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Stem Cells
Egocentric and Allocentric Visuospatial Working Memory in Premotor Huntington's Disease: a Double Dissociation with Caudate and Hippocampal Volumes
Apr 21, 2017   Neuropsychologia
Possin KL, Kim H, Geschwind MD, Moskowitz T, Johnson ET, Sha SJ, Apple A, Xu D, Miller BL, Finkbeiner S, Hess CP, Kramer JH
Egocentric and Allocentric Visuospatial Working Memory in Premotor Huntington's Disease: a Double Dissociation with Caudate and Hippocampal Volumes
Apr 21, 2017
Neuropsychologia
Our brains represent spatial information in egocentric (self-based) or allocentric (landmark-based) coordinates. Rodent studies have demonstrated a critical role for the caudate in egocentric navigation and the hippocampus in allocentric navigation. We administered tests of egocentric and allocentric working memory to individuals with premotor Huntington's disease (pmHD), which is associated with early caudate nucleus atrophy, and controls. Each test had 80 trials during which subjects were asked to remember 2 locations over 1-sec delays. The only difference between these otherwise identical tests was that locations could only be coded in self-based or landmark-based coordinates. We applied a multiatlas-based segmentation algorithm and computed point-wise Jacobian determinants to measure regional variations in caudate and hippocampal volumes from 3T MRI. As predicted, the pmHD patients were significantly more impaired on egocentric working memory. Only egocentric accuracy correlated with caudate volumes, specifically the dorsolateral caudate head, right more than left, a region that receives dense efferents from dorsolateral prefrontal cortex. In contrast, only allocentric accuracy correlated with hippocampal volumes, specifically intermediate and posterior regions that connect strongly with parahippocampal and posterior parietal cortices. These results indicate that the distinction between egocentric and allocentric navigation applies to working memory. The dorsolateral caudate is important for egocentric working memory, which can explain the disproportionate impairment in pmHD. Allocentric working memory, in contrast, relies on the hippocampus and is relatively spared in pmHD. Copyright © 2017. Published by Elsevier Ltd.
CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors
Apr 21, 2017   Scientific Reports
Ishibashi M, Neri S, Hashimoto H, Miyashita T, Yoshida T,   . . . . . .   , Tsuboi M, Masutomi K, Goto K, Ochiai A, Ishii G
CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors
Apr 21, 2017
Scientific Reports
Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.
Metabolomic and Proteomic Analysis of Maize Embryonic Callus induced from immature embryo
Apr 22, 2017   Scientific Reports
Ge F, Hu H, Huang X, Zhang Y, Wang Y, Li Z, Zou C, Peng H, Li L, Gao S, Pan G, Shen Y
Metabolomic and Proteomic Analysis of Maize Embryonic Callus induced from immature embryo
Apr 22, 2017
Scientific Reports
The low ratio of embryonic callus (EC) induction has inhibited the rapid development of maize genetic engineering. Still, little is known to explain the genotype-dependence of EC induction. Here, we performed a large-scale, quantitative analysis of the maize EC metabolome and proteome at three typical induction stages in two inbred lines with a range of EC induction capabilities. Comparison of the metabolomes and proteomes suggests that the differential molecular responses begin at an early stage of development and continue throughout the process of EC formation. The two inbred lines show different responses under various conditions, such as metal ion binding, cell enlargement, stem cell formation, meristematic activity maintenance, somatic embryogenesis, cell wall synthesis, and hormone signal transduction. Furthermore, the differences in hormone (auxin, cytokinin, gibberellin, salicylic acid, jasmonic acid, brassinosteroid and ethylene) synthesis and transduction ability could partially explain the higher EC induction ratio in the inbred line 18-599R. During EC formation, repression of the "histone deacetylase 2 and ERF transcription factors" complex in 18-599R activated the expression of downstream genes, which further promoted EC induction. Together, our data provide new insights into the molecular regulatory mechanism responsible for efficient EC induction in maize.
Quiescence of adult oligodendrocyte precursor cells requires thyroid hormone and hypoxia to activate Runx1
Apr 22, 2017   Scientific Reports
Tokumoto Y, Tamaki S, Kabe Y, Takubo K, Suematsu M
Quiescence of adult oligodendrocyte precursor cells requires thyroid hormone and hypoxia to activate Runx1
Apr 22, 2017
Scientific Reports
The adult mammalian central nervous system (CNS) contains a population of slowly dividing oligodendrocyte precursor cells (OPCs), i.e., adult OPCs, which supply new oligodendrocytes throughout the life of animal. While adult OPCs develop from rapidly dividing perinatal OPCs, the mechanisms underlying their quiescence remain unknown. Here, we show that perinatal rodent OPCs cultured with thyroid hormone (TH) under hypoxia become quiescent and acquire adult OPCs-like characteristics. The cyclin-dependent kinase inhibitor p15/INK4b plays crucial roles in the TH-dependent cell cycle deceleration in OPCs under hypoxia. Klf9 is a direct target of TH-dependent signaling. Under hypoxic conditions, hypoxia-inducible factors mediates runt-related transcription factor 1 activity to induce G1 arrest in OPCs through enhancing TH-dependent p15/INK4b expression. As adult OPCs display phenotypes of adult somatic stem cells in the CNS, the current results shed light on environmental requirements for the quiescence of adult somatic stem cells during their development from actively proliferating stem/progenitor cells.
FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology
Apr 22, 2017   Blood
Vo KK, Jarocha DJ, Lyde RB, Hayes V, Thom CS, Sullivan SK, French DL, Poncz M
FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology
Apr 22, 2017
Blood
Friend Leukemia Virus Integration 1 (FLI1), a critical transcription factor (TF) during megakaryocyte differentiation, is amongst genes hemizygously deleted in Jacobsen syndrome, resulting in a macrothrombocytopenia termed Paris-Trousseau syndrome (PTSx). Recently, heterozygote human FLI1 mutations have been ascribed to cause thrombocytopenia. We studied induced-pluripotent stem cell (iPSC)-derived megakaryocytes (iMegs) to better understand these clinical disorders, beginning with iPSCs generated from a PTSx patient and iPSCs from a control line with a targeted heterozygous FLI1 knockout (FLI1+/-). PTSx and FLI1+/- iMegs replicate many of the described megakaryocyte/platelet features including a decrease in iMeg yield and fewer platelets released per iMeg. Platelets released in vivo from infusion of these iMegs had poor half-lives and functionality. We noted that the closely-linked ETS Proto-Oncogene 1 (ETS1) is over-expressed in these FLI1-deficient iMegs, suggesting that FLI1 negatively regulates ETS1 in megakaryopoiesis. Finally, we examined whether FLI1 overexpression would affect megakaryopoiesis and thrombopoiesis. We found increased yield of non-injured, in vitro iMeg yield and increased in vivo yield, half-life and functionality of released platelets. These studies confirm FLI1 heterozygosity results in pleiotropic defects similar to those noted with other critical megakaryocyte-specific TFs; however, unlike those TFs, FLI1 overexpression improved yield and functionality. Copyright © 2017 American Society of Hematology.
Clinicopathologic, Radiologic, and Molecular Study of 23 Combined Hepatocellular-Cholangiocarcinomas with Stem Cell Features, Cholangiolocellular Type
Apr 22, 2017   Human Pathology
Chen J, He J, Deng M, Wu HY, Shi J, Mao L, Sun Q, Tang M, Fan XS, Qiu YD, Huang Q
Clinicopathologic, Radiologic, and Molecular Study of 23 Combined Hepatocellular-Cholangiocarcinomas with Stem Cell Features, Cholangiolocellular Type
Apr 22, 2017
Human Pathology
Cholangiolocellular carcinoma is a type of intrahepatic cholangiocarcinoma (ICC). According to the 2010 World Health Organization classification, this carcinoma is a combined hepatocellular-cholangiocarcinoma with stem cell features, cholangiolocellular type (CHC-SC-CLC). The aim of this study was to compare the clinicopathologic characteristics of CHC-SC-CLC and conventional ICC. Based on the gross and histologic characteristics, we divided consecutive ICC tumors into CHC-SC-CLC (n = 23), mass-forming (MF, n = 57), and non-MF (n = 22) groups. Compared with MF and non-MF groups, the CHC-SC-CLC group featured history of hepatolithiasis or bile duct operation in significantly fewer patients (4.3% versus 14.8% and 86.4%, respectively; P < .001) and was more common in the right lobe (70% versus 47% and 27%; P =.033) but lower frequency of invasive growth or peritumoral Glisson's sheath invasion (PGSI; 61% and 22% versus 77% and 33% and 100% and 86%, respectively; P = .002 and P < .001) and absence of mucous production (0 versus 77% and 96%; P < .001). In CHC-SC-CLCs, the mutation rate of isocitrate dehydrogenase 1 (IDH1) or IDH2 was significantly higher (35%) than in MF (4%) or non-MF (0) ICCs (P < .001). The 1-, 3-, and 5-year post-resection survival rates were also significantly better with CHC-SC-CLCs (93%, 79%, and 52%, respectively) than with MF (72%, 46%, and 40%) or non-MF (61%, 18%, and 0) ICCs (P = .041). Thus, CHC-SC-CLC tumors demonstrated an indolent growth pattern, more frequent IDH1/2 gene mutations, and better prognosis than MF or non-MF ICC tumors. Copyright © 2017. Published by Elsevier Inc.
Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing
Apr 21, 2017   Oncotarget
Xue D, Zhang W, Chen E, Gao X, Liu L, Ye C, Tan Y, Pan Z, Li H
Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing
Apr 21, 2017
Oncotarget
Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.
A Determined "Hesitation" on H3K27me3 Empowers Stem Cells to Differentiate
Apr 21, 2017   Molecular Cell
Huang X, Wang J
A Determined "Hesitation" on H3K27me3 Empowers Stem Cells to Differentiate
Apr 21, 2017
Molecular Cell
To uncover the precise mechanisms coordinating proliferation and fate choice of stem cells, in this issue of Molecular Cell and in an accompanying paper in Cell Reports, Mazo and colleagues (Petruk et al. 2017a, 2017b) reveal that delayed accumulation of H3K27me3 on nascent DNA is essential to recruit pioneer transcription factors in stem cell differentiation. Copyright © 2017 Elsevier Inc. All rights reserved.
Genetic analysis of α-synuclein 3' untranslated region and its corresponding microRNAs in relation to Parkinson's compared to dementia with Lewy bodies
Apr 21, 2017   Alzheimer's & Dementia : The Journal Of The Alzheimer's Association
Tagliafierro L, Glenn OC, Zamora ME, Beach TG, Woltjer RL, Lutz MW, Chiba-Falek O
Genetic analysis of α-synuclein 3' untranslated region and its corresponding microRNAs in relation to Parkinson's compared to dementia with Lewy bodies
Apr 21, 2017
Alzheimer's & Dementia : The Journal Of The Alzheimer's Association
The α-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A computational analysis of SNCA 3' untranslated region to identify potential microRNA (miRNA) binding sites and quantitative real-time PCR to determine their expression in isogenic induced pluripotent stem cell-derived dopaminergic and cholinergic neurons as a model of PD and DLB, respectively, were performed. In addition, we performed a deep sequencing analysis of the SNCA 3' untranslated region of autopsy-confirmed cases of PD, DLB, and normal controls, followed by genetic association analysis of the identified variants. We identified four miRNA binding sites and observed a neuronal-type-specific expression profile for each miRNA in the different isogenic induced pluripotent stem cell-derived dopaminergic and cholinergic neurons. Furthermore, we found that the short structural variant rs33988309 poly-T was moderately associated with DLB but not with PD. We suggest that the regulation of SNCA expression through miRNAs is neuronal-type-specific expression. Furthermore, genetic variability in the SNCA gene may contribute to synucleinopathies in a pathology-specific manner. Copyright © 2017. Published by Elsevier Inc.
Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST-2 randomised placebo-controlled clinical trial
Apr 21, 2017   European Heart Journal
Wollert KC, Meyer GP, Müller-Ehmsen J, Tschöpe C, Bonarjee V,   . . . . . .   , Dickstein K, Schultheiss HP, Ladage D, Greulich S, Bauersachs J
Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST-2 randomised placebo-controlled clinical trial
Apr 21, 2017
European Heart Journal
Intracoronary infusion of autologous nucleated bone marrow cells (BMCs) enhanced the recovery of left ventricular ejection fraction (LVEF) after ST-segment elevation myocardial infarction (STEMI) in the randomised-controlled, open-label BOOST trial. We reassessed the therapeutic potential of nucleated BMCs in the randomised placebo-controlled, double-blind BOOST-2 trial conducted in 10 centres in Germany and Norway. Using a multiple arm design, we investigated the dose-response relationship and explored whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on BMC efficacy. Between 9 March 2006 and 16 July 2013, 153 patients with large STEMI were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose (hi)BMCs, low-dose (lo)BMCs, irradiated hiBMCs, or irradiated loBMCs 8.1 ± 2.6 days after percutaneous coronary intervention (PCI) in addition to guideline-recommended medical treatment. Change in LVEF from baseline (before cell infusion) to 6 months as determined by MRI was the primary endpoint. The trial is registered at Current Controlled Trials (ISRCTN17457407). Baseline LVEF was 45.0 ± 8.5% in the overall population. At 6 months, LVEF had increased by 3.3 percentage points in the control group and 4.3 percentage points in the hiBMC group. The estimated treatment effect was 1.0 percentage points (95% confidence interval, -2.6 to 4.7; P = 0.57). The treatment effect of loBMCs was 0.5 percentage points (-3.0 to 4.1; P = 0.76). Likewise, irradiated BMCs did not have significant treatment effects. BMC transfer was safe and not associated with adverse clinical events. The BOOST-2 trial does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF treated according to current standards of early PCI and drug therapy.
Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA
Apr 21, 2017   Human Molecular Genetics
Herai RH, Negraes PD, Muotri AR
Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA
Apr 21, 2017
Human Molecular Genetics
Mitochondria are thought to have originated as free-living prokaryotes. Mitochondria organelles have small circular genomes with substantial structural (absence of histones and introns) and genetic similarity to bacteria. Contrary to the prevailing concept of intronless mitochondria, here we present evidences that mitochondrial RNA transcripts (mtRNA) are not limited to policystronic molecules, but also processed as nuclei-like transcripts that are differentially spliced and expressed in a cell-type specific manner. The presence of canonical splice sites in the mtRNA introns and of core components of the nuclei-encoded spliceosome machinery within the mitochondrial organelle suggest that nuclei-encoded spliceosome can mediate splicing of mtRNA. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Involvement of Polo-like kinase 1 (Plk1) in quiescence regulation of cancer stem-like cells of the gastric cancer cell lines
Apr 21, 2017   Oncotarget
Zhu L, Xing S, Zhang L, Yu JM, Lin C, Yang WJ
Involvement of Polo-like kinase 1 (Plk1) in quiescence regulation of cancer stem-like cells of the gastric cancer cell lines
Apr 21, 2017
Oncotarget
Cancer stem cells (CSCs) have been hypothesized to initiate tumor growth and be resistant to chemoradiotherapy, and these processes appear to be closely related to CSC quiescence. Here, a CSC-like cell population with a high level of CD44 expression was obtained from the human gastric cancer cell lines MKN45 and MKN74. Using a PKH26-labeling retention assay, quiescent CSC-like cells with low levels of Ki67 and PCNA expression were found in spheres formed in serum-free medium, and exhibited resistance to drug and radiation treatments. Polo-like kinase 1 (Plk1) and ribosomal S6 kinase 1 (RSK1) were silenced in the quiescent CSC-like cells. The Plk1-specific inhibitors inhibited the activation of RSK1 and induced quiescence in the CSC-like cells, but increased RSK1 activity and resulted in apoptosis in non-CSCs. Furthermore, RSK1 silencing by inhibitors activated Plk1 and had no effect on the growth of spheres in the CSC-like cells, but did not affect phosphorylation of Plk1 and led to decreased proliferation in non-CSCs. Our results showed that Plk1 and RSK1 play important roles in the conversion of CSCs between active and quiescent states.
Reassembling embryos in vitro from component stem cells
Apr 21, 2017   Cell Research
Kubaczka C, Daley GQ
Reassembling embryos in vitro from component stem cells
Apr 21, 2017
Cell Research
Researchers at the University of Cambridge, UK have succeeded in reconstructing mouse embryos by combining pluripotent embryonic and multipotent trophoblast stem cells in a 3D scaffold; the study from the laboratory of Professor Zernicka-Goetz, recently published in Science, provides a break-through tool to probe early mammalian development outside the uterus. Achieving a similar feat with human cells might necessitate reconsideration of the 14-day rule as a limitation of such research.
Salvage use of allogeneic HSCT after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the EBMT Chronic Malignancies Working Party
Apr 21, 2017   Haematologica
Sobh M, Michallet M, Dubois V, Iacobelli S, Koster L,   . . . . . .   , Beguin Y, Gluckman E, Ruggeri A, Garderet L, Kröger N
Beyond growth signaling: Paneth cells metabolically suppport ISCs
Apr 21, 2017   Cell Research
Dayton TL, Clevers H
Beyond growth signaling: Paneth cells metabolically suppport ISCs
Apr 21, 2017
Cell Research
Single Lgr5 intestinal stem cells (ISCs) can be expanded in vitro into epithelial organoids or "mini-guts", self-organizing cellular structures that recreate the intestinal differentiation program; Paneth cells, which constitute the intestinal stem cell niche, secrete stem cell growth signals, and are thus essential for this process. In a recent paper published in Nature, Rodríguez-Colman et al. describe how Paneth cells may be supporting the metabolic state of ISCs.
A computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue
Apr 21, 2017   Nature Communications
Talos F, Mitrofanova A, Bergren SK, Califano A, Shen MM
A computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue
Apr 21, 2017
Nature Communications
To date, reprogramming strategies for generating cell types of interest have been facilitated by detailed understanding of relevant developmental regulatory factors. However, identification of such regulatory drivers often represents a major challenge, as specific gene combinations may be required for reprogramming. Here we show that a computational systems approach can identify cell type specification genes (master regulators) that act synergistically, and demonstrate its application for reprogramming of fibroblasts to prostate tissue. We use three such master regulators (FOXA1, NKX3.1 and androgen receptor, AR) in a primed conversion strategy starting from mouse fibroblasts, resulting in prostate tissue grafts with appropriate histological and molecular properties that respond to androgen-deprivation. Moreover, generation of reprogrammed prostate does not require traversal of a pluripotent state. Thus, we describe a general strategy by which cell types and tissues can be generated even with limited knowledge of the developmental pathways required for their specification in vivo.
Direct comparison of distinct naive pluripotent states in human embryonic stem cells
Apr 21, 2017   Nature Communications
Warrier S, Van der Jeught M, Duggal G, Tilleman L, Sutherland E,   . . . . . .   , Mestdagh P, Van de Sompele J, Deforce D, De Sutter P, Heindryckx B
Direct comparison of distinct naive pluripotent states in human embryonic stem cells
Apr 21, 2017
Nature Communications
Until recently, human embryonic stem cells (hESCs) were shown to exist in a state of primed pluripotency, while mouse embryonic stem cells (mESCs) display a naive or primed pluripotent state. Here we show the rapid conversion of in-house-derived primed hESCs on mouse embryonic feeder layer (MEF) to a naive state within 5-6 days in naive conversion media (NCM-MEF), 6-10 days in naive human stem cell media (NHSM-MEF) and 14-20 days using the reverse-toggle protocol (RT-MEF). We further observe enhanced unbiased lineage-specific differentiation potential of naive hESCs converted in NCM-MEF, however, all naive hESCs fail to differentiate towards functional cell types. RNA-seq analysis reveals a divergent role of PI3K/AKT/mTORC signalling, specifically of the mTORC2 subunit, in the different naive hESCs. Overall, we demonstrate a direct evaluation of several naive culture conditions performed in the same laboratory, thereby contributing to an unbiased, more in-depth understanding of different naive hESCs.
Melatonin antagonizes interleukin-18-mediated inhibition on neural stem cell proliferation and differentiation
Apr 21, 2017   Journal Of Cellular And Molecular Medicine
Li Z, Li X, Chan MTV, Wu WKK, Tan D, Shen J
Melatonin antagonizes interleukin-18-mediated inhibition on neural stem cell proliferation and differentiation
Apr 21, 2017
Journal Of Cellular And Molecular Medicine
Neural stem cells (NSCs) are self-renewing, pluripotent and undifferentiated cells which have the potential to differentiate into neurons, oligodendrocytes and astrocytes. NSC therapy for tissue regeneration, thus, gains popularity. However, the low survivals rate of the transplanted cell impedes its utilities. In this study, we tested whether melatonin, a potent antioxidant, could promote the NSC proliferation and neuronal differentiation, especially, in the presence of the pro-inflammatory cytokine interleukin-18 (IL-18). Our results showed that melatonin per se indeed exhibited beneficial effects on NSCs and IL-18 inhibited NSC proliferation, neurosphere formation and their differentiation into neurons. All inhibitory effects of IL-18 on NSCs were significantly reduced by melatonin treatment. Moreover, melatonin application increased the production of both brain-derived and glial cell-derived neurotrophic factors (BDNF, GDNF) in IL-18-stimulated NSCs. It was observed that inhibition of BDNF or GDNF hindered the protective effects of melatonin on NSCs. A potentially protective mechanism of melatonin on the inhibition of NSC's differentiation caused IL-18 may attribute to the up-regulation of these two major neurotrophic factors, BNDF and GNDF. The findings indicate that melatonin may play an important role promoting the survival of NSCs in neuroinflammatory diseases. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Induced pluripotent stem cells reduce neutrophil chemotaxis via activating GRK2 in endotoxin-induced acute lung injury
Apr 21, 2017   Respirology (Carlton, Vic.)
Su VY, Chiou SH, Lin CS, Chen WC, Yu WK, Chen YW, Chen CY, Yang KY
Induced pluripotent stem cells reduce neutrophil chemotaxis via activating GRK2 in endotoxin-induced acute lung injury
Apr 21, 2017
Respirology (Carlton, Vic.)
We investigated the effect of induced pluripotent stem cells (iPSCs) in moderating neutrophil chemotaxis in endotoxin-induced acute lung injury (ALI). Male C57BL/6 mice at 8-12 weeks of age were studied. Murine iPSCs were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathological findings, neutrophil counts in peripheral blood and bronchoalveolar lavage fluid (BALF), bone marrow (BM) cell distribution, expression of chemokine receptors and regulatory signalling pathways were analysed after 24 h. Human neutrophils isolated from acute respiratory distress syndrome patients were used in a cell migration assay. iPSCs significantly decreased the histopathological changes of ALI in mice compared to treatment with control cells. Numbers and activity levels of neutrophils in BALF were reduced in iPSC-treated ALI mice. The iPSC therapy restored neutrophil counts in the peripheral blood of ALI mice, but the percentages of mature neutrophils in BM were similar between iPSC-treated and -untreated groups. The iPSCs mediated a downregulation of the chemotactic response to endotoxin by reducing chemokine (C-X-C motif) receptor 2 (CXCR2) expression on mouse peripheral blood neutrophils. This result was confirmed by an in vitro human neutrophil migration assay. In addition, iPSCs or conditioned medium from iPSCs enhanced expression of G protein-coupled receptor kinase 2 (GRK2) on the surface of blood neutrophils in ALI mice. iPSCs reduce neutrophil chemotaxis in endotoxin-induced ALI. These effects are associated with an enhancement of GRK2 activity and reduction of CXCR2 expression. © 2017 Asian Pacific Society of Respirology.
Human circulating and tissue gastric cancer stem cells display distinct epithelial-mesenchymal features and behaviors
Apr 21, 2017   Journal Of Cancer Research And Clinical Oncology
Zhang S, Shang Y, Chen T, Zhou X, Meng W, Fan C, Lu R, Huang Q, Li X, Hong X, Zhou Z, Hu J, Mo X
Human circulating and tissue gastric cancer stem cells display distinct epithelial-mesenchymal features and behaviors
Apr 21, 2017
Journal Of Cancer Research And Clinical Oncology
Metastasis is a leading cause of cancer-related-deaths worldwide. Recently, cancer stem cells (CSCs) have been believed to be responsible for tumor initiation and metastasis, but till now, difference of cellular features and behaviors between CSCs from tumor tissues (TCSCs) and circulation (CCSCs) remains largely unknown, which hinders the progression of targeted therapies for metastasis. Here, we provide the features of circulating gastric cancer stem cells (CGCSCs) isolated from human gastric adenocarcinoma. The CGCSCs and TGCSCs were culture in a same serum free stem cell culture medium, however the morphology are different with each other. EMT-associated markers were measured by Immunofluorescence, Western Blotting, and RT-PCR methods, and the results indicated that the CGCSCs and TGCSCs carry different epithelial-mesenchymal features. And then, proliferation and apoptosis assays revealed that the CGCSCs exhibited characteristics of higher proliferation and resistance to apoptosis in vitro. Soft agar assay and nude mice tumorigenicity assay displayed strong tumorigenicity of CGCSCs. Finally, Matrigel invasion assays and in vivo experimental metastasis assay were also performed, which demonstrated that CGCSCs carry high invasive and metastatic capabilities than TGCSCs. As expected, the CGCSCs indeed showed extremely invasive and metastatic properties. They also exhibited distinctive mesenchymal phenotypes, high self-renewal, proliferative capabilities, tumor induction and low apoptosis. Interestingly, CGCSCs show small cell-size than TGCSCs (tissue gastric cancer stem cells). The findings might help us to understand the biological characteristic of CGCSCs deeply, and give light to strategies for cancer therapies.
Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia
Apr 21, 2017   Journal Of Molecular Medicine (Berlin, Germany)
Basilico S, Göttgens B
Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia
Apr 21, 2017
Journal Of Molecular Medicine (Berlin, Germany)
Haematopoietic stem cells (HSC) are situated at the apex of the haematopoietic differentiation hierarchy, ensuring the life-long supply of mature haematopoietic cells and forming a reservoir to replenish the haematopoietic system in case of emergency such as acute blood loss. To maintain a balanced production of all mature lineages and at the same time secure a stem cell reservoir, intricate regulatory programs have evolved to control multi-lineage differentiation and self-renewal in haematopoietic stem and progenitor cells (HSPCs). Leukaemogenic mutations commonly disrupt these regulatory programs causing a block in differentiation with simultaneous enhancement of proliferation. Here, we briefly summarize key aspects of HSPC regulatory programs, and then focus on their disruption by leukaemogenic fusion genes containing the mixed lineage leukaemia (MLL) gene. Using MLL as an example, we explore important questions of wider significance that are still under debate, including the importance of cell of origin, to what extent leukaemia oncogenes impose specific regulatory programs and the relevance of leukaemia stem cells for disease development and prognosis. Finally, we suggest that disruption of stem cell regulatory programs is likely to play an important role in many other pathologies including ageing-associated regenerative failure.
Transcription Factor Antagonism Controls Enteroendocrine Cell Specification from Intestinal Stem Cells
Apr 21, 2017   Scientific Reports
Li Y, Pang Z, Huang H, Wang C, Cai T, Xi R
Transcription Factor Antagonism Controls Enteroendocrine Cell Specification from Intestinal Stem Cells
Apr 21, 2017
Scientific Reports
The balanced maintenance and differentiation of local stem cells is required for Homeostatic renewal of tissues. In the Drosophila midgut, the transcription factor Escargot (Esg) maintains undifferentiated states in intestinal stem cells, whereas the transcription factors Scute (Sc) and Prospero (Pros) promote enteroendocrine cell specification. However, the mechanism through which Esg and Sc/Pros coordinately regulate stem cell differentiation is unknown. Here, by combining chromatin immunoprecipitation analysis with genetic studies, we show that both Esg and Sc bind to a common promoter region of pros. Moreover, antagonistic activity between Esg and Sc controls the expression status of Pros in stem cells, thereby, specifying whether stem cells remain undifferentiated or commit to enteroendocrine cell differentiation. Our study therefore reveals transcription factor antagonism between Esg and Sc as a novel mechanism that underlies fate specification from intestinal stem cells in Drosophila.
Double duty for mammary stem cell niche
Apr 21, 2017   Science (New York, N.Y.)
Purnell BA
Decoding hormones for a stem cell niche
Apr 21, 2017   Science (New York, N.Y.)
Robertson C
Prognostic impact of PD-1 and its ligands in renal cell carcinoma
Apr 22, 2017   Medical Oncology (Northwood, London, England)
Erlmeier F, Weichert W, Schrader AJ, Autenrieth M, Hartmann A, Steffens S, Ivanyi P
Prognostic impact of PD-1 and its ligands in renal cell carcinoma
Apr 22, 2017
Medical Oncology (Northwood, London, England)
Programmed death-1 receptor (PD-1) and programmed death-1 receptor-ligand (PD-L1) have been suggested to play a role as prognostic markers in clear cell renal cell carcinoma (ccRCC). The association between PD-L1 and prognosis seems to be more robust than for PD-1. Further, preliminary analyses suggest that neither PD-1 nor its ligands play a role as prognostic markers in non-clear cell RCC, while the prognostic role of PD-L2 in ccRCC as well as in non-clear cell RCC remains unclear.

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