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Stem Cells
Modeling Glanzmann thrombasthenia using patient specific iPSCs and restoring platelet aggregation function by CD41 overexpression
Feb 24, 2017   Stem Cell Research
Hu L, Du L, Zhao Y, Li W, Ouyang Q, Zhou D, Lu G, Lin G
Modeling Glanzmann thrombasthenia using patient specific iPSCs and restoring platelet aggregation function by CD41 overexpression
Feb 24, 2017
Stem Cell Research
Glanzmann thrombasthenia (GT) is a rare monogenic hemorrhagic disorder involving aggregation defect of non-nuclear platelets. In this study we generated induced pluripotent stem cells (iPSCs) from skin fibroblasts of a GT patient with complex heterogeneous mutations of ITGA2B gene. GT-iPSCs could be successfully differentiated into platelets (GT-iPS-platelets). GT-iPS-platelets were CD41-/CD42b+/CD61- and were platelet activation marker (PAC-1) negative after adenosine diphosphate (ADP) activation. Furthermore, GT-iPS-platelets were defective in platelet aggregation tests in vitro. Moreover, exogenous expression of the wild-type ITGA2B gene in GT-iPS platelets restored CD41 expression and normal platelet aggregation. Our study suggested that patient-specific iPSCs could be a potential target of stem cell based gene therapy for platelet diseases.Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Umbilical Cord Stem Cells in the Treatment of Corneal Disease
Feb 24, 2017   Survey Of Ophthalmology
Ziaei M, Zhang J, Patel D, McGhee CN
Umbilical Cord Stem Cells in the Treatment of Corneal Disease
Feb 24, 2017
Survey Of Ophthalmology
Stem cells are capable of giving rise to progenies with specific functional and morphological traits and, in recent years, extraordinary scientific advances have initiated an era of hope for clinical regenerative strategies and tissue engineering applications. We appraise the potential benefits of human umbilical cord derived stem cell therapy and consider current approaches to utilize these stem cells in corneal epithelial, stromal, and endothelial disorders.Copyright © 2017. Published by Elsevier Inc.
Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells
Feb 24, 2017   Molecular And Cellular Endocrinology
Poliandri A, Miller D, Howard S, Nobles M, Ruiz-Babot G, Harmer S, Tinker A, McKay T, Guasti L, Dunkel L
Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells
Feb 24, 2017
Molecular And Cellular Endocrinology
GnRH neurons are fundamental for reproduction in all vertebrates, integrating all reproductive inputs. The inaccessibility of human GnRH-neurons has been a major impediment to studying the central control of reproduction and its disorders. Here, we report the efficient generation of kisspeptin responsive GnRH-secreting neurons by directed differentiation of human Embryonic Stem Cells and induced-Pluripotent Stem Cells derived from a Kallman Syndrome patient and a healthy family member. The protocol involves the generation of intermediate Neural Progenitor Cells (NPCs) through long-term Bone morphogenetic protein 4 inhibition, followed by terminal specification of these NPCs in media containing Fibroblast Growth Factor 8 and a NOTCH inhibitor. The resulting GnRH-expressing and -secreting neurons display a neuroendocrine gene expression pattern and present spontaneous calcium transients that can be stimulated by kisspeptin. These in vitro generated GnRH expressing cells provide a new resource for studying the molecular mechanisms underlying the development and function of GnRH neurons.Copyright © 2017. Published by Elsevier B.V.
Histone H1 defect in escort cells triggers germline tumor in Drosophila ovary
Feb 24, 2017   Developmental Biology
Yang Z, Sun J, Hu Y, Wang F, Wang X,   . . . . . .   , Li H, Chang Z, Liu LP, Liu Q, Ni JQ
Histone H1 defect in escort cells triggers germline tumor in Drosophila ovary
Feb 24, 2017
Developmental Biology
Drosophila ovary is recognized as one of the best model systems to study stem cell biology in vivo. We had previously identified an autonomous role of the histone H1 in germline stem cell (GSC) maintenance. Here, we found that histone H1 depletion in escort cells (ECs) resulted in an increase of spectrosome-containing cells (SCCs), an ovary tumor-like phenotype. Further analysis showed that the Dpp pathway is excessively activated in these SCC cells, while the expression of bam is attenuated. In the H1-depleted ECs, both transposon activity and DNA damage had increased dramatically, followed by EC apoptosis, which is consistent with the role of H1 in other somatic cells. Surprisingly, H1-depleted ECs acquired cap cell characteristics including dpp expression, and the resulting abnormal Dpp level inhibits SCC further differentiation. Most interestingly, double knockdown of H1 and dpp in ECs can reduce the number of SCCs to the normal level, indicating that the additional Dpp secreted by ECs contributes to the germline tumor. Taken together, our findings indicate that histone H1 is an important epigenetic factor in controlling EC characteristics and a key suppressor of germline tumor.Copyright © 2017. Published by Elsevier Inc.
World TB Day 2017: Advances, Challenges and Opportunities in the "End-TB" Era
Feb 24, 2017   International Journal Of Infectious Diseases : IJID : Official Publication Of The International Society For Infectious Diseases
Petersen E, Maeurer M, Marais B, Migliori GB, Mwaba P, Ntoumi F, Vilaplana C, Kim K, Schito M, Zumla A
World TB Day 2017: Advances, Challenges and Opportunities in the "End-TB" Era
Feb 24, 2017
International Journal Of Infectious Diseases : IJID : Official Publication Of The International Society For Infectious Diseases
The hypoxia-inducible factors HIF1α and HIF2α are dispensable for embryonic muscle development but essential for postnatal muscle regeneration
Feb 24, 2017   The Journal Of Biological Chemistry
Yang X, Yang S, Wang C, Kuang S
The hypoxia-inducible factors HIF1α and HIF2α are dispensable for embryonic muscle development but essential for postnatal muscle regeneration
Feb 24, 2017
The Journal Of Biological Chemistry
Muscle satellite cells are myogenic stem cells whose quiescence, activation, self-renewal, and differentiation are influenced by oxygen supply, an environmental regulator of stem cell activity. Accordingly, stem cell-specific oxygen signaling pathways precisely control the balance between muscle growth and regeneration in response to oxygen fluctuations, and hypoxia-inducible factors (HIFs) are central mediators of these cellular responses. However, the in vivo roles of HIFs in quiescent satellite cells and activated satellite cells (myoblasts) are poorly understood. Using transgene mouse models for cell-specific HIF expression, we show here that HIF1α and HIF2α are preferentially expressed in pre- and post-differentiation myoblasts, respectively. Interestingly, double knockouts of HIF1α and HIF2α (HIF1α/2α dKO) generated with the MyoDCre system in embryonic myoblasts resulted in apparently normal muscle development and growth. However, HIF1α/2α dKO produced with the tamoxifen-inducible, satellite cell-specific Pax7CreER system in postnatal satellite cells delayed injury-induced muscle repair because of a reduced number of myoblasts during regeneration. Analysis of satellite cell dynamics on myofibers confirmed that HIF1α/2α dKO myoblasts exhibit reduced self-renewal but more pronounced differentiation under hypoxic conditions. Mechanistically, the HIF1α/2α dKO blunted hypoxia-induced activation of Notch signaling, a key determinant of satellite cell self-renewal. We conclude that HIF1α and HIF2α are dispensable for muscle stem cell function under normoxia, but are required for maintaining satellite cell self-renewal in hypoxic environments. Our insights into a critical mechanism in satellite cell homeostasis during muscle regeneration could help inform research efforts to treat muscle diseases or improve muscle function.Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Intra-bone marrow injection of trace elements co-doped calcium phosphate microparticles for the treatment of osteoporotic rat
Feb 24, 2017   Journal Of Biomedical Materials Research. Part A
Yang X, Xu S, Chen X, He D, Ke X, Zhang L, Yang G, Liu A, Mou X, Xia W, Gou Z
Intra-bone marrow injection of trace elements co-doped calcium phosphate microparticles for the treatment of osteoporotic rat
Feb 24, 2017
Journal Of Biomedical Materials Research. Part A
Osteoporotic femur fractures are the most common fragility fracture and account for approximately one million injuries per year. Local intervention by intra-marrow injection is potentially a good choice for preventing osteoporotic bone loss when the osteoporotic femoral fracture was treated. Previously, it was shown that trace element co-doped calcium phosphate (teCaP) implants could stimulate osteoporotic bone marrow mesenchymal stem cell activity in vitro and bone regeneration in femoral bone defects in osteoporotic animal models. They hypothesized that local intra-marrow injection of teCaP particles could improve bone function because the teCaP can sustain release of biologically essential inorganic minerals and improve bone remodeling in osteoporosis. The teCaP and CaP particles were synthesized in simulated body fluid with and without adding silicon, zinc and strontium ions. Female rats (8 months) were ovariectomized (OVX) or sham-operated, and then intervened in the femoral marrow space at 12 months old. Groups include: (1) saline water; (2) CaP particles; and (3) teCaP particles. After 2-3 months of intervention, the sham groups showed higher bone mineral density (MBD) in the femur, and teCaP group increased the BMD in the OVX groups. The compressive strength of the OVX-teCaP group was significantly higher than that in the OVX-CaP group. Significant differences between OVX-teCaP and OVX-CaP groups were found for bone mineral microarchitecture, bone mineral density, and trace mineral content, but not for feces composition. These results confirm the teCaP particles could suppress osteoporotic bone loss by local intramarrow injection. Therefore, this biomaterial could be used as a next-generation combination treatment for osteoporotic trauma and osteoporosis itself. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2017.© 2017 Wiley Periodicals, Inc.
Idiopathic Parkinson's disease patient-derived induced pluripotent stem cells function as midbrain dopaminergic neurons in rodent brains
Feb 24, 2017   Journal Of Neuroscience Research
Kikuchi T, Morizane A, Doi D, Okita K, Nakagawa M, Yamakado H, Inoue H, Takahashi R, Takahashi J
Idiopathic Parkinson's disease patient-derived induced pluripotent stem cells function as midbrain dopaminergic neurons in rodent brains
Feb 24, 2017
Journal Of Neuroscience Research
Patient-specific induced pluripotent stem cells (iPSCs) are a promising source for cell transplantation therapy. In Parkinson's disease (PD) patients, however, their vulnerability and the transmission of pathological α-Synuclein are possible drawbacks that may prevent PD-specific iPSCs (PDiPSCs) from being used in clinical settings. In this study, we generated iPSCs from idiopathic PD patients and found that there was no significant vulnerability between dopaminergic (DA) neurons generated from healthy individuals and idiopathic PD patients. PDiPSC-derived DA neurons survived and functioned in the brains of PD model rats. In addition, in the brains of α-Synuclein transgenic mice, PDiPSC-derived DA neurons did not cause pathological α-Synuclein accumulation in the host brain or in the grafts. These results suggested that iPSCs derived from idiopathic PD patients are feasible as donor cells for autologous transplantation to treat PD. © 2017 Wiley Periodicals, Inc.© 2017 Wiley Periodicals, Inc.
De novo DNA methylation during monkey pre-implantation embryogenesis
Feb 24, 2017   Cell Research
Gao F, Niu Y, Sun YE, Lu H, Chen Y,   . . . . . .   , Sun N, Si W, Wang H, Ji W, Tan T
De novo DNA methylation during monkey pre-implantation embryogenesis
Feb 24, 2017
Cell Research
Critical epigenetic regulation of primate embryogenesis entails DNA methylome changes. Here we report genome-wide composition, patterning, and stage-specific dynamics of DNA methylation in pre-implantation rhesus monkey embryos as well as male and female gametes studied using an optimized tagmentation-based whole-genome bisulfite sequencing method. We show that upon fertilization, both paternal and maternal genomes undergo active DNA demethylation, and genome-wide de novo DNA methylation is also initiated in the same period. By the 8-cell stage, remethylation becomes more pronounced than demethylation, resulting in an increase in global DNA methylation. Promoters of genes associated with oxidative phosphorylation are preferentially remethylated at the 8-cell stage, suggesting that this mode of energy metabolism may not be favored. Unlike in rodents, X chromosome inactivation is not observed during monkey pre-implantation development. Our study provides the first comprehensive illustration of the 'wax and wane' phases of DNA methylation dynamics. Most importantly, our DNA methyltransferase loss-of-function analysis indicates that DNA methylation influences early monkey embryogenesis.Cell Research advance online publication 24 February 2017; doi:10.1038/cr.2017.25.
Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response
Feb 24, 2017   Stem Cells Translational Medicine
Giordano S, Zhao X, Chen YF, Litovsky SH, Hage FG, Townes TM, Sun CW, Wu LC, Oparil S, Xing D
Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response
Feb 24, 2017
Stem Cells Translational Medicine
Recruitment of neutrophils and monocytes/macrophages to the site of vascular injury is mediated by binding of chemoattractants to interleukin (IL) 8 receptors RA and RB (IL8RA/B) C-C chemokine receptors (CCR) 2 and 5 expressed on neutrophil and monocyte/macrophage membranes. Endothelial cells (ECs) derived from rat-induced pluripotent stem cells (RiPS) were transduced with adenovirus containing cDNA of IL8RA/B and/or CCR2/5. We hypothesized that RiPS-ECs overexpressing IL8RA/B (RiPS-IL8RA/B-ECs), CCR2/5 (RiPS-CCR2/5-ECs), or both receptors (RiPS-IL8RA/B+CCR2/5-ECs) will inhibit inflammatory responses and neointima formation in balloon-injured rat carotid artery. Twelve-week-old male Sprague-Dawley rats underwent balloon injury of the right carotid artery and intravenous infusion of (a) saline vehicle, (b) control RiPS-Null-ECs (ECs transduced with empty virus), (c) RiPS-IL8RA/B-ECs, (d) RiPS-CCR2/5-ECs, or (e) RiPS-IL8RA/B+CCR2/5-ECs. Inflammatory mediator expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 hours postinjury by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Neointima formation was assessed at 14 days postinjury. RiPS-ECs expressing the IL8RA/B or CCR2/5 homing device targeted the injured arteries and decreased injury-induced inflammatory cytokine expression, neutrophil/macrophage infiltration, and neointima formation. Transfused RiPS-ECs overexpressing IL8RA/B and/or CCR2/5 prevented inflammatory responses and neointima formation after vascular injury. Targeted delivery of iPS-ECs with a homing device to inflammatory mediators in injured arteries provides a novel strategy for the treatment of cardiovascular diseases. © Stem Cells Translational Medicine 2016.© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
Pediatric nonrhabdomyosarcoma soft tissue sarcomas arising at visceral sites
Feb 24, 2017   Pediatric Blood & Cancer
Ferrari A, Magni C, Bergamaschi L, Cecchetto G, Alaggio R,   . . . . . .   , Chiaravalli S, Affinita MC, Scagnellato A, Casanova M, Bisogno G
Pediatric nonrhabdomyosarcoma soft tissue sarcomas arising at visceral sites
Feb 24, 2017
Pediatric Blood & Cancer
BACKGROUND: Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) may rarely occur in visceral tissues, and little is known about their clinical history. The present study retrospectively analyzed a group of patients prospectively registered in Italian pediatric protocols conducted between 1979 and 2004. METHODS: Inclusion criteria for the study were as follows: a pathological diagnosis of "adult-type NRSTS," arising at visceral sites (lung-pleurae, liver, kidney, and mesentery-bowel); age under 18 years; no previous treatment except for primary surgery; available clinical data; and written consent. RESULTS: Thirty cases with visceral NRSTS were collected and analyzed. Sites of origin were as follows: mesentery-bowel in 12 cases, lung-pleurae in 11, liver in 5, and kidney in 2. According to the Intergroup Rhabdomyosarcoma Study (IRS) surgical grouping system, patients were classified as follows: nine IRS group I, three group II, 12 group III, and six group IV. Patients were treated with a multimodal approach including surgery, radiotherapy, and/or chemotherapy, according to their characteristics. For the series as a whole, the 5-year event-free and overall survival rates were 33.3% and 40.0%, respectively. The IRS group (reflecting the feasibility of initial complete resection) emerged as the main prognostic factor. Survival rates also correlated with tumor size and local invasiveness, histological subtype, and tumor sites (the worst outcome was seen for tumors arising in the lung and pleurae). CONCLUSIONS: This study confirmed that visceral NRSTS are aggressive tumors carrying a worse prognosis than pediatric NRSTS arising in soft tissues of the extremities. Local treatment remains the main challenge for these tumors. © 2017 Wiley Periodicals, Inc.
A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction
Feb 23, 2017   Biomaterials
Awada HK, Long DW, Wang Z, Hwang MP, Kim K, Wang Y
A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction
Feb 23, 2017
Biomaterials
After myocardial infarction (MI), the heart undergoes fibrotic pathological remodeling instead of repair and regeneration. With multiple pathologies developing after MI, treatment using several proteins is expected to address this range of pathologies more effectively than a single-agent therapy. A factorial design of experiments study guided us to combine three complementary factors in one injection: tissue inhibitor of metalloproteinases-3 (TIMP-3) was embedded in a fibrin gel for signaling in the initial phase of the treatment, while basic fibroblast growth factor (FGF-2) and stromal cell-derived factor 1-alpha (SDF-1α) were embedded in heparin-based coacervates for sustained release and distributed within the same fibrin gel to exert their effects over a longer period. The gel was then tested in a rat model of myocardial infarction. Contractility of rat hearts treated with the protein coacervate-gel composite stabilized and slightly improved after the first week while contractility continued to decrease in rats treated with free proteins or saline over the 8 week study period. Hearts receiving the protein coacervate-gel composite treatment also exhibited reduced ventricular dilation, inflammation, fibrosis, and extracellular matrix (ECM) degradation. Revascularization, cardiomyocyte preservation, stem cell homing, and increased myocardial strain likely all contributed to the repair. This study demonstrates the potential of a multifactorial therapeutic approach in MI, using three complementary proteins delivered sequentially for comprehensive healing. The study also shows the necessity of controlled delivery for growth factors and cytokines to be an effective treatment.Copyright © 2017. Published by Elsevier Ltd.
A novel redox regulator, MnTnBuOE-2-PyP
Feb 23, 2017   Redox Biology
Zhao Y, Carroll DW, You Y, Chaiswing L, Wen R, Batinic-Haberle I, Bondada S, Liang Y, St Clair DK
A novel redox regulator, MnTnBuOE-2-PyP
Feb 23, 2017
Redox Biology
The signaling of reactive oxygen species (ROS) is essential for the maintenance of normal cellular function. However, whether and how ROS regulate stem cells are unclear. Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of mouse hematopoietic stem/progenitor cells (HSPC) under physiological conditions are enhanced. Importantly, giving MnTnBuOE-2-PyPCopyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging
Feb 23, 2017   Stem Cell Reviews
Ratajczak MZ, Bartke A, Darzynkiewicz Z
Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging
Feb 23, 2017
Stem Cell Reviews
The dream of slowing down the aging process has always inspired mankind. Since stem cells are responsible for tissue and organ rejuvenation, it is logical that we should search for encoded mechanisms affecting life span in these cells. However, in adult life the hierarchy within the stem cell compartment is still not very well defined, and evidence has accumulated that adult tissues contain rare stem cells that possess a broad trans-germ layer differentiation potential. These most-primitive stem cells-those endowed with pluripotent or multipotent differentiation ability and that give rise to other cells more restricted in differentiation, known as tissue-committed stem cells (TCSCs) - are of particular interest. In this review we present the concept supported by accumulating evidence that a population of so-called very small embryonic-like stem cells (VSELs) residing in adult tissues positively impacts the overall survival of mammals, including humans. These unique cells are prevented in vertebrates from premature depletion by decreased sensitivity to growth hormone (GH), insulin (INS), and insulin-like growth factor (IGF) signaling, due to epigenetic changes in paternally imprinted genes that regulate their resistance to these factors. In this context, we can envision nutrient response GH/INS/IGF signaling pathway as a lethal factor for these most primitive stem cells and an important culprit in aging.
Therapeutic Application of Placental Mesenchymal Stem Cells Reprogrammed Neurospheres in Spinal Cord Injury of SCID
Feb 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Sabapathy V, Herbert FJ, Kumar S
Therapeutic Application of Placental Mesenchymal Stem Cells Reprogrammed Neurospheres in Spinal Cord Injury of SCID
Feb 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
Mesenchymal stromal cells (MSCs) and induced pluripotent stem cells (iPSCs) have stimulated much interest in the scientific community and hopes among the general public since their discovery in 1966 due to a variety of potential applications it has in the field of regenerative medicine. Copious amount of literature, as well as long-term animal and human clinical trials, indicates that MSCs can be successfully used for therapeutic purpose without any extreme adversities. MSCs have been isolated from adult and fetal tissues. Recently, MSCs from placenta have generated much inquisitiveness. In this article, we will demonstrate the step-by-step procedure for isolating human placental MSCs from term placenta, reprogramming of placental MSCs into iPSCs using plasmid vectors, evaluation of functional recovery in mice spinal cord injury models, and in vivo tracking of the transplanted cells.
Modeling Williams syndrome with induced pluripotent stem cells
Feb 23, 2017   Neurogenesis (Austin, Tex.)
Chailangkarn T, Muotri AR
Modeling Williams syndrome with induced pluripotent stem cells
Feb 23, 2017
Neurogenesis (Austin, Tex.)
The development of induced pluripotent stem cells (iPSCs) like never before has opened novel opportunity to study diseases in relevant cell types. In our recent study, Williams syndrome (WS), a rare genetic neurodevelopmental disorder, that is caused by hemizygous deletion of 25-28 genes on chromosome 7, is of interest because of its unique cognitive and social profiles. Little is known about haploinsufficiency effect of those deleted genes on molecular and cellular phenotypes at the neural level due to the lack of relevant human cellular model. Using the cellular reprogramming approach, we reported that WS iPSC-derived neural progenitor cells (NPCs) has increased apoptosis and therefore increased doubling time, which could be rescued by complementation of frizzled 9, one of the genes typically deleted in WS. Moreover, WS iPSC-derived CTIP2-positive pyramidal neurons exhibit morphologic alterations including longer total dendrites and increasing dendritic spine number. In addition, WS iPSC-derived neurons show an increase in calcium transient frequency and synchronized activity likely due to increased number of dendritic spines and synapses. Our work integrated cross-level data from genetics to behavior of WS individuals and revealed altered cellular phenotypes in WS human NPCs and neurons that could be validated in other model systems such as magnetic resonance imaging (MRI) in live subjects and postmortem brain tissues.
Decellularized bone matrix grafts for calvaria regeneration
Feb 23, 2017   Journal Of Tissue Engineering
Lee DJ, Diachina S, Lee YT, Zhao L, Zou R, Tang N, Han H, Chen X, Ko CC
Decellularized bone matrix grafts for calvaria regeneration
Feb 23, 2017
Journal Of Tissue Engineering
Decellularization is a promising new method to prepare natural matrices for tissue regeneration. Successful decellularization has been reported using various tissues including skin, tendon, and cartilage, though studies using hard tissue such as bone are lacking. In this study, we aimed to define the optimal experimental parameters to decellularize natural bone matrix using 0.5% sodium dodecyl sulfate and 0.1% NH
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
Feb 23, 2017   Science Translational Medicine
Ler LD, Ghosh S, Chai X, Thike AA, Heng HL,   . . . . . .   , Creasy CL, Pang ST, McCabe MT, Poon SL, Teh BT
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
Feb 23, 2017
Science Translational Medicine
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, Copyright © 2017, American Association for the Advancement of Science.
Therapeutic Application of Human Wharton Jelly Mesenchymal Stem Cells in Skin Injury of SCID
Feb 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Sabapathy V, Sundaram B, Kumar S
Therapeutic Application of Human Wharton Jelly Mesenchymal Stem Cells in Skin Injury of SCID
Feb 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
Mesenchymal stem cells (MSCs) are blossoming as a credible source for regenerative medical applications. The use of fetal MSCs is gaining momentum for therapeutic use. The ease of isolation, enhanced characteristics, and immunomodulation properties renders the utilization of fetal MSCs for numerous clinical applications. In this article, we will demonstrate a step-by-step protocol for isolation of Wharton's jelly MSCs (WJMSCs) from the human umbilical cord matrix, preparation of human platelet lysate, fabricating amniotic membrane scaffold and mice model to study skin regeneration using a combination of MSCs and decellularized amniotic membrane scaffold.
Isolation, Characterization, and Expansion of Cancer Stem Cells
Feb 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Torre-Healy LA, Berezovsky A, Lathia JD
Isolation, Characterization, and Expansion of Cancer Stem Cells
Feb 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
The ability to isolate, characterize, and expand distinct tumor cell populations from primary tissue or xenografts is vital to identifying molecular mechanisms specific to cancer stem cells. Once cells have been extracted from tissue, there are multiple methods by which they can be sorted and cultured. We will describe the approaches that can be taken from cancer stem cell isolation through expansion, including Magnetic-activated Cell Sorting (MACS), Fluorescence-activated Cell Sorting (FACS), the use of reporter systems, and various cell culture methods.
Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding
Feb 23, 2017   Neuron
Falk S, Bugeon S, Ninkovic J, Pilz GA, Postiglione MP, Cremer H, Knoblich JA, Götz M
Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding
Feb 23, 2017
Neuron
The developmental mechanisms regulating the number of adult neural stem cells (aNSCs) are largely unknown. Here we show that the cleavage plane orientation in murine embryonic radial glia cells (RGCs) regulates the number of aNSCs in the lateral ganglionic eminence (LGE). Randomizing spindle orientation in RGCs by overexpression of Insc or a dominant-negative form of Lgn (dnLgn) reduces the frequency of self-renewing asymmetric divisions while favoring symmetric divisions generating two SNPs. Importantly, these changes during embryonic development result in reduced seeding of aNSCs. Interestingly, no effects on aNSC numbers were observed when Insc was overexpressed in postnatal RGCs or aNSCs. These data suggest a new mechanism for controlling aNSC numbers and show that the role of spindle orientation during brain development is highly time and region dependent.Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Resveratrol Enhances Self-renewal of Mouse Embryonic Stem Cells
Feb 23, 2017   Journal Of Cellular Biochemistry
Li N, Du Z, Shen Q, Lei Q, Zhang Y, Zhang M, Hua J
Resveratrol Enhances Self-renewal of Mouse Embryonic Stem Cells
Feb 23, 2017
Journal Of Cellular Biochemistry
Resveratrol (RSV) has been shown to affect the differentiation of several types of stem cells, while the detailed mechanism is elusive. Here, we aim to investigate the function of RSV in self-renewal of mouse embryonic stem cells (ESCs) and the related mechanisms. In contrast with its reported roles, we found unexpectedly that differentiated ESCs or iPSCs treated by RSV would not show further differentiation, but regained a naïve pluripotency state with higher expressions of core transcriptional factors and with the ability to differentiate into all three germ layers when transplanted in vivo. In accordance with these findings, RSV also enhanced cell cycle progression of ESCs via regulating cell cycle-related proteins. Finally, enhanced activation of JAK/STAT3 signaling pathway and suppressed activation of mTOR were found essential in enhancing the self-renewal of ESCs by RSV. Our finding discovered a novel function of RSV in enhancing the self-renewal of ESCs, and suggested that the timing of treatment and concentration of RSV determined the final effect of it. Our work may contribute to understanding of RSV in the self-renewal maintenance of pluripotent stem cells, and may also provide help to the generation and maintenance of iPSCs in vitro. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals
Feb 23, 2017   The Prostate
Huang H, Du T, Zhang Y, Lai Y, Li K, Fan X, Zhu D, Lin T, Xu K, Huang J, Liu L, Guo Z
Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals
Feb 23, 2017
The Prostate
BACKGROUND: SHARPIN, SHANK-associated RH domain interacting protein, associates with a linear ubiquitin chain assembly complex (LUBAC) to regulate inflammation and immunity. It has been reported that SHARPIN is highly expressed in several human tumors including ovarian cancer and liver cancer. We found that SHARPIN is also highly expressed in prostate cancer cell lines of DU145, LNCAP, and PC-3. Suppression of SHARPIN caused an inhibition of NF-κB signal and decreases in tumorigenesis of cultured cells in NOD/SCID mouse model. Overexpression of SHARPIN in prostate cancer cells promoted cell growth and reduced apoptosis through NF-kB/ERK/Akt pathway and apoptosis-associated proteins. METHODS: We analyzed the expression of SHARPIN in prostate cancer tissues from 95 patients and its relationship with other clinical characteristics associated with PCA malignancies and patient survivals, and examined the impacts of SHARPIN suppression with siRNA on proliferation, angiogenesis, invasion, and expression levels of MMP-9 of prostate cancer cells and metastasis to lung by these cells in nude mice. RESULTS: High levels of SHARPIN were associated with high malignancies of PCA and predicted shorter survivals of PCA patients. Suppression of SHARPIN impaired cell proliferation, angiogenesis, and invasion and reduced levels of MMP-9 in prostate cancer cells and reduced the size of metastatic lung tumors induced by these cells in mice. CONCLUSIONS: SHARPIN enhances the metastasis of prostate cancer and impair patient survivals. Prostate. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure
Feb 23, 2017   Chinese Medical Journal
Shi C, Shen H, Fan LJ, Guan J, Zheng XB, Chen X, Liang R, Zhang XW, Cui QH, Sun KK, Zhao ZR, Han HJ
Endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure
Feb 23, 2017
Chinese Medical Journal
BACKGROUND: At present, a diagnostic tool with high specificity for impaired endometrial receptivity, which may lead to implantation failure, remains to be developed. We aimed to assess the different endometrial microRNA (miRNA) signatures for impaired endometrial receptivity by microarray analysis. METHODS: A total of 12 repeated implantation failure (RIF) patients and 10 infertile patients, who conceived and delivered after one embryo transfer attempt, were recruited as RIF and control groups, respectively. Endometrial specimens from the window of implantation (WOI) were collected from these two groups. MiRNA microarray was conducted on seven and five samples from the RIF and control groups, respectively. Comparative, functional, and network analyses were performed for the microarray results. Quantitative real-time polymerase chain reaction (PCR) was performed on other samples to validate the expression of specific miRNAs. RESULTS: Compared with those in the control group, the expression levels of 105 miRNAs in the RIF group were found to be significantly up- or down-regulated (at least 2-fold) by microarray analysis. The most relevant miRNA functional sets of these dysregulated miRNAs were miR-30 family, human embryonic stem cell regulation, epithelial-mesenchymal transition, and miRNA tumor suppressors by tool for annotations of microRNA analysis. Network regulatory analysis found 176 miRNA-mRNA interactions, and the top 3 core miRNAs were has-miR-4668-5p, has-miR-429, and has-miR-5088. Expression levels of the 18 selected miRNAs in new samples by real-time PCR were found to be regulated with the same trend, as the result of microarray analysis. CONCLUSIONS: There is a significant different expression of certain miRNAs in the WOI endometrium for RIF patients. These miRNAs may contribute to impaired endometrial receptivity.
Chemotherapy-Induced Ca
Feb 23, 2017   Cell Reports
Lu H, Chen I, Shimoda LA, Park Y, Zhang C, Tran L, Zhang H, Semenza GL
Chemotherapy-Induced Ca
Feb 23, 2017
Cell Reports
Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer.Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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