-dependent chromatin remodelling complexes, the enzymes that covalently modify histone tails and proteins involved in DNA methylation.
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Stem Cell Ageing and Apoptosis
Ageing has been defined as the process of deterioration of many body functions over the lifespan of an individual. In spite of the number of different theories about ageing, there is a general consensus in identifying ageing effects in a reduced capacity to regenerate injured tissues or organs and an increased propensity to infections and cancer. In recent years the stem cell theory of ageing has gained much attention. Adult stem cells residing in mammalian tissues are essential for tissue homeostasis and repair throughout adult life. With advancing age, the highly regulated molecular signalling necessary to ensure proper cellular, tissue, and organ homeostasis loses coordination and leads, as a consequence, to a compromised potential of regeneration and repair of damaged cells and tissues. Although a complete comprehension of the molecular mechanisms involved in stem cell ageing and apoptosis is far to be reached, recent studies are beginning to unravel the processes involved in stem cell ageing, particularly in adult skeletal muscle stem cells, namely satellite cells. Thus, the focus of this review is to analyse the relationship between stem cell ageing and apoptosis with a peculiar attention to human satellite cells as compared to haematopoietic stem cells. Undoubtedly, the knowledge of age-related changes of stem cells will help in understanding the ageing process itself and will provide novel therapeutic challenges for improved tissue regeneration.
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Role of miRNAs in Muscle Stem Cell Biology: Proliferation, Differentiation and Death
Authors: Stefania Crippa, Marco Cassano and Maurilio SampaolesimiRNAs are small non-coding RNAs that regulate post-transcriptionally gene expression by degradation or translational repression of specific target mRNAs. In the 90s, lin-4 and let-7 were firstly identified as small regulatory RNAs able to control C. elegans larval development, by specifically targeting the 3'UTR of lin-14 and lin-28, respectively. These findings have introduced a novel and wide layer of complexity in the regulation of mRNA and protein expression. Lin-4 and let-7 are now considered the founding members of an abundant class of small fine-tuned RNAs, called microRNAs (miRNAs), in viruses, green algae, plants, flies, worms, and in mammals. In humans, the estimated number of genes encoding for miRNAs is as high as 1000 and around 30% of the protein-coding genes are post-transcriptionally controlled by miRNAs. This article reviews the role of miRNAs in regulating several biological responses in muscle cells, ranging from proliferation, differentiation and adaptation to stress cues. Cardiac and skeletal muscles are powerful examples to summarize the activity of miRNAs in cell fate specification, lineage differentiation and metabolic pathways. Indeed, specific miRNAs control the number of proliferating muscle progenitors to guarantee the proper formation of the heart and muscle fibers and to assure the self-renewal of muscle progenitors during adult tissue regeneration. On the other side, several other miRNAs promote the differentiation of muscle progenitors into skeletal myofibers or into cardiomyocytes, where metabolic activity, survival and remodeling process in response to stress, injury and chronic diseases are also fine-tuned by miRNAs.
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The Use of Proteomics for Systematic Analysis of Normal and Transformed Hematopoietic Stem Cells
Authors: Sara Cadeco, Andrew J.K. Williamson and Anthony D. WhettonBlood cell production involves the commitment and differentiation of hematopoietic stem cells to committed progenitor cells which undergo a programmed development to form mature cells such as neutrophils, macrophages and lymphocytes. This complex process can be disrupted in diseases such as the leukemias and myeloproliferative disorders by oncogenes such as protein tyrosine kinases. The analysis of expression patterns for specific genes suggests that the regulation of protein expression can be achieved in a posttranslational fashion. Post-translational protein modification, such as phosphorylation and acetylation govern events in blood cell production and yet cannot be measured using conventional molecular biology approaches. For this reason a suite of techniques in mass spectrometry needs to be applied to define regulation and disregulation in normal and abnormal hematopoiesis. These approaches include discovery proteomics with relative quantification of thousands of proteins. Alternatively targeted examination of a single protein to identify its interaction partners or post-translational modifications using mass spectrometry reveals much mechanistic detail. The use of mass spectrometry and proteomics approaches in stem cell and leukemia studies has thus far revealed a good deal of information on hematopoiesis. Further application of the proteomics approach is a necessity to gain true insight into regulatory processes governing the production of billions of blood cells a day, and ways in which that process can be manipulated to therapeutic advantage.
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Nuclear PI-PLCβ1 and Myelodysplastic Syndromes: Genetics and Epigenetics
Among cellular second messengers inositides play key roles in signal transduction pathways. Indeed, nuclear phosphoinositide- specific phospholipase C (PI-PLC) β1 and Akt are involved in cell cycle progression and apoptosis. Nuclear lipid metabolism has raised interest in the last years, mainly because of its link with haematopoietic progenitor cells. Myelodysplastic syndromes (MDS) are stem-cell clonal diseases characterized by an impaired hempoiesis and a differentiation defect in one or more of the bone marrow lineages, often leading to progression to acute myeloid leukaemia (AML). The MDS evolution to AML is not completely understood but, at a molecular level, the nuclear inositide signalling pathways can play an important role in this process.
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Neural Stem Cell Niches in Health and Diseases
Authors: Ilaria Decimo, Francesco Bifari, Mauro Krampera and Guido FumagalliPresence of neural stem cells in adult mammalian brains, including human, has been clearly demonstrated by several studies. The functional significance of adult neurogenesis is slowly emerging as new data indicate the sensitivity of this event to several “every day” external stimuli such as physical activity, learning, enriched environment, aging, stress and drugs. In addition, neurogenesis appears to be instrumental for task performance involving complex cognitive functions. Despite the growing body of evidence on the functional significance of NSC and despite the bulk of data concerning the molecular and cellular properties of NSCs and their niches, several critical questions are still open. In this work we review the literature describing i) old and new sites where NSC niche have been found in the CNS; ii) the intrinsic factors regulating the NSC potential; iii) the extrinsic factors that form the niche microenvironment. Moreover, we analyse NSC niche activation in iv) physiological and v) pathological conditions. Given the not static nature of NSCs that continuously change phenotype in response to environmental clues, a unique “identity card” for NSC identification is still lacking. Moreover, the multiple location of NSC niches that increase in diseases, leaves open the question of whether and how these structures communicate throughout long distance. We propose a model where all the NSC niches in the CNS may be connected in a functional network using the threads of the meningeal net as tracks.
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Targeting the Cancer Initiating Cell: The Ultimate Target for Cancer Therapy
Authors: James A. McCubrey, Linda S. Steelman, Stephen L. Abrams, Negin Misaghian, William H. Chappell, Jorg Basecke, Ferdinando Nicoletti, Massimo Libra, Giovanni Ligresti, Francac Stivala, Danijela Maksimovic-Ivanic, Sanja Mijatovic, Giuseppeo Montalto, Melchiorre Cervello, Piotr Laidler, Antonio Bonati, Camilla Evangelisti, Lucio Cocco and Alberto M. MartelliAn area of therapeutic interest in cancer biology and treatment is targeting the cancer stem cell, more appropriately referred to as the cancer initiating cell (CIC). CICs comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts in genetically modified murine models. CICs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation and metastasis. CICs may lay dormant after various cancer therapies which eliminate the more rapidly proliferating bulk cancer (BC) mass. However, CICs may remerge after therapy is discontinued as they may represent cells which were either intrinsically resistant to the original therapeutic approach or they have acquired mutations which confer resistance to the primary therapy. In experimental mouse tumor transplant models, CICs have the ability to transfer the tumor to immunocompromised mice very efficiently while the BCs are not able to do so as effectively. Often CICs display increased expression of proteins involved in drug resistance and hence they are intrinsically resistant to many chemotherapeutic approaches. Furthermore, the CICs may be in a suspended state of proliferation and not sensitive to common chemotherapeutic and radiological approaches often employed to eliminate the rapidly proliferating BCs. Promising therapeutic approaches include the targeting of certain signal transduction pathways (e.g., RAC, WNT, PI3K, PML) with small molecule inhibitors or targeting specific cell-surface molecules (e.g., CD44), with effective cytotoxic antibodies. The existence of CICs could explain the high frequency of relapse and resistance to many currently used cancer therapies. New approaches should be developed to effectively target the CIC which could vastly improve cancer therapies and outcomes. This review will discuss recent concepts of targeting CICs in certain leukemia models.
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The Combined Use of Mesenchymal Stromal Cells and Scaffolds for Bone Repair
Authors: Gabriela Ciapetti, Donatella Granchi and Nicola BaldiniA general principle of stem cell therapy is to exploit the natural ability of the human body to heal through the process of regeneration. Here, we review the current status of cell therapy based on adult mesenchymal stem cells (MSC) with emphasis on therapeutic application in bone-related diseases. The main issues for an effective bone engineering strategy include: - A sufficient number of bone-forming cells, where cell yield, separation, expansion, commitment, as well as patient age, are all variables to be considered; - An ECM-like scaffold conductive for and informative to cells, where structural/physico-chemical/mechanical parameters, administration form (injectable or free-form), and degradation rate have to be tuned according to the clinical application; - Biochemical signals, such as growth factors/cytokines to induce osteogenic differentiation, where the choice between autogenous or exogenous sourcing, dose, timing, etc. are critical; - An adequate blood supply, provided by angiogenetic factors, pre-vascularization, pre-implant co-culture of vessel and bone progenitors. We also discuss the safety and efficacy of different approaches, as well as bottlenecks hampering rapid translation of adult MSC therapy from the laboratories to the clinics. A central paradigm for the effective regeneration of bone tissue is the re-creation at the site of injury of a microenvironment as close as possible to the natural MSC repository in the body. This would allow adult MSC to serve as cellular factories, i.e. to express paracrine activity in situ by secretion of inflammatory and reparative cytokines and to cooperate with other cells. The results from a wide array of in vitro and in vivo studies, as well as from some clinical trials, are expanding the range of clinical protocols for bone repair, that is the ultimate goal of orthopaedics.
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Clinical Applications and Biosafety of Human Adult Mesenchymal Stem Cells
Authors: E. Mariani and A. FacchiniMesenchymal Stem Cells (MSCs) are a population of adherent cells that can differentiate into mesenchymal lineage populations (cartilage, bone and fat tissue). In addition, they seem to be able to differentiate also into a broader type of lineages other than the original mesodermal germ layer. Bone marrow MSCs are a standard in the field of adult stem cell biology and clinical applications; however adipose-derived MSCs are becoming an attractive alternative due to their minimally invasive accessibility and availability in the body. MSCs modulate several effector immune functions by interacting both with innate and adoptive immune responses. Several local signals from the tissue microenvironment, together with cytokine and soluble factors released by MSCs influence anti-inflammatory and tissue repair properties of infused MSCs. Therefore, cellular therapies utilizing ex vivo expanded MSCs may be an interesting approach for inflammatory and autoimmune diseases. Biosafety is still one of the most important aspects; therefore the production of clinical-grade MSCs requires the careful identification and control of all the phases of cell manipulation and release. Many clinical applications of adult MSCs are in progress and are using bone marrow or adipose tissue-derived MSCs for the treatment of Graft Versus Host Disease (GVHD), inflammatory joint diseases and osteocartilagineous defects, digestive tract, cardiovascular and neurological diseases.
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Amniotic Fluid Stem Cells: a Promising Therapeutic Resource for Cell-Based Regenerative Therapy
Stem cells have been proposed as a powerful tool in the treatment of several human diseases, both for their ability to represent a source of new cells to replace those lost due to tissue injuries or degenerative diseases, and for the ability of produce trophic molecules able to minimize damage and promote recovery in the injured tissue. Different cell types, such as embryonic, fetal or adult stem cells, human fetal tissues and genetically engineered cell lines, have been tested for their ability to replace damaged cells and to restore the tissue function after transplantation. Amniotic fluid -derived Stem cells (AFS) are considered a novel resource for cell transplantation therapy, due to their high renewal capacity, the “in vitro” expression of embryonic cell lineage markers, and the ability to differentiate in tissues derived from all the three embryonic layers. Moreover, AFS do not produce teratomas when transplanted into animals and are characterized by a low antigenicity, which could represent an advantage for cell transplantation or cell replacement therapy. The present review focuses on the biological features of AFS, and on their potential use in the treatment of pathological conditions such as ischemic brain injury and bone damages.
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Volumes & issues
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)