scholarly journals ASXL2 Is Required for Normal Hematopoiesis and Loss of asxl2 Leads to Myeloid Malignancies in Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1509-1509
Author(s):  
Jianping Li ◽  
Fuhong He ◽  
Peng Zhang ◽  
Shi Chen ◽  
Hui Shi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Myeloid Cell ◽  
Gene Set Enrichment Analysis ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Myeloid Malignancies

Abstract Somatic mutations and chromosomal translocations of genes have emerged as major drivers in a range of hematopoietic malignancies. While ASXL1 is mutated in all forms of myeloid malignancies, ASXL2 is specifically mutated in t(8;21) AML patients. ASXL1 and ASXL2 mutations are mutually exclusive in t(8;21) AML. Despite the importance of ASXL2 mutations in clinical, it's role in leukemogenesis remain unknown. In the current study, we sought to dissect the role of ASXL2 in normal hematopoiesis and to identify the molecular mechanisms by which Asxl2 loss contributes to myeloid malignancies. In the current study, we utilized a mouse model of Asxl2 to characterize the hematopoietic features of in vivo. Asxl2-/- mice were characterized by pancytopenia and dysplastic features, including hyposegmented (bilobed) neutrophils with fine nuclear bridging (consistent with pseudo Pelger-Huët) and increased number of polychromatophilic red blood cells (RBCs), reminiscent of myelodysplastic syndrome (MDS). Flow cytometric analyses revealed that Asxl2-/- mice had an increased proportion of granulocytic/monocytic cells (Gr-1+/Mac1+) in the PB, BM and spleens compared to WT mice. The histologic analysis of the Asxl2+/- and Asxl2-/- spleen sections showed disrupted splenic architecture with an increased proportion of myeloid cells and massive accumulation of myeloperoxidase (MPO) positive cells in WT spleens. Asxl2-/- mice had an increased long-term (LH)-HSCs and granulocyte-macrophage progenitor (GMP) cells compared to WT mice.Consistently, the paired-daughter cell assays revealed that Asxl2-/- CD34-LSK BM cells had a higher proportion of cells with symmetric self-renewal capacity (SS, 62%) than WT cells (33%). In contrast, a significant reduction in the cells with symmetric differentiation potential was observed in Asxl2-/- HSCs (18%) compared to WT HSCs (40%), indicating a critical role of ASXL2 in the balance between the symmetric and asymmetric division of HSCs. Transplantation assays revealed that recipients transplanted with Asxl2-/- and Asxl2+/- bone marrow cells had shortened lifespan due to the development of MDS or AML, suggesting a cell-autonomous effect of Asxl2-loss in HSC/HPC functions. Furthermore, Asxl2-loss further increase the colony-forming potential and colony replating capacity of AML1-ETO expressing HSCs in vitro, suggesting a cooperative effect between AML1/ETO9a and Asxl2+/-to promote HSC self-renewal. RNA-seq analysis showed a unique signature of Asxl2-/- LK cells compared to WT LK cells. Gene set enrichment analysis revealed that altered expressed genes in Asxl2-/-LK cells were enriched in myeloid cell differentiation, hematopoiesis, apoptosis, and chromatin/nucleosome assembly signature. ChIP-seq analysis showed that differentially expressed genes were associated with dysregulated histone enhancer markers, including H3K27ac, H3K4me1, and H3K4me2. Further analysis demonstrated that the alteration of H3K27ac enrichment had a greater impact on gene expression, in comparison to H3K4me1/2. KEGG pathway analysis showed that genes with differential H3K27ac signals were enriched for hematopoietic cell lineage, cancer signaling pathway and myeloid leukemia development. IPA analysis further confirmed that genes with altered enrichment levels of were enriched in myeloid cell differentiation and apoptosis pathways. Altogether, these data suggest that ASXL2 regulates gene expression mainly through enhancer markers. Our results demonstrate that ASXL2 plays an important role in normal hematopoiesis, and Asxl2-loss in mice is sufficient to cause MDS-like disease and leukemia transformation. These results indicate that ASXL2 functions as a tumor suppressor in myelopoiesis. The Asxl2 knock-out mice present an ideal model for unveiling the mechanisms underlying the Asxl2-loss mediated multiple-step pathogenesis of myeloid malignancies and for testing novel therapeutic agents for myeloid malignant patients with ASXL2 alterations. Further studies to dissect the possible roles of ASXL2alterations in leukemogenesis and to identify therapeutic vulnerabilities they may create are ongoing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transcription Factor Bach1 and Bach2 Control Common Myeloid Progenitor Cell Differentiation Under Infectious Stimuli

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1164-1164
Author(s):  
Hiroki Kato ◽  
Ari Itoh-Nakadai ◽  
Risa Ebina-Shibuya ◽  
Masahiro Kobayashi ◽  
Mitsuyo Matsumoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Progenitor Cells ◽  
Research Funding ◽  
Myeloid Cell ◽  
Gene Set Enrichment Analysis ◽  
Mrna Levels ◽  
Myeloid Progenitor ◽  
Dd Mice ◽  
Stimulation Of

Abstract Background: Erythrocyte and granulocyte/macrophage develop from common myeloid progenitor (CMP) (Akashi et al., 2000). Differentiation of hematopoietic progenitor cells is precisely controlled by multiple transcription factors, among which GATA1, C/EBPα, C/EBPβ and Spi-C play pivotal roles in erythrocyte and granulocyte/macrophage differentiation (Mancini et al., 2012; Pongubala et al., 2008; Hirai et al., 2006; Haldar et al., 2014). However, the mechanism by which the differentiation of CMP controlled under infectious condition has been unclear. Bach1 and Bach2 belong to the basic region-leucine zipper family and recognize Maf-recognition elements (Oyake et al., 1996). They promote B cell development by repressing the myeloid genes such as Cebpb and Spic in common lymphoid progenitor cells (Itoh-Nakadai et al., 2014). In addition, Bach1 regulates several target genes related to iron/heme homeostasis such as globin genes and hemeoxygenase-1, and Bach2 may similarly regulate these genes (Igarashi, 2014). Therefore, it is expected that both Bach1 and Bach2 play redundant roles in erythropoiesis. To figure out their roles in erythroid and myeloid cell differentiation, we performed hematological and transcriptomics analyses using Bach1-/- Bach2-/- (double-deficient; DD) mice. Methods: The generation of DD mice on the C57BL/6J background and Bach2 reporter mice with red fluorescent protein coding cDNA inserted in the Bach2 locus were described previously (Itoh-Nakadai et al., 2014). Mice between 8-12 weeks old were analyzed in the present study. Bone marrow (BM) cells were stained with specific combinations of antibodies to identify erythroid/myeloid progenitor and mature cells (Sheila et al., 2008; Cornelis et al., 2007; Socolovsky et al., 2001). Flow cytometry analysis and cell sorting were performed by using FACSAriaⅡ(BD) and FlowJo software (TreeStar). For infectious simulation of CMP, sorted CMPs were incubated with 1μg/ml LPS (Sigma) for 48h and RNA was purified with RNeasy micro kit (Qiagen). Quantitative PCR by using SuperscriptⅢ reverse transcriptase (Invitrogen) and Light Cycler system (Roche) was performed according to manufacturer's instructions. Microarray analysis by using Sure-Print G3 mouse GE microarray slide (Agilent) was performed as previously described (Itoh-Nakadai et al., 2014) and the results were analyzed by using GeneSpring software (Agilent). We used Gene Set Enrichment Analysis (GSEA) to interpret gene expression data (Subramanian et al., 2005; Mootha et al., 2003). LPS stimulation (50 μg/body) of mice was performed as previously described (Ryan et al., 2008). Data were analyzed by the two-sided Student's t-test and p - values of <0.05 were considered statistically significant. Results: DD mice show mild normocytic anemia compered to wild-type (WT), Bach1-/-, and Bach2-/- mice (hemoglobin; 14.4±0.2, 14.0±0.3, 13.5±0.3 and 11.9±0.7 g/dl, for WT, Bach1-/-, Bach2-/- and DD, respectively, p<0.05 for comparison between DD and other genotypes, n=7). Immature and mature erythroblast populations were significantly decreased in BM of DD (immature; 25.8±1.78, 15.6±1.4, mature; 27.6±3.3, 17.4±2.3×106/body for WT and DD, respectively, p<0.05, n=6). Megakaryocyte-erythroid progenitor (MEP)/granulocyte-monocyte progenitor (GMP) ratio was significantly decreased in BM of DD (MEP/GMP: 0.13±0.01, 0.07±0.01 for WT and DD, respectively, p<0.05, n=5). Bach2 expression was detected in CMP, MEP and even GMP by using Bach2-RFP mice. LPS stimulation of WT CMP significantly decreased mRNA levels of Bach1, Bach2 and Gata1. On the other hand, Cebpb and Spic mRNA levels were significantly increased. LPS stimulation of WT mice induced significant increase of granulocyte and decrease of erythrocyte and B lymphocyte in BM, which was consistent with previous reports. It was also shown that LPS stimulation significantly decreased MEP/ GMP ratio. According to the clustering analysis of the microarray data of CMP sorted from WT and DD mice, they showed clearly different expression profiles. GSEA showed that CMP of DD skewed to myeloid cell lineage and lost the erythroid gene expression compared to WT. Conclusions: Bach1 and Bach2 control the differentiation of CMP to erythroid cell or myeloid cell by repressing myeloid genes such as Cebpb and Spic. Infectious stimuli may promote myeloid cell differentiation by reducing the expression of Bach1 and Bach2 in CMP. Disclosures Fujiwara: Chugai Pharmaceutical CO., LTD: Research Funding. Harigae:Chugai Pharmaceutical CO., LTD: Research Funding.

scholarly journals Essential role of spi-1–like (spi-1l) in zebrafish myeloid cell differentiation

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 2038-2046 ◽  
Author(s):  
Alex Bukrinsky ◽  
Kevin J. P. Griffin ◽  
Yan Zhao ◽  
Shuo Lin ◽  
Utpal Banerjee
Keyword(s):  
Functional Analysis ◽  
Transcription Factor ◽  
Cell Differentiation ◽  
Essential Role ◽  
Critical Role ◽  
Myeloid Cell ◽  
Myeloid Differentiation ◽  
Adult Kidney ◽  
Necessary And Sufficient

The ETS protein Spi-1/Pu.1 plays a pivotal and widespread role throughout hematopoiesis in many species. This study describes the identification, characterization, and functional analysis of a new zebrafish spi transcription factor spi-1–like (spi-1l) that is expressed in primitive myeloid cells, erythro-myelo progenitor cells, and in the adult kidney. Spi-1l functions genetically downstream of etsrp, scl, and spi-1/pu.1 in myeloid differentiation. Spi-1l is coexpressed in a subset of spi-1/pu.1 cells and its function is necessary and sufficient for macrophage and granulocyte differentiation. These results establish a critical role for spi-1l in zebrafish myeloid cell differentiation.

scholarly journals RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Rabindranath Bera ◽  
Ming-Chun Chiu ◽  
Ying-Jung Huang ◽  
Tung-Huei Lin ◽  
Ming-Chung Kuo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Mouse Bone Marrow ◽  
Myeloid Malignancies ◽  
Inhibitor Of Dna Binding

Abstract Background Additional sex combs-like 1 (ASXL1) mutations have been described in all forms of myeloid neoplasms including chronic myelomonocytic leukemia (CMML) and associated with inferior outcomes, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) remains poorly understood. Transformation of CMML to secondary AML (sAML) is one of the leading causes of death in CMML patients. Previously, we observed that transcription factor RUNX1 mutations (RUNX1-MT) coexisted with ASXL1-MT in CMML and at myeloid blast phase of chronic myeloid leukemia. The contribution of RUNX1 mutations in the pathogenesis of myeloid transformation in ASXL1-mutated leukemia, however, remains unclear. Methods To evaluate the leukemogenic role of RUNX1-MT in ASXL1-mutated cells, we co-expressed RUNX1-MT (R135T) and ASXL1-MT (R693X) in different cell lines and performed immunoblot, co-immunoprecipitation, gene expression microarray, quantitative RT-PCR, cell proliferation, differentiation, and clonogenic assays for in vitro functional analyses. The in vivo effect was investigated using the C57BL/6 mouse bone marrow transplantation (BMT) model. Results Co-expression of two mutant genes increased myeloid stem cells in animal model, suggesting that cooperation of RUNX1 and ASXL1 mutations played a critical role in leukemia transformation. The expression of RUNX1 mutant in ASXL1-mutated myeloid cells augmented proliferation, blocked differentiation, and increased self-renewal activity. At 9 months post-BMT, mice harboring combined RUNX1 and ASXL1 mutations developed disease characterized by marked splenomegaly, hepatomegaly, and leukocytosis with a shorter latency. Mice transduced with both ASXL1 and RUNX1 mutations enhanced inhibitor of DNA binding 1 (ID1) expression in the spleen, liver, and bone marrow cells. Bone marrow samples from CMML showed that ID1 overexpressed in coexisted mutations of RUNX1 and ASXL1 compared to normal control and either RUNX1-MT or ASXL1-MT samples. Moreover, the RUNX1 mutant protein was more stable than WT and increased HIF1-α and its target ID1 gene expression in ASXL1 mutant cells. Conclusion The present study demonstrated the biological and functional evidence for the critical role of RUNX1-MT in ASXL1-mutated leukemia in the pathogenesis of myeloid malignancies.

scholarly journals The Transcription Factor OVOL2 Represses ID2 and Drives Differentiation of Trophoblast Stem Cells and Placental Development in Mice

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 840 ◽  
Author(s):  
Mariyan J. Jeyarajah ◽  
Gargi Jaju Bhattad ◽  
Dendra M. Hillier ◽  
Stephen J. Renaud
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Critical Role ◽  
Dominant Negative ◽  
Placental Development ◽  
Differentiation Potential ◽  
Helix Loop Helix ◽  
Trophoblast Stem

Trophoblasts are the first cell type to be specified during embryogenesis, and they are essential for placental morphogenesis and function. Trophoblast stem (TS) cells are the progenitor cells for all trophoblast lineages; control of TS cell differentiation into distinct trophoblast subtypes is not well understood. Mice lacking the transcription factor OVO-like 2 (OVOL2) fail to produce a functioning placenta, and die around embryonic day 10.5, suggesting that OVOL2 may be critical for trophoblast development. Therefore, our objective was to determine the role of OVOL2 in mouse TS cell fate. We found that OVOL2 was highly expressed in mouse placenta and differentiating TS cells. Placentas and TS cells lacking OVOL2 showed poor trophoblast differentiation potential, including increased expression of stem-state associated genes (Eomes, Esrrb, Id2) and decreased levels of differentiation-associated transcripts (Gcm1, Tpbpa, Prl3b1, Syna). Ectopic OVOL2 expression in TS cells elicited precocious differentiation. OVOL2 bound proximate to the gene encoding inhibitor of differentiation 2 (ID2), a dominant negative helix-loop-helix protein, and directly repressed its activity. Overexpression of ID2 was sufficient to reinforce the TS cell stem state. Our findings reveal a critical role of OVOL2 as a regulator of TS cell differentiation and placental development, in-part by coordinating repression of ID2.

scholarly journals Reorganisation of chromatin during erythroid differentiation

2019 ◽  
Vol 23 (1) ◽  
pp. 95-99
Author(s):  
A. A. Khabarova ◽  
A. S. Ryzhkova ◽  
N. R. Battulin
Keyword(s):  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Erythroid Differentiation ◽  
Gene Activity ◽  
Nuclear Space ◽  
Specific Cell ◽  
Cell Type ◽  
Differentiation Potential

A totipotent zygote has unlimited potential for differentiation into all cell types found in an adult organism. During ontogenesis proliferating and maturing cells gradually lose their differentiation potential, limiting the spectrum of possible developmental transitions to a specific cell type. Following the initiation of the developmental program cells acquire specific morphological and functional properties. Deciphering the mechanisms that coordinate shifts in gene expression revealed a critical role of three-dimensional chromatin structure in the regulation of gene activity during lineage commitment. Several levels of DNA packaging have been recently identified using chromosome conformation capture based techniques such a Hi-C. It is now clear that chromatin regions with high transcriptional activity assemble into Mb-scale compartments in the nuclear space, distinct from transcriptionally silent regions. More locally chromatin is organized into topological domains, serving as functionally insulated units with cell type – specific regulatory loop interactions. However, molecular mechanisms establishing and maintaining such 3D organization are yet to be investigated. Recent focus on studying chromatin reorganization accompanying cell cycle progression and cellular differentiation partially explained some aspects of 3D genome folding. Throughout erythropoiesis cells undergo a dramatic reorganization of the chromatin landscape leading to global nuclear condensation and transcriptional silencing, followed by nuclear extrusion at the final stage of mammalian erythropoiesis. Drastic changes of genome architecture and function accompanying erythroid differentiation seem to be an informative model for studying the ways of how genome organization and dynamic gene activity are connected. Here we summarize current views on the role of global rearrangement of 3D chromatin structure in erythroid differentiation.

scholarly journals Gene expression in mouse brain following chronic hypoxia: role of sarcospan in glial cell death

2008 ◽  
Vol 32 (3) ◽  
pp. 370-379 ◽  
Author(s):  
Dan Zhou ◽  
Jiyi Wang ◽  
Matthew A. Zapala ◽  
Jin Xue ◽  
Nicholas J. Schork ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
High Altitude ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Brain Regions ◽  
Cortical Region ◽  
Chronic Lung Diseases

Hypoxia is a hallmark of respiratory, neurological, or hematological diseases as well as life at high altitude. For example, chronic constant hypoxia (CCH) occurs in chronic lung diseases or at high altitude, whereas chronic intermittent hypoxia (CIH) occurs in diseases such as sleep apnea or sickle cell disease. Despite the fact that such conditions are frequent, the cellular and molecular mechanisms underlying the effect of hypoxia, whether constant or intermittent, are not well understood. In this study, we first determined the effect of CCH and CIH on global gene expression in different regions of mouse brain using microarrays and then investigated the biological role of genes of interest. We found that: 1) in the cortical region, the expression level of 80 genes was significantly altered by CIH (16 up- and 64 downregulated), and this number increased to 137 genes following CCH (34 up- and 103 downregulated); 2) a similar number of gene alterations was identified in the hippocampal area, and the majority of the changes in this region were upregulations; 3) two genes (Sspn and Ttc27) were downregulated in both brain regions and following both treatments; and 4) RNA interference-mediated knockdown of Sspn increased cell death in hypoxia in a cell culture system. We conclude that CIH or CCH induced significant and distinguishable alterations in gene expression in cortex and hippocampus and that Sspn seems to play a critical role in inducing cell death under hypoxic conditions.

scholarly journals Decreased myoblast differentiation in chronic binge alcohol-administered simian immunodeficiency virus-infected male macaques: role of decreased miR-206

2017 ◽  
Vol 313 (3) ◽  
pp. R240-R250 ◽  
Author(s):  
L. Simon ◽  
S. M. Ford ◽  
K. Song ◽  
P. Berner ◽  
C. Vande Stouwe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Simian Immunodeficiency Virus ◽  
Critical Role ◽  
Myoblast Differentiation ◽  
Differentiation Potential ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Underlying Mechanisms

Skeletal muscle stem cells play a critical role in regeneration of myofibers. We previously demonstrated that chronic binge alcohol (CBA) markedly attenuates myoblast differentiation potential and myogenic gene expression. Muscle-specific microRNAs (miRs) are implicated in regulation of myogenic genes. The aim of this study was to determine whether myoblasts isolated from asymptomatic CBA-administered simian immunodeficiency virus (SIV)-infected macaques treated with antiretroviral therapy (ART) showed similar impairments and, if so, to elucidate potential underlying mechanisms. Myoblasts were isolated from muscle at 11 mo after SIV infection from CBA/SIV macaques and from time-matched sucrose (SUC)-treated SIV-infected (SUC/SIV) animals and age-matched controls. Myoblast differentiation and myogenic gene expression were significantly decreased in myoblasts from SUC/SIV and CBA/SIV animals compared with controls. SIV and CBA decreased muscle-specific miR-206 in plasma and muscle and SIV decreased miR-206 expression in myoblasts, with no statistically significant changes in other muscle-specific miRs. These findings were associated with a significant increase in histone deacetylase 4 (HDAC4) and decrease in myogenic enhancer factor 2C (MEF2C) expression in CBA/SIV muscle. Transfection with miR-206 inhibitor decreased myotube differentiation, increased expression of HDAC4, and decreased MEF2C, suggesting a critical role of miR-206 in myogenesis. Moreover, HDAC4 was confirmed to be a direct miR-206 target. These results support a mechanistic role for decreased miR-206 in suppression of myoblast differentiation resulting from chronic alcohol and SIV infection. The parallel changes in skeletal muscle and circulating levels of miR-206 warrant studies to establish the possible use of plasma miR-206 as an indicator of impaired muscle function.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

2020 ◽  
Vol 17 (4) ◽  
pp. 394-401
Author(s):  
Yuanhua Wu ◽  
Yuan Huang ◽  
Jing Cai ◽  
Donglan Zhang ◽  
Shixi Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Activity ◽  
Ht22 Cells ◽  
Cerebral Ischemic ◽  
Cerebral Ischemic Reperfusion ◽  
And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

Metabolic Regulation and Related Molecular Mechanisms in Various Stem Cell Functions

2020 ◽  
Vol 15 (6) ◽  
pp. 531-546 ◽  
Author(s):  
Hwa-Yong Lee ◽  
In-Sun Hong
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Oxidative Phosphorylation ◽  
Metabolic Pathways ◽  
Critical Role ◽  
The Self ◽  
Specific Cell ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Cell Functions

Recent studies on the mechanisms that link metabolic changes with stem cell fate have deepened our understanding of how specific metabolic pathways can regulate various stem cell functions during the development of an organism. Although it was originally thought to be merely a consequence of the specific cell state, metabolism is currently known to play a critical role in regulating the self-renewal capacity, differentiation potential, and quiescence of stem cells. Many studies in recent years have revealed that metabolic pathways regulate various stem cell behaviors (e.g., selfrenewal, migration, and differentiation) by modulating energy production through glycolysis or oxidative phosphorylation and by regulating the generation of metabolites, which can modulate multiple signaling pathways. Therefore, a more comprehensive understanding of stem cell metabolism could allow us to establish optimal culture conditions and differentiation methods that would increase stem cell expansion and function for cell-based therapies. However, little is known about how metabolic pathways regulate various stem cell functions. In this context, we review the current advances in metabolic research that have revealed functional roles for mitochondrial oxidative phosphorylation, anaerobic glycolysis, and oxidative stress during the self-renewal, differentiation and aging of various adult stem cell types. These approaches could provide novel strategies for the development of metabolic or pharmacological therapies to promote the regenerative potential of stem cells and subsequently promote their therapeutic utility.

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