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Cells, Volume 1, Issue 4 (December 2012) – 34 articles , Pages 667-1327

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10 KiB  
Correction
Publisher's Note added on 24 January 2014
by Shu-Kun Lin
Cells 2012, 1(4), 951-960; https://doi.org/10.3390/cells1040951 - 24 Jan 2014
Cited by 40 | Viewed by 3959
Abstract
Publisher's Note added on 24 January 2014: Cells, Volume 1, Pages 951-960 are taken as blank pages because of a pagination error in the preceding paper. We apologize for any inconvenience caused to our readers. Full article
684 KiB  
Review
Cytoskeletal Regulation of Dermal Regeneration
by Xanthe L. Strudwick and Allison J. Cowin
Cells 2012, 1(4), 1313-1327; https://doi.org/10.3390/cells1041313 - 19 Dec 2012
Cited by 14 | Viewed by 7281
Abstract
Wound healing results in the repair of injured tissues however fibrosis and scar formation are, more often than not the unfortunate consequence of this process. The ability of lower order vertebrates and invertebrates to regenerate limbs and tissues has been all but lost [...] Read more.
Wound healing results in the repair of injured tissues however fibrosis and scar formation are, more often than not the unfortunate consequence of this process. The ability of lower order vertebrates and invertebrates to regenerate limbs and tissues has been all but lost in mammals; however, there are some instances where glimpses of mammalian regenerative capacity do exist. Here we describe the unlocked potential that exists in mammals that may help us understand the process of regeneration post-injury and highlight the potential role of the actin cytoskeleton in this process. The precise function and regulation of the cytoskeleton is critical to the success of the healing process and its manipulation may therefore facilitate regenerative healing. The gelsolin family of actin remodelling proteins in particular has been shown to have important functions in wound healing and family member Flightless I (Flii) is involved in both regeneration and repair. Understanding the interactions between different cytoskeletal proteins and their dynamic control of processes including cellular adhesion, contraction and motility may assist the development of therapeutics that will stimulate regeneration rather than repair. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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222 KiB  
Review
Time to Reconsider Stem Cell Induction Strategies
by Hans-Werner Denker
Cells 2012, 1(4), 1293-1312; https://doi.org/10.3390/cells1041293 - 17 Dec 2012
Cited by 21 | Viewed by 7782
Abstract
Recent developments in stem cell research suggest that it may be time to reconsider the current focus of stem cell induction strategies. During the previous five years, approximately, the induction of pluripotency in somatic cells, i.e., the generation of so-called ‘induced pluripotent [...] Read more.
Recent developments in stem cell research suggest that it may be time to reconsider the current focus of stem cell induction strategies. During the previous five years, approximately, the induction of pluripotency in somatic cells, i.e., the generation of so-called ‘induced pluripotent stem cells’ (iPSCs), has become the focus of ongoing research in many stem cell laboratories, because this technology promises to overcome limitations (both technical and ethical) seen in the production and use of embryonic stem cells (ESCs). A rapidly increasing number of publications suggest, however, that it is now possible to choose instead other, alternative ways of generating stem and progenitor cells bypassing pluripotency. These new strategies may offer important advantages with respect to ethics, as well as to safety considerations. The present communication discusses why these strategies may provide possibilities for an escape from the dilemma presented by pluripotent stem cells (self-organization potential, cloning by tetraploid complementation, patenting problems and tumor formation risk). Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
432 KiB  
Review
Signals and Cells Involved in Regulating Liver Regeneration
by Liang-I. Kang, Wendy M. Mars and George K. Michalopoulos
Cells 2012, 1(4), 1261-1292; https://doi.org/10.3390/cells1041261 - 13 Dec 2012
Cited by 102 | Viewed by 14621
Abstract
Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, [...] Read more.
Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF) and their receptors (MET and EGFR). In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the regenerative process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes fail to participate in this process, the biliary compartment is mobilized to generate populations of progenitor cells which transdifferentiate into hepatocytes and restore liver size. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Neovascularization in Tissue Engineering
by Jennifer C.-Y. Chung and Dominique Shum-Tim
Cells 2012, 1(4), 1246-1260; https://doi.org/10.3390/cells1041246 - 11 Dec 2012
Cited by 156 | Viewed by 6505
Abstract
A prerequisite for successful tissue engineering is adequate vascularization that would allow tissue engineering constructs to survive and grow. Angiogenic growth factors, alone and in combination, have been used to achieve this, and gene therapy has been used as a tool to enable [...] Read more.
A prerequisite for successful tissue engineering is adequate vascularization that would allow tissue engineering constructs to survive and grow. Angiogenic growth factors, alone and in combination, have been used to achieve this, and gene therapy has been used as a tool to enable sustained release of these angiogenic proteins. Cell-based therapy using endothelial cells and their precursors presents an alternative approach to tackling this challenge. These studies have occurred on a background of advancements in scaffold design and assays for assessing neovascularization. Finally, several studies have already attempted to translate research in neovascularization to clinical use in the blossoming field of therapeutic angiogenesis. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Macro and Microfluidic Flows for Skeletal Regenerative Medicine
by Brandon D. Riehl and Jung Yul Lim
Cells 2012, 1(4), 1225-1245; https://doi.org/10.3390/cells1041225 - 11 Dec 2012
Cited by 156 | Viewed by 8552
Abstract
Fluid flow has a great potential as a cell stimulatory tool for skeletal regenerative medicine, because fluid flow-induced bone cell mechanotransduction in vivo plays a critical role in maintaining healthy bone homeostasis. Applications of fluid flow for skeletal regenerative medicine are [...] Read more.
Fluid flow has a great potential as a cell stimulatory tool for skeletal regenerative medicine, because fluid flow-induced bone cell mechanotransduction in vivo plays a critical role in maintaining healthy bone homeostasis. Applications of fluid flow for skeletal regenerative medicine are reviewed at macro and microscale. Macroflow in two dimensions (2D), in which flow velocity varies along the normal direction to the flow, has explored molecular mechanisms of bone forming cell mechanotransduction responsible for flow-regulated differentiation, mineralized matrix deposition, and stem cell osteogenesis. Though 2D flow set-ups are useful for mechanistic studies due to easiness in in situ and post-flow assays, engineering skeletal tissue constructs should involve three dimensional (3D) flows, e.g., flow through porous scaffolds. Skeletal tissue engineering using 3D flows has produced promising outcomes, but 3D flow conditions (e.g., shear stress vs. chemotransport) and scaffold characteristics should further be tailored. Ideally, data gained from 2D flows may be utilized to engineer improved 3D bone tissue constructs. Recent microfluidics approaches suggest a strong potential to mimic in vivo microscale interstitial flows in bone. Though there have been few microfluidics studies on bone cells, it was demonstrated that microfluidic platform can be used to conduct high throughput screening of bone cell mechanotransduction behavior under biomimicking flow conditions. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Adaptive and Pathogenic Responses to Stress by Stem Cells during Development
by Ladan Mansouri, Yufen Xie and Daniel A. Rappolee
Cells 2012, 1(4), 1197-1224; https://doi.org/10.3390/cells1041197 - 10 Dec 2012
Cited by 35 | Viewed by 11159
Abstract
Cellular stress is the basis of a dose-dependent continuum of responses leading to adaptive health or pathogenesis. For all cells, stress leads to reduction in macromolecular synthesis by shared pathways and tissue and stress-specific homeostatic mechanisms. For stem cells during embryonic, fetal, and [...] Read more.
Cellular stress is the basis of a dose-dependent continuum of responses leading to adaptive health or pathogenesis. For all cells, stress leads to reduction in macromolecular synthesis by shared pathways and tissue and stress-specific homeostatic mechanisms. For stem cells during embryonic, fetal, and placental development, higher exposures of stress lead to decreased anabolism, macromolecular synthesis and cell proliferation. Coupled with diminished stem cell proliferation is a stress-induced differentiation which generates minimal necessary function by producing more differentiated product/cell. This compensatory differentiation is accompanied by a second strategy to insure organismal survival as multipotent and pluripotent stem cells differentiate into the lineages in their repertoire. During stressed differentiation, the first lineage in the repertoire is increased and later lineages are suppressed, thus prioritized differentiation occurs. Compensatory and prioritized differentiation is regulated by at least two types of stress enzymes. AMP-activated protein kinase (AMPK) which mediates loss of nuclear potency factors and stress-activated protein kinase (SAPK) that does not. SAPK mediates an increase in the first essential lineage and decreases in later lineages in placental stem cells. The clinical significance of compensatory and prioritized differentiation is that stem cell pools are depleted and imbalanced differentiation leads to gestational diseases and long term postnatal pathologies. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Review
Genetic Systems to Investigate Regulation of Oncogenes and Tumour Suppressor Genes in Drosophila
by Jue Er Amanda Lee, Nicola J. Cranna, Arjun S. Chahal and Leonie M. Quinn
Cells 2012, 1(4), 1182-1196; https://doi.org/10.3390/cells1041182 - 05 Dec 2012
Cited by 1 | Viewed by 8714
Abstract
Animal growth requires coordination of cell growth and cell cycle progression with developmental signaling. Loss of cell cycle control is extremely detrimental, with reduced cycles leading to impaired organ growth and excessive proliferation, potentially resulting in tissue overgrowth and driving tumour initiation. Due [...] Read more.
Animal growth requires coordination of cell growth and cell cycle progression with developmental signaling. Loss of cell cycle control is extremely detrimental, with reduced cycles leading to impaired organ growth and excessive proliferation, potentially resulting in tissue overgrowth and driving tumour initiation. Due to the high level of conservation between the cell cycle machinery of Drosophila and humans, the appeal of the fly model continues to be the means with which we can use sophisticated genetics to provide novel insights into mammalian growth and cell cycle control. Over the last decade, there have been major additions to the genetic toolbox to study development in Drosophila. Here we discuss some of the approaches available to investigate the potent growth and cell cycle properties of the Drosophila counterparts of prominent cancer genes, with a focus on the c-Myc oncoprotein and the tumour suppressor protein FIR (Hfp in flies), which behaves as a transcriptional repressor of c-Myc. Full article
(This article belongs to the Special Issue Imaging in Cell Biology and Development)
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Article
Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats
by Qing Zhang, Christopher Miller, Jesse Bible, Jiliang Li, Xiaoqing Xu, Nozer Mehta, James Gilligan, Agnès Vignery and Jodi A. Carlson Scholz
Cells 2012, 1(4), 1168-1181; https://doi.org/10.3390/cells1041168 - 05 Dec 2012
Cited by 6 | Viewed by 8538
Abstract
Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased [...] Read more.
Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Article
Apoptotic Volume Decrease (AVD) Is Independent of Mitochondrial Dysfunction and Initiator Caspase Activation
by Emi Maeno, Takeshi Tsubata and Yasunobu Okada
Cells 2012, 1(4), 1156-1167; https://doi.org/10.3390/cells1041156 - 05 Dec 2012
Cited by 31 | Viewed by 6661
Abstract
Persistent cell shrinkage is a major hallmark of apoptotic cell death. The early-phase shrinkage, which starts within 30−120 min after apoptotic stimulation and is called apoptotic volume decrease (AVD), is known to be accomplished by activation of K+ channels and volume-sensitive outwardly [...] Read more.
Persistent cell shrinkage is a major hallmark of apoptotic cell death. The early-phase shrinkage, which starts within 30−120 min after apoptotic stimulation and is called apoptotic volume decrease (AVD), is known to be accomplished by activation of K+ channels and volume-sensitive outwardly rectifying (VSOR) Cl channels in a manner independent of caspase-3 activation. However, it is controversial whether AVD depends on apoptotic dysfunction of mitochondria and activation of initiator caspases. Here, we observed that AVD is induced not only by a mitochondrial apoptosis inducer, staurosporine (STS), in mouse B lymphoma WEHI-231 cells, but also by ligation of the death receptor Fas in human B lymphoblastoid SKW6.4 cells, which undergo Fas-mediated apoptosis without involving mitochondria. Overexpression of Bcl-2 failed to inhibit the STS-induced AVD in WEHI-231 cells. These results indicate that AVD does not require the mitochondrial pathway of apoptosis. In human epithelial HeLa cells stimulated with anti-Fas antibody or STS, the AVD induction was found to precede activation of caspase-8 and caspase-9 and to be resistant to pan-caspase blockers. Thus, it is concluded that the AVD induction is an early event independent of the mitochondrial apoptotic signaling pathway and initiator caspase activation. Full article
(This article belongs to the Special Issue Apoptosis)
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Article
The Anti-Apoptotic Role of Neuroglobin
by Thomas Brittain
Cells 2012, 1(4), 1133-1155; https://doi.org/10.3390/cells1041133 - 23 Nov 2012
Cited by 48 | Viewed by 8549
Abstract
The small heme-protein neuroglobin is expressed at high concentrations in certain brain neurons and in the rod cells of the retina. This paper reviews the many studies which have recently identified a protective role for neuroglobin, in a wide range of situations involving [...] Read more.
The small heme-protein neuroglobin is expressed at high concentrations in certain brain neurons and in the rod cells of the retina. This paper reviews the many studies which have recently identified a protective role for neuroglobin, in a wide range of situations involving apoptotic cell death. The origins of this protective mechanism are discussed in terms of both experimental results and computational modeling of the intrinsic pathway of apoptosis, which shows that neuroglobin can intervene in this process by a reaction with released mitochondrial cytochrome c. An integrated model, based on the various molecular actions of both neuroglobin and cytochrome c, is developed, which accounts for the cellular distribution of neuroglobin. Full article
(This article belongs to the Special Issue Apoptosis)
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Article
Intravital Microscopy Reveals Differences in the Kinetics of Endocytic Pathways between Cell Cultures and Live Animals
by Andrius Masedunskas, Natalie Porat-Shliom, Kamil Rechache, Myo-Pale' Aye and Roberto Weigert
Cells 2012, 1(4), 1121-1132; https://doi.org/10.3390/cells1041121 - 16 Nov 2012
Cited by 58 | Viewed by 7061
Abstract
Intravital microscopy has enabled imaging of the dynamics of subcellular structures in live animals, thus opening the door to investigating membrane trafficking under physiological conditions. Here, we sought to determine whether the architecture and the environment of a fully developed tissue influences the [...] Read more.
Intravital microscopy has enabled imaging of the dynamics of subcellular structures in live animals, thus opening the door to investigating membrane trafficking under physiological conditions. Here, we sought to determine whether the architecture and the environment of a fully developed tissue influences the dynamics of endocytic processes. To this aim, we imaged endocytosis in the stromal cells of rat salivary glands both in situ and after they were isolated and cultured on a solid surface. We found that the internalization of transferrin and dextran, two molecules that traffic via distinct mechanisms, is substantially altered in cultured cells, supporting the idea that the three dimensional organization of the tissue and the cues generated by the surrounding environment strongly affect membrane trafficking events. Full article
(This article belongs to the Special Issue Imaging in Cell Biology and Development)
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169 KiB  
Review
Surface Markers for Chondrogenic Determination: A Highlight of Synovium-Derived Stem Cells
by Douglas D. Campbell and Ming Pei
Cells 2012, 1(4), 1107-1120; https://doi.org/10.3390/cells1041107 - 16 Nov 2012
Cited by 28 | Viewed by 7108
Abstract
Cartilage tissue engineering is a promising field in regenerative medicine that can provide substantial relief to people suffering from degenerative cartilage disease. Current research shows the greatest chondrogenic potential for healthy articular cartilage growth with minimal hypertrophic differentiation to be from mesenchymal stem [...] Read more.
Cartilage tissue engineering is a promising field in regenerative medicine that can provide substantial relief to people suffering from degenerative cartilage disease. Current research shows the greatest chondrogenic potential for healthy articular cartilage growth with minimal hypertrophic differentiation to be from mesenchymal stem cells (MSCs) of synovial origin. These stem cells have the capacity for differentiation into multiple cell lineages related to mesenchymal tissue; however, evidence exists for cell surface markers that specify a greater potential for chondrogenesis than other differentiation fates. This review will examine relevant literature to summarize the chondrogenic differentiation capacities of tested synovium-derived stem cell (SDSC) surface markers, along with a discussion about various other markers that may hold potential, yet require further investigation. With this information, a potential clinical benefit exists to develop a screening system for SDSCs that will produce the healthiest articular cartilage possible. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Article
Cellular Stress Following Water Deprivation in the Model Legume Lotus japonicus
by Marco Betti, Carmen Pérez-Delgado, Margarita García-Calderón, Pedro Díaz, Jorge Monza and Antonio J. Márquez
Cells 2012, 1(4), 1089-1106; https://doi.org/10.3390/cells1041089 - 13 Nov 2012
Cited by 29 | Viewed by 7945
Abstract
Drought stress is one of the most important factors in the limitation of plant productivity worldwide. In order to cope with water deprivation, plants have adopted several strategies that produce major changes in gene expression. In this paper, the response to drought stress [...] Read more.
Drought stress is one of the most important factors in the limitation of plant productivity worldwide. In order to cope with water deprivation, plants have adopted several strategies that produce major changes in gene expression. In this paper, the response to drought stress in the model legume Lotus japonicus was studied using a transcriptomic approach. Drought induced an extensive reprogramming of the transcriptome as related to various aspects of cellular metabolism, including genes involved in photosynthesis, amino acid metabolism and cell wall metabolism, among others. A particular focus was made on the genes involved in the cellular stress response. Key genes involved in the control of the cell cycle, antioxidant defense and stress signaling, were modulated as a consequence of water deprivation. Genes belonging to different families of transcription factors were also highly responsive to stress. Several of them were homologies to known stress-responsive genes from the model plant Arabidopsis thaliana, while some novel transcription factors were peculiar to the L. japonicus drought stress response. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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448 KiB  
Review
Mesenchymal Stem or Stromal Cells from Amnion and Umbilical Cord Tissue and Their Potential for Clinical Applications
by Andrea Lindenmair, Tim Hatlapatka, Gregor Kollwig, Simone Hennerbichler, Christian Gabriel, Susanne Wolbank, Heinz Redl and Cornelia Kasper
Cells 2012, 1(4), 1061-1088; https://doi.org/10.3390/cells1041061 - 12 Nov 2012
Cited by 136 | Viewed by 12161
Abstract
Mesenchymal stem or stromal cells (MSC) have proven to offer great promise for cell-based therapies and tissue engineering applications, as these cells are capable of extensive self-renewal and display a multilineage differentiation potential. Furthermore, MSC were shown to exhibit immunomodulatory properties and display [...] Read more.
Mesenchymal stem or stromal cells (MSC) have proven to offer great promise for cell-based therapies and tissue engineering applications, as these cells are capable of extensive self-renewal and display a multilineage differentiation potential. Furthermore, MSC were shown to exhibit immunomodulatory properties and display supportive functions through parakrine effects. Besides bone marrow (BM), still today the most common source of MSC, these cells were found to be present in a variety of postnatal and extraembryonic tissues and organs as well as in a large variety of fetal tissues. Over the last decade, the human umbilical cord and human amnion have been found to be a rich and valuable source of MSC that is bio-equivalent to BM-MSC. Since these tissues are discarded after birth, the cells are easily accessible without ethical concerns. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Regenerative Effects of Mesenchymal Stem Cells: Contribution of Muse Cells, a Novel Pluripotent Stem Cell Type that Resides in Mesenchymal Cells
by Shohei Wakao, Yasumasa Kuroda, Fumitaka Ogura, Taeko Shigemoto and Mari Dezawa
Cells 2012, 1(4), 1045-1060; https://doi.org/10.3390/cells1041045 - 08 Nov 2012
Cited by 64 | Viewed by 15882
Abstract
Mesenchymal stem cells (MSCs) are easily accessible and safe for regenerative medicine. MSCs exert trophic, immunomodulatory, anti-apoptotic, and tissue regeneration effects in a variety of tissues and organs, but their entity remains an enigma. Because MSCs are generally harvested from mesenchymal tissues, such [...] Read more.
Mesenchymal stem cells (MSCs) are easily accessible and safe for regenerative medicine. MSCs exert trophic, immunomodulatory, anti-apoptotic, and tissue regeneration effects in a variety of tissues and organs, but their entity remains an enigma. Because MSCs are generally harvested from mesenchymal tissues, such as bone marrow, adipose tissue, or umbilical cord as adherent cells, MSCs comprise crude cell populations and are heterogeneous. The specific cells responsible for each effect have not been clarified. The most interesting property of MSCs is that, despite being adult stem cells that belong to the mesenchymal tissue lineage, they are able to differentiate into a broad spectrum of cells beyond the boundary of mesodermal lineage cells into ectodermal or endodermal lineages, and repair tissues. The broad spectrum of differentiation ability and tissue-repairing effects of MSCs might be mediated in part by the presence of a novel pluripotent stem cell type recently found in adult human mesenchymal tissues, termed multilineage-differentiating stress enduring (Muse) cells. Here we review recently updated studies of the regenerative effects of MSCs and discuss their potential in regenerative medicine. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Article
A Novel Type III Endosome Transmembrane Protein, TEMP
by Rajith N. Aturaliya, Markus C. Kerr and Rohan D. Teasdale
Cells 2012, 1(4), 1029-1044; https://doi.org/10.3390/cells1041029 - 05 Nov 2012
Cited by 71 | Viewed by 7066
Abstract
As part of a high-throughput subcellular localisation project, the protein encoded by the RIKEN mouse cDNA 2610528J11 was expressed and identified to be associated with both endosomes and the plasma membrane. Based on this, we have assigned the name TEMP for Type III [...] Read more.
As part of a high-throughput subcellular localisation project, the protein encoded by the RIKEN mouse cDNA 2610528J11 was expressed and identified to be associated with both endosomes and the plasma membrane. Based on this, we have assigned the name TEMP for Type III Endosome Membrane Protein. TEMP encodes a short protein of 111 amino acids with a single, alpha-helical transmembrane domain. Experimental analysis of its membrane topology demonstrated it is a Type III membrane protein with the amino-terminus in the lumenal, or extracellular region, and the carboxy-terminus in the cytoplasm. In addition to the plasma membrane TEMP was localized to Rab5 positive early endosomes, Rab5/Rab11 positive recycling endosomes but not Rab7 positive late endosomes. Video microscopy in living cells confirmed TEMP's plasma membrane localization and identified the intracellular endosome compartments to be tubulovesicular. Overexpression of TEMP resulted in the early/recycling endosomes clustering at the cell periphery that was dependent on the presence of intact microtubules. The cellular function of TEMP cannot be inferred based on bioinformatics comparison, but its cellular distribution between early/recycling endosomes and the plasma membrane suggests a role in membrane transport. Full article
(This article belongs to the Special Issue Imaging in Cell Biology and Development)
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Review
Decellularized Tendon Extracellular Matrix—A Valuable Approach for Tendon Reconstruction?
by Gundula Schulze-Tanzil, Onays Al-Sadi, Wolfgang Ertel and Anke Lohan
Cells 2012, 1(4), 1010-1028; https://doi.org/10.3390/cells1041010 - 05 Nov 2012
Cited by 41 | Viewed by 13586
Abstract
Tendon healing is generally a time-consuming process and often leads to a functionally altered reparative tissue. Using degradable scaffolds for tendon reconstruction still remains a compromise in view of the required high mechanical strength of tendons. Regenerative approaches based on natural decellularized allo- [...] Read more.
Tendon healing is generally a time-consuming process and often leads to a functionally altered reparative tissue. Using degradable scaffolds for tendon reconstruction still remains a compromise in view of the required high mechanical strength of tendons. Regenerative approaches based on natural decellularized allo- or xenogenic tendon extracellular matrix (ECM) have recently started to attract interest. This ECM combines the advantages of its intrinsic mechanical competence with that of providing tenogenic stimuli for immigrating cells mediated, for example, by the growth factors and other mediators entrapped within the natural ECM. A major restriction for their therapeutic application is the mainly cell-associated immunogenicity of xenogenic or allogenic tissues and, in the case of allogenic tissues, also the risk of disease transmission. A survey of approaches for tendon reconstruction using cell-free tendon ECM is presented here, whereby the problems associated with the decellularization procedures, the success of various recellularization strategies, and the applicable cell types will be thoroughly discussed. Encouraging in vivo results using cell-free ECM, as, for instance, in rabbit models, have already been reported. However, in comparison to native tendon, cells remain mostly inhomogeneously distributed in the reseeded ECM and do not align. Hence, future work should focus on the optimization of tendon ECM decellularization and recolonization strategies to restore tendon functionality. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Human Stem Cells and Articular Cartilage Regeneration
by Atsuyuki Inui, Takashi Iwakura and A. Hari Reddi
Cells 2012, 1(4), 994-1009; https://doi.org/10.3390/cells1040994 - 05 Nov 2012
Cited by 36 | Viewed by 8779
Abstract
The regeneration of articular cartilage damaged due to trauma and posttraumatic osteoarthritis is an unmet medical need. Current approaches to regeneration and tissue engineering of articular cartilage include the use of chondrocytes, stem cells, scaffolds and signals, including morphogens and growth factors. Stem [...] Read more.
The regeneration of articular cartilage damaged due to trauma and posttraumatic osteoarthritis is an unmet medical need. Current approaches to regeneration and tissue engineering of articular cartilage include the use of chondrocytes, stem cells, scaffolds and signals, including morphogens and growth factors. Stem cells, as a source of cells for articular cartilage regeneration, are a critical factor for articular cartilage regeneration. This is because articular cartilage tissue has a low cell turnover and does not heal spontaneously. Adult stem cells have been isolated from various tissues, such as bone marrow, adipose, synovial tissue, muscle and periosteum. Signals of the transforming growth factor beta superfamily play critical roles in chondrogenesis. However, adult stem cells derived from various tissues tend to differ in their chondrogenic potential. Pluripotent stem cells have unlimited proliferative capacity compared to adult stem cells. Chondrogenesis from embryonic stem (ES) cells has been studied for more than a decade. However, establishment of ES cells requires embryos and leads to ethical issues for clinical applications. Induced pluripotent stem (iPS) cells are generated by cellular reprogramming of adult cells by transcription factors. Although iPS cells have chondrogenic potential, optimization, generation and differentiation toward articular chondrocytes are currently under intense investigation. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Redox Mechanisms in Regulation of Adipocyte Differentiation: Beyond a General Stress Response
by Guei-Sheung Liu, Elsa C. Chan, Masayoshi Higuchi, Gregory J. Dusting and Fan Jiang
Cells 2012, 1(4), 976-993; https://doi.org/10.3390/cells1040976 - 05 Nov 2012
Cited by 78 | Viewed by 16879
Abstract
In this review, we summarize advances in our understanding of redox-sensitive mechanisms that regulate adipogenesis. Current evidence indicates that reactive oxygen species may act to promote both the initiation of adipocyte lineage commitment of precursor or stem cells, and the terminal differentiation of [...] Read more.
In this review, we summarize advances in our understanding of redox-sensitive mechanisms that regulate adipogenesis. Current evidence indicates that reactive oxygen species may act to promote both the initiation of adipocyte lineage commitment of precursor or stem cells, and the terminal differentiation of preadipocytes to mature adipose cells. These can involve redox regulation of pathways mediated by receptor tyrosine kinases, peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), and CCAAT/enhancer binding protein β (C/EBPβ). However, the precise roles of ROS in adipogenesis in vivo remain controversial. More studies are needed to delineate the roles of reactive oxygen species and redox signaling mechanisms, which could be either positive or negative, in the pathogenesis of obesity and related metabolic disorders. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Review
Cell and Gene Therapy Approaches for Cardiac Vascularization
by Ludovic Melly, Stefano Boccardo, Friedrich Eckstein, Andrea Banfi and Anna Marsano
Cells 2012, 1(4), 961-975; https://doi.org/10.3390/cells1040961 - 05 Nov 2012
Cited by 36 | Viewed by 7228
Abstract
Despite encouraging preclinical results for therapeutic angiogenesis in ischemia, a suitable approach providing sustained, safe and efficacious vascular growth in the heart is still lacking. Vascular Endothelial Growth Factor (VEGF) is the master regulator of angiogenesis, but it also can easily induce aberrant [...] Read more.
Despite encouraging preclinical results for therapeutic angiogenesis in ischemia, a suitable approach providing sustained, safe and efficacious vascular growth in the heart is still lacking. Vascular Endothelial Growth Factor (VEGF) is the master regulator of angiogenesis, but it also can easily induce aberrant and dysfunctional vascular growth if its expression is not tightly controlled. Control of the released level in the microenvironment around each cell in vivo and its distribution in tissue are critical to induce stable and functional vessels for therapeutic angiogenesis. The present review discusses the limitations and perspectives of VEGF gene therapy and of different cell-based approaches for the implementation of therapeutic angiogenesis in the treatment of cardiac ischemia. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Unfolded Protein Responses With or Without Unfolded Proteins?
by Erik L. Snapp
Cells 2012, 1(4), 926-950; https://doi.org/10.3390/cells1040926 - 01 Nov 2012
Cited by 19 | Viewed by 8244
Abstract
The endoplasmic reticulum (ER) is the site of secretory protein biogenesis. The ER quality control (QC) machinery, including chaperones, ensures the correct folding of secretory proteins. Mutant proteins and environmental stresses can overwhelm the available QC machinery. To prevent and resolve accumulation of [...] Read more.
The endoplasmic reticulum (ER) is the site of secretory protein biogenesis. The ER quality control (QC) machinery, including chaperones, ensures the correct folding of secretory proteins. Mutant proteins and environmental stresses can overwhelm the available QC machinery. To prevent and resolve accumulation of misfolded secretory proteins in the ER, cells have evolved integral membrane sensors that orchestrate the Unfolded Protein Response (UPR). The sensors, Ire1p in yeast and IRE1, ATF6, and PERK in metazoans, bind the luminal ER chaperone BiP during homeostasis. As unfolded secretory proteins accumulate in the ER lumen, BiP releases, and the sensors activate. The mechanisms of activation and attenuation of the UPR sensors have exhibited unexpected complexity. A growing body of data supports a model in which Ire1p, and potentially IRE1, directly bind unfolded proteins as part of the activation process. However, evidence for an unfolded protein-independent mechanism has recently emerged, suggesting that UPR can be activated by multiple modes. Importantly, dysregulation of the UPR has been linked to human diseases including Type II diabetes, heart disease, and cancer. The existence of alternative regulatory pathways for UPR sensors raises the exciting possibility for the development of new classes of therapeutics for these medically important proteins. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Article
Successful Reconstruction of Tooth Germ with Cell Lines Requires Coordinated Gene Expressions from the Initiation Stage
by Akihiko Komine and Yasuhiro Tomooka
Cells 2012, 1(4), 905-925; https://doi.org/10.3390/cells1040905 - 30 Oct 2012
Cited by 79 | Viewed by 6362
Abstract
Tooth morphogenesis is carried out by a series of reciprocal interactions between the epithelium and mesenchyme in embryonic germs. Previously clonal dental epithelial cell (epithelium of molar tooth germ (emtg)) lines were established from an embryonic germ. They were odontogenic when combined with [...] Read more.
Tooth morphogenesis is carried out by a series of reciprocal interactions between the epithelium and mesenchyme in embryonic germs. Previously clonal dental epithelial cell (epithelium of molar tooth germ (emtg)) lines were established from an embryonic germ. They were odontogenic when combined with a dental mesenchymal tissue, although the odontogenesis was quantitatively imperfect. To improve the microenvironment in the germs, freshly isolated dental epithelial cells were mixed with cells of lines, and germs were reconstructed in various combinations. The results demonstrated that successful tooth construction depends on the mixing ratio, the age of dental epithelial cells and the combination with cell lines. Analyses of gene expression in these germs suggest that some signal(s) from dental epithelial cells makes emtg cells competent to communicate with mesenchymal cells and the epithelial and mesenchymal compartments are able to progress odontogenesis from the initiation stage. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Article
Effects of mTOR Inhibitors on Components of the Salvador-Warts-Hippo Pathway
by Jonathan Chiang and Julian A. Martinez-Agosto
Cells 2012, 1(4), 886-904; https://doi.org/10.3390/cells1040886 - 19 Oct 2012
Cited by 14 | Viewed by 8836
Abstract
The MST/Salvador-Warts-Hippo and mTOR/Akt/PI3K growth signaling pathways have been established as important modulators of cell growth, proliferation and cell survival in controlling organ size in Drosophila and mammals. Here, we sought to determine the role of the MST family of kinases, some of [...] Read more.
The MST/Salvador-Warts-Hippo and mTOR/Akt/PI3K growth signaling pathways have been established as important modulators of cell growth, proliferation and cell survival in controlling organ size in Drosophila and mammals. Here, we sought to determine the role of the MST family of kinases, some of which are components of the Hippo pathway, and their closely related Sterile 20-like kinases (STK) as candidates for mediating cross-talk between the Hippo and mTOR pathways. Expression analysis in the HepG2 and MCF7 cell lines demonstrated common expression of MST1/2/4, MAP4K3/4/5, STK 24 (MST3), STK25, STK39, Pak1, SLK, Stradα/β and TAO2. All components of the Hippo signaling pathway are present in both cell lines except for YAP1 in MCF7 cells. mTOR inhibition via rapamycin decreases TAZ levels in HepG2 but not MCF7 cells and increases TEAD1 levels in MCF7 but not HepG2 cells, suggesting a selective role of the mTOR pathway in regulating these Hippo targets in a cell type-specific manner. Furthermore, the cellular localization of TAZ changes in response to mTORC1/2 inhibitors and Akt inhibition. These findings demonstrate the mTOR-dependent regulation of Hippo signaling at the level of the transcriptional regulators TAZ and TEAD1 and highlight the potential role for mTOR inhibitors in regulating Hippo-signaling dependent tumors. Full article
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Review
The Potential for Resident Lung Mesenchymal Stem Cells to Promote Functional Tissue Regeneration: Understanding Microenvironmental Cues
by Robert F. Foronjy and Susan M. Majka
Cells 2012, 1(4), 874-885; https://doi.org/10.3390/cells1040874 - 19 Oct 2012
Cited by 70 | Viewed by 10311
Abstract
Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a [...] Read more.
Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Recent Advances towards the Clinical Application of Stem Cells for Retinal Regeneration
by Silke Becker, Hari Jayaram and G. Astrid Limb
Cells 2012, 1(4), 851-873; https://doi.org/10.3390/cells1040851 - 18 Oct 2012
Cited by 15 | Viewed by 7475
Abstract
Retinal degenerative diseases constitute a major cause of irreversible blindness in the world. Stem cell-based therapies offer hope for these patients at risk of or suffering from blindness due to the deterioration of the neural retina. Various sources of stem cells are currently [...] Read more.
Retinal degenerative diseases constitute a major cause of irreversible blindness in the world. Stem cell-based therapies offer hope for these patients at risk of or suffering from blindness due to the deterioration of the neural retina. Various sources of stem cells are currently being investigated, ranging from human embryonic stem cells to adult-derived induced pluripotent stem cells as well as human Müller stem cells, with the first clinical trials to investigate the safety and tolerability of human embryonic stem cell-derived retinal pigment epithelium cells having recently commenced. This review aims to summarize the latest advances in the development of stem cell strategies for the replacement of retinal neurons and their supportive cells, the retinal pigment epithelium (RPE) affected by retinal degenerative conditions. Particular emphasis will be given to the advances in stem cell transplantation and the challenges associated with their translation into clinical practice. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Trophic Actions of Bone Marrow-Derived Mesenchymal Stromal Cells for Muscle Repair/Regeneration
by Chiara Sassoli, Sandra Zecchi-Orlandini and Lucia Formigli
Cells 2012, 1(4), 832-850; https://doi.org/10.3390/cells1040832 - 17 Oct 2012
Cited by 26 | Viewed by 7997
Abstract
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent the leading candidate cell in tissue engineering and regenerative medicine. These cells can be easily isolated, expanded in vitro and are capable of providing significant functional benefits after implantation in the damaged muscle tissues. Despite their [...] Read more.
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent the leading candidate cell in tissue engineering and regenerative medicine. These cells can be easily isolated, expanded in vitro and are capable of providing significant functional benefits after implantation in the damaged muscle tissues. Despite their plasticity, the participation of BM-MSCs to new muscle fiber formation is controversial; in fact, emerging evidence indicates that their therapeutic effects occur without signs of long-term tissue engraftment and involve the paracrine secretion of cytokines and growth factors with multiple effects on the injured tissue, including modulation of inflammation and immune reaction, positive extracellular matrix (ECM) remodeling, angiogenesis and protection from apoptosis. Recently, a new role for BM-MSCs in the stimulation of muscle progenitor cells proliferation has been demonstrated, suggesting the potential ability of these cells to influence the fate of local stem cells and augment the endogenous mechanisms of repair/regeneration in the damaged tissues. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Review
Multiple Strategies for Translesion Synthesis in Bacteria
by Paul J. Ippoliti, Nicholas A. DeLateur, Kathryn M. Jones and Penny J. Beuning
Cells 2012, 1(4), 799-831; https://doi.org/10.3390/cells1040799 - 15 Oct 2012
Cited by 45 | Viewed by 8273
Abstract
Damage to DNA is common and can arise from numerous environmental and endogenous sources. In response to ubiquitous DNA damage, Y-family DNA polymerases are induced by the SOS response and are capable of bypassing DNA lesions. In Escherichia coli, these Y-family polymerases [...] Read more.
Damage to DNA is common and can arise from numerous environmental and endogenous sources. In response to ubiquitous DNA damage, Y-family DNA polymerases are induced by the SOS response and are capable of bypassing DNA lesions. In Escherichia coli, these Y-family polymerases are DinB and UmuC, whose activities are modulated by their interaction with the polymerase manager protein UmuD. Many, but not all, bacteria utilize DinB and UmuC homologs. Recently, a C-family polymerase named ImuC, which is similar in primary structure to the replicative DNA polymerase DnaE, was found to be able to copy damaged DNA and either carry out or suppress mutagenesis. ImuC is often found with proteins ImuA and ImuB, the latter of which is similar to Y‑family polymerases, but seems to lack the catalytic residues necessary for polymerase activity. This imuAimuBimuC mutagenesis cassette represents a widespread alternative strategy for translesion synthesis and mutagenesis in bacteria. Bacterial Y‑family and ImuC DNA polymerases contribute to replication past DNA damage and the acquisition of antibiotic resistance. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Review
p53 -Dependent and -Independent Nucleolar Stress Responses
by Karl Holmberg Olausson, Monica Nistér and Mikael S. Lindström
Cells 2012, 1(4), 774-798; https://doi.org/10.3390/cells1040774 - 15 Oct 2012
Cited by 84 | Viewed by 14631
Abstract
The nucleolus has emerged as a cellular stress sensor and key regulator of p53-dependent and -independent stress responses. A variety of abnormal metabolic conditions, cytotoxic compounds, and physical insults induce alterations in nucleolar structure and function, a situation known as nucleolar or ribosomal [...] Read more.
The nucleolus has emerged as a cellular stress sensor and key regulator of p53-dependent and -independent stress responses. A variety of abnormal metabolic conditions, cytotoxic compounds, and physical insults induce alterations in nucleolar structure and function, a situation known as nucleolar or ribosomal stress. Ribosomal proteins, including RPL11 and RPL5, become increasingly bound to the p53 regulatory protein MDM2 following nucleolar stress. Ribosomal protein binding to MDM2 blocks its E3 ligase function leading to stabilization and activation of p53. In this review we focus on a number of novel regulators of the RPL5/RPL11-MDM2-p53 complex including PICT1 (GLTSCR2), MYBBP1A, PML and NEDD8. p53-independent pathways mediating the nucleolar stress response are also emerging and in particular the negative control that RPL11 exerts on Myc oncoprotein is of importance, given the role of Myc as a master regulator of ribosome biogenesis. We also briefly discuss the potential of chemotherapeutic drugs that specifically target RNA polymerase I to induce nucleolar stress. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Review
14-3-3 Proteins are Regulators of Autophagy
by Mercedes Pozuelo-Rubio
Cells 2012, 1(4), 754-773; https://doi.org/10.3390/cells1040754 - 15 Oct 2012
Cited by 48 | Viewed by 10247
Abstract
14-3-3 proteins are implicated in the regulation of proteins involved in a variety of signaling pathways. 14-3-3-dependent protein regulation occurs through phosphorylation-dependent binding that results, in many cases, in the release of survival signals in cells. Autophagy is a cell digestion process that [...] Read more.
14-3-3 proteins are implicated in the regulation of proteins involved in a variety of signaling pathways. 14-3-3-dependent protein regulation occurs through phosphorylation-dependent binding that results, in many cases, in the release of survival signals in cells. Autophagy is a cell digestion process that contributes to overcoming nutrient deprivation and is initiated under stress conditions. However, whether autophagy is a cell survival or cell death mechanism remains under discussion and may depend on context. Nevertheless, autophagy is a cellular process that determines cell fate and is tightly regulated by different signaling pathways, some of which, for example MAPK, PI3K and mTOR, are tightly regulated by 14-3-3 proteins. It is therefore important to understand the role of 14-3-3 protein in modulating the autophagic process. Within this context, direct binding of 14-3-3 to mTOR regulatory proteins, such as TSC2 and PRAS40, connects 14-3-3 with autophagy regulatory processes. In addition, 14-3-3 binding to human vacuolar protein sorting 34 (hVps34), a class III phosphatidylinositol-3-kinase (PI3KC3), indicates the involvement of 14-3-3 proteins in regulating autophagosome formation. hVps34 is involved in vesicle trafficking processes such as autophagy, and its activation is needed for initiation of autophagy. Chromatography and overlay techniques suggest that hVps34 directly interacts with 14-3-3 proteins under physiological conditions, thereby maintaining hVps34 in an inactive state. In contrast, nutrient starvation promotes dissociation of the 14-3-3–hVps34 complex, thereby enhancing hVps34 lipid kinase activity. Thus, 14-3-3 proteins are regulators of autophagy through regulating key components of the autophagic machinery. This review summarizes the role of 14-3-3 protein in the control of target proteins involved in regulating the master switches of autophagy. Full article
(This article belongs to the Special Issue Autophagy)
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