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1
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Zhang T, Zheng Y, Zhang F, Wang X, Du J, Wang X. MiR-199a-5p inhibits dermal papilla cells proliferation by regulating VEGFA expression in cashmere goat. Gene 2024; 893:147901. [PMID: 37839765 DOI: 10.1016/j.gene.2023.147901] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 09/27/2023] [Accepted: 10/12/2023] [Indexed: 10/17/2023]
Abstract
Hair follicles undergo a renewal cycle consisting of anagen, telogen and catagen stages. MicroRNA (miRNA) plays a crucial role in this process. Recent studies have shown that miR-199a-5p, which exhibits differential expression between anagen and telogen stages in the hair follicle cycle of cashmere goats, inhibits the proliferation of various cell types, including skin keratinocytes and vascular endothelial cells. Since the proliferation of dermal papilla cells (DPCs) is a key factor in the hair follicle cycle, we utilized DPCs to investigate the function and molecular mechanism of miR-199a-5p in cashmere goats. Our functional analysis revealed that miR-199a-5p significantly suppressed cell viability and proliferation of DPCs, as evidenced by MTT, EdU and RT-qPCR methods. Subsequently, we investigated the regulatory mechanism of miR-199a-5p. Through bioinformatics analysis, a potential correlation between lnc102173187 and miR-199a-5p was predicted. However, the dual luciferase reporter assay revealed no interaction between lnc102173187 and miR-199a-5p. Further investigation using dual-luciferase reporter assay, RT-qPCR, and western blot results confirmed that VEGFA was the target gene of miR-199a-5p from. The functional experiment demonstrated that VEGFA promoted the proliferation of DPCs, and antagonized the inhibitory effect of miR-199a-5p on DPCs proliferation. Taken together, this research revealed the role of miR-199a-5p and VEGFA on the proliferation of dermal papilla cells in cashmere goat, which would enrich the theoretical basis for hair follicle development, and could also serve as a marker cofactor to play an important reference and guidance role in the breeding, improvement and optimization of cashmere goat breeds.
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Affiliation(s)
- Tongtong Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Yujie Zheng
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Fan Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Xinmiao Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Jiamian Du
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Xin Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
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2
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Li Q, Wang L, Tang C, Wang X, Yu Z, Ping X, Ding M, Zheng L. Adipose Tissue Exosome circ_sxc Mediates the Modulatory of Adiposomes on Brain Aging by Inhibiting Brain dme-miR-87-3p. Mol Neurobiol 2024; 61:224-238. [PMID: 37597108 DOI: 10.1007/s12035-023-03516-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/14/2023] [Indexed: 08/21/2023]
Abstract
Aging of the brain usually leads to the decline of neurological processes and is a major risk factor for various neurodegenerative diseases, including sleep disturbances and cognitive decline. Adipose tissue exosomes, as adipocyte-derived vesicles, may mediate the regulatory processes of adipose tissue on other organs, including the brain; however, the regulatory mechanisms remain unclear. We analyzed the sleep-wake behavior of young (10 days) and old (40 days) Drosophila and found that older Drosophila showed increased sleep fragmentation, which is similar to mammalian aging characteristics. To investigate the cross-tissue regulatory mechanisms of adiposity on brain aging, we extracted 10-day and 40-day Drosophila adipose tissue exosomes and identified circRNAs with age-dependent expression differences by RNA-seq and differential analysis. Furthermore, by combining data from 3 datasets of the GEO database (GSE130158, GSE24992, and GSE184559), circ_sxc that was significantly downregulated with age was finally screened out. Moreover, dme-miR-87-3p, a conserved target of circ_sxc, accumulates in the brain with age and exhibits inhibitory effects in predicted binding relationships with neuroreceptor ligand genes. In summary, the current study showed that the Drosophila brain could obtain circ_sxc by uptake of adipose tissue exosomes which crossed the blood-brain barrier. And circ_sxc suppressed brain miR-87-3p expression through sponge adsorption, which in turn regulated the expression of neurological receptor ligand proteins (5-HT1B, GABA-B-R1, Rdl, Rh7, qvr, NaCP60E) and ensured brain neuronal synaptic signaling normal function of synaptic signaling. However, with aging, this regulatory mechanism is dysregulated by the downregulation of the adipose exosome circ_sxc, which contributes to the brain exhibiting sleep disturbances and other "aging" features.
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Affiliation(s)
- Qiufang Li
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China
| | - Lingxiao Wang
- The Center for Heart Development, State Key Laboratory of Development Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
| | - Chao Tang
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China
| | - Xiaoya Wang
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China
| | - Zhengwen Yu
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China
| | - Xu Ping
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China
| | - Meng Ding
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China
| | - Lan Zheng
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha, Hunan, China.
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3
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Zhang WH, Jiang L, Li M, Liu J. MicroRNA‑124: an emerging therapeutic target in central nervous system disorders. Exp Brain Res 2023; 241:1215-1226. [PMID: 36961552 PMCID: PMC10129929 DOI: 10.1007/s00221-022-06524-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 01/31/2022] [Indexed: 03/25/2023]
Abstract
The central nervous system (CNS) consists of neuron and non-neuron cells including neural stem/precursor cells (NSPCs), neuroblasts, glia cells (mainly astrocyte, oligodendroglia and microglia), which thereby form a precise and complicated network and exert diverse functions through interactions of numerous bioactive ingredients. MicroRNAs (miRNAs), with small size approximately ~ 21nt and as well-documented post-transcriptional key regulators of gene expression, are a cluster of evolutionarily conserved endogenous non-coding RNAs. More than 2000 different miRNAs has been discovered till now. MicroRNA-124(miR-124), the most brain-rich microRNA, has been validated to possess important functions in the central nervous system, including neural stem cell proliferation and differentiation, cell fate determination, neuron migration, synapse plasticity and cognition, cell apoptosis etc. According to recent studies, herein, we provide a review of this conversant miR-124 to further understand the potential functions and therapeutic and clinical value in brain diseases.
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Affiliation(s)
- Wen-Hao Zhang
- Department of Pediatrics, Chinese PLA Medical School/Chinese PLA General Hospital, Beijing, 100095, China
- Department of Pediatrics, The 4th Hospital of Hebei Medical University, Shijiazhuang, 050010, China
| | - Lian Jiang
- Department of Pediatrics, The 4th Hospital of Hebei Medical University, Shijiazhuang, 050010, China
| | - Mei Li
- Department of Pediatrics, The 4th Hospital of Hebei Medical University, Shijiazhuang, 050010, China
| | - Jing Liu
- Department of Pediatrics, Chinese PLA Medical School/Chinese PLA General Hospital, Beijing, 100095, China.
- Department of Neonatology, Maternal and Child Health Hospital of Chaoyang District, Chaoyang District, Beijing, 100020, China.
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4
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Li Y, Zhang S, Cui K, Cao L, Fan Y, Fang B. miR-872-5p/FOXO3a/Wnt signaling feed-forward loop promotes proliferation of endogenous neural stem cells after spinal cord ischemia-reperfusion injury in rats. FASEB J 2023; 37:e22760. [PMID: 36607643 DOI: 10.1096/fj.202200962rrrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 12/17/2022] [Accepted: 12/27/2022] [Indexed: 01/07/2023]
Abstract
The activation of endogenous neural stem cells (NSCs) is considered an important mechanism of neural repair after mechanical spinal cord injury; however, whether endogenous NSC proliferation can also occur after spinal cord ischemia-reperfusion injury (SCIRI) remains unclear. In this study, we aimed to verify the existence of endogenous NSC proliferation after SCIRI and explore the underlying molecular mechanism. NSC proliferation was observed after SCIRI in vivo and oxygen-glucose deprivation and reperfusion (OGD/R) in vitro, accompanied by a decrease in forkhead box protein O 3a (FOXO3a) expression. This downward trend was regulated by the increased expression of microRNA-872-5p (miR-872-5p). miR-872-5p affected NSC proliferation by targeting FOXO3a to increase the expression of β-catenin and T-cell factor 4 (TCF4). In addition, TCF4 in turn acted as a transcription factor to increase the expression level of miR-872-5p, and knockdown of FOXO3a enhanced the binding of TCF4 to the miR-872-5p promoter. In conclusion, SCIRI in vivo and OGD/R in vitro stimulated the miR-872-5p/FOXO3a/β-catenin-TCF4 pathway, thereby promoting NSC proliferation. At the same time, FOXO3a affected TCF4 transcription factor activity and miR-872-5p expression, forming a positive feedback loop that promotes NSC proliferation.
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Affiliation(s)
- Yuanyuan Li
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Shaoqiong Zhang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Kaile Cui
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Linyan Cao
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Yiting Fan
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Bo Fang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
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Elias AE, Nuñez TA, Kun B, Kreiling JA. primiReference: a reference for analysis of primary-microRNA expression in single-nucleus sequencing data. J Genet Genomics 2023; 50:108-121. [PMID: 36371075 PMCID: PMC9974815 DOI: 10.1016/j.jgg.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022]
Abstract
Single-nucleus RNA-sequencing technology has revolutionized understanding of nuanced changes in gene expression between cell types within tissues. Unfortunately, our understanding of regulatory RNAs, such as microRNAs (miRNAs), is limited through both single-cell and single-nucleus techniques due to the short length of miRNAs in the cytoplasm and the incomplete reference of longer primary miRNA (pri-miRNA) transcripts in the nucleus. We build a custom reference to align and count pri-miRNA sequences in single-nucleus data. Using young and aged subventricular zone (SVZ) nuclei, we show differential expression of pri-miRNAs targeting genes involved in neural stem cells (NSC) differentiation in the aged SVZ. Furthermore, using wild-type and 5XFAD mouse model cortex nuclei, to validate the use of primiReference, we find cell-type-specific expression of pri-miRNAs known to be involved in Alzheimer's disease (AD). pri-miRNAs likely contribute to NSC dysregulation with age and AD pathology. primiReference is paramount in capturing a global profile of gene expression and regulation in single-nucleus data and can provide key insights into cell-type-specific expression of pri-miRNAs, paving the way for future studies of regulation and pathway dysregulation. By looking at pri-miRNA abundance and transcriptional differences, regulation of gene expression by miRNAs in disease and aging can be further explored.
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Affiliation(s)
- Amy E Elias
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA
| | - Thomas A Nuñez
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA
| | - Bianca Kun
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA
| | - Jill A Kreiling
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA.
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Zhuang W, Liu H, He Z, Ju J, Gao Q, Shan Z, Lei L. miR-92a-2-5p Regulates the Proliferation and Differentiation of ASD-Derived Neural Progenitor Cells. Curr Issues Mol Biol 2022; 44:2431-2442. [PMID: 35735607 PMCID: PMC9222067 DOI: 10.3390/cimb44060166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 11/16/2022] Open
Abstract
Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with abnormal behavior. However, the pathogenesis of ASD remains to be clarified. It has been demonstrated that miRNAs are essential regulators of ASD. However, it is still unclear how miR-92a-2-5p acts on the developing brain and the cell types directly. In this study, we used neural progenitor cells (NPCs) derived from ASD-hiPSCs as well as from neurotypical controls to examine the effects of miR-92a-2-5p on ASD-NPCs proliferation and neuronal differentiation, and whether miR-92a-2-5p could interact with genetic risk factor, DLG3 for ASD. We observed that miR-92a-2-5p upregulated in ASD-NPCs results in decreased proliferation and neuronal differentiation. Inhibition of miR-92a-2-5p could promote proliferation and neuronal differentiation of ASD-NPCs. DLG3 was negatively regulated by miR-92a-2-5p in NPCs. Our results suggest that miR-92a-2-5p is a strong risk factor for ASD and potentially contributes to neuropsychiatric disorders.
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Affiliation(s)
| | | | | | | | | | | | - Lei Lei
- Correspondence: (Z.S.); (L.L.)
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Zhang YF, Li XX, Cao XL, Ji CC, Gao XY, Gao D, Han H, Yu F, Zheng MH. MicroRNA-582-5p Contributes to the Maintenance of Neural Stem Cells Through Inhibiting Secretory Protein FAM19A1. Front Cell Neurosci 2022; 16:866020. [PMID: 35685988 PMCID: PMC9171424 DOI: 10.3389/fncel.2022.866020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 05/04/2022] [Indexed: 11/15/2022] Open
Abstract
Epigenetic regulations on the maintenance of neural stem cells (NSCs) are complicated and far from been fully understood. Our previous findings have shown that after blocking Notch signaling in NSCs in vivo, the stemness of NSCs decreases, accompanied by the downregulated expression of miR-582-5p. In the current study, we further investigated the function and mechanism of miR-582-5p in the maintenance of NSCs in vitro and in vivo. After transfecting a mimic of miR-582-5p, the formation of neurospheres and proliferation of NSCs and intermediate progenitor cells (NS/PCs) were enhanced, and the expression of stemness markers such as Sox2, Nestin, and Pax6 also increased. The results were reversed after transfection of an inhibitor of miR-582-5p. We further generated miR-582 knock-out (KO) mice to investigate its function in vivo, and we found that the number of NSCs in the subventricular zone (SVZ) region decreased and the number of neuroblasts increased in miR-582 deficient mice, indicating reduced stemness and enhanced neurogenesis of NSCs. Moreover, RNA-sequencing and molecular biological analysis revealed that miR-582-5p regulates the stemness and proliferation of NSCs by inhibiting secretory protein FAM19A1. In summary, our research uncovered a new epigenetic mechanism that regulates the maintenance of NSCs, therefore providing novel targets to amplify NSCs in vitro and to promote neurogenesis in vivo during brain pathology and aging.
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Affiliation(s)
- Yu-Fei Zhang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Life Sciences, Northwest A&F University, Yangling, China
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
| | - Xin-Xin Li
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
- Xi’ an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi’an, China
| | - Xiu-Li Cao
- Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, China
| | - Chen-Chen Ji
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
| | - Xiang-Yu Gao
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
| | - Dan Gao
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
| | - Hua Han
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
- *Correspondence: Hua Han,
| | - Fei Yu
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Life Sciences, Northwest A&F University, Yangling, China
- Fei Yu,
| | - Min-Hua Zheng
- Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, China
- Min-Hua Zheng,
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8
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Tu YK, Hsueh YH, Huang HC. Human olfactory ensheathing cell-derived extracellular vesicles: miRNA profile and neuroprotective effect. Curr Neurovasc Res 2021; 18:395-408. [PMID: 34645375 DOI: 10.2174/1567202618666211012162111] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Extracellular vesicle (EV)-based therapy has been identified as a leading alternative approach in several disease models. EV derived from the olfactory ensheathing cell (OEC) has been documented for its strong neuro-regenerative capacity. However, no information on its cargo that may contribute to its therapeutic effect has been available. OBJECTIVE To report the first miRNA profile of human OEC (hOEC) -EV, and investigate the neuroprotective effects. METHODS hOEC-EV was isolated and sequenced. We established in vitro experiments to assess the therapeutic potential of hOEC-EVs with respect to insulted neural progenitor cells (NPCs), and the angiogenesis effect. Secondary post-injury insults were imitated using t-BHP-mediated oxidative stress. RESULTS We noted a strong abundance of hOEC-EV-miRNAs, including hsa-miR148a-3p, has-miR151a-3p and several members of let-7 family. The common targets of 15 miRNAs among the top 20 miRNAs were thrombospondin 1 and cyclin dependent kinase 6. We demonstrated that hOEC-EVs promote normal NPC proliferation and differentiation to neuron-like morphologies with prolonged axons. hOEC-EVs protect cells from t-BHP mediated apoptosis. We also found that the migration rate of either NPCs or endothelial cells significantly improved with hOEC-EVs. Furthermore, in vitro tube formation assays indicated that angiogenesis, an important process for tissue repair, was significantly enhanced in human umbilical vein endothelial cells exposed to hOEC-EVs. CONCLUSION Our results revealed that hOEC-EVs exert neuroprotective effects by protecting cells from apoptosis and promoting in vitro biological processes that are important to neural tissue repair, including neural cell proliferation, axonal growth, and cell migration, in addition to enhancing angiogenesis. </p>.
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Affiliation(s)
- Yuan-Kun Tu
- Department of Orthopedic Surgery, E-Da Hospitall, I-Shou University, Kaohsiung city. Taiwan
| | - Yu-Huan Hsueh
- Department of Orthopedic Surgery, E-Da Hospitall, I-Shou University, Kaohsiung city. Taiwan
| | - Hsien-Chang Huang
- Department of Orthopedic Surgery, E-Da Hospitall, I-Shou University, Kaohsiung city. Taiwan
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Jia J, Wang M, Liu M, Tan Z, Cui Y, Yu M. MiR-421 Binds to PINK1 and Enhances Neural Stem Cell Self-Renewal via HDAC3-Dependent FOXO3 Activation. Front Cell Dev Biol 2021; 9:621187. [PMID: 34354990 PMCID: PMC8329493 DOI: 10.3389/fcell.2021.621187] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 05/12/2021] [Indexed: 12/30/2022] Open
Abstract
Dysfunctions of neural stem cells (NSCs) often lead to a variety of neurological diseases. Thus, therapies based on NSCs have gained increasing attention recently. It has been documented that microRNA (miR)-421 represses the autophagy and apoptosis of mouse hippocampal neurons and confers a role in the repair of ischemic brain injury (IBI). Herein, we aimed to illustrate the effects of miR-421 on NSC self-renewal. The downstream factors of miR-421 were predicted initially, followed by gain- and loss-of-function assays to examine their effects on NSC self-renewal. Immunoprecipitation and dual luciferase assays were conducted to validate the interaction among miR-421, PTEN-induced putative kinase 1 (PINK1), HDAC3, and forkhead box O3 (FOXO3). A mouse model with IBI was developed to substantiate the impact of the miR-421/PINK1/HDAC3/FOXO3 axis on NSC self-renewal. The expression of miR-421 was downregulated during differentiation of human embryonic NSCs, and miR-421 overexpression accelerated NSC self-renewal. Besides, miR-421 targeted PINK1 and restricted its expression in NSCs and further suppressed HDAC3 phosphorylation and enhanced FOXO3 acetylation. In conclusion, our data elucidated that miR-421 overexpression may facilitate NSC self-renewal through the PINK1/HDAC3/FOXO3 axis, which may provide potential therapeutic targets for the development of novel therapies for IBI.
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Affiliation(s)
- Jiaoying Jia
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ming Wang
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Min Liu
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhigang Tan
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Cui
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Mengqiang Yu
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, China
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Zhang J, Zhang X, Cong S, Zhang J, Zhang A, Pan L, Ma J. miR-195-5p Regulates the Phenotype Switch of CCSM Cells by Targeting Smad7. Sex Med 2021; 9:100349. [PMID: 34087534 PMCID: PMC8240331 DOI: 10.1016/j.esxm.2021.100349] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/04/2021] [Accepted: 03/07/2021] [Indexed: 11/30/2022] Open
Abstract
INTRODUCTION Phenotype switch refers to the process in which smooth muscle cells change from contractile type to synthetic type and acquire the ability of proliferation. Phenotypic transformation involves many changes of cell function, such as collagen deposition and fibrosis, which affect the normal erectile function of penis. AIM To investigate the role of miR-195-5p in regulating the Phenotype switch of the corpus cavernosum smooth muscle (CCSM) cells. METHODS A small mother against decapentaplegic 7(Smad7) virus vector and a miR-195-5p mimics or an si-Smad7 viral vector and a miR-195-5p inhibitor were transfected into CCSM cells. The cells were obtained by primary culture of rat corpus cavernosum smooth muscle tissue. Real-time polymerase chain reaction (PCR) experiments, Western blotting, hematoxylin-eosin (HE) staining, transwell experiments, MTT assays, and flow cytometry were used to detect miR-195-5p, Smad7, phenotype switch markers of CCSM cells and related protein expression, as well as changes in cell morphology, migration, proliferation and apoptosis. MAIN OUTCOME MEASURE To study the regulation of miR-195-5p in CCSM cells by overexpression and silencing strategies. RESULTS Overexpressed miR-195-5p promoted the transformation of CCSM cells from a contractile type to a synthetic type. Meanwhile, the migration ability and proliferation ability of CCSM cells increased, and the apoptosis rate decreased. The expression-silencing of miR-195-5p gave rise to the opposite effect. The results of the rescue experiment demonstrated that overexpressed Smad7 rescued the inhibitory of the switch of the CCSM cell phenotype from the contractile type to the synthesis type caused by overexpression of miR-195-5p alone. Moreover, the enhancement effect of the migration ability and proliferation ability of CCSM cells was also eliminated, and the apoptosis rate was increased. Silencing miR-195-5p and Smad7 at the same time resulted in the opposite effect. CONCLUSION miR-195-5p may regulate the phenotype switch of CCSM cells by targeting Smad7. Zhang J, Zhang X, Zhang J, et al. miR-195-5p Regulates the Phenotype Switch of CCSM Cells by Targeting Smad7. Sex Med 2021;9:100349.
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Affiliation(s)
- Jing Zhang
- Jiangsu Health Vocational College, Nanjing, China
| | - Xingyuan Zhang
- Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Center, Nanjing, China
| | - Shengnan Cong
- School of Nursing, Nanjing Medical University, Jiangsu, China
| | - Jingjing Zhang
- Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Center, Nanjing, China
| | - Aixia Zhang
- Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Center, Nanjing, China
| | - Lianjun Pan
- Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Center, Nanjing, China.
| | - Jiehua Ma
- Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Center, Nanjing, China.
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11
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Zhang L, Zhang T, Sun D, Cheng G, Ren H, Hong H, Chen L, Jiao X, Du Y, Zou Y, Wang L. Diagnostic value of dysregulated microribonucleic acids in the placenta and circulating exosomes in gestational diabetes mellitus. J Diabetes Investig 2021; 12:1490-1500. [PMID: 33411988 PMCID: PMC8354507 DOI: 10.1111/jdi.13493] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 12/26/2020] [Accepted: 01/01/2021] [Indexed: 12/19/2022] Open
Abstract
Aims/Introduction Differentially expressed microribonucleic acids (miRNAs) in the placenta and circulating exosomes are of diagnostic value for gestational diabetes mellitus (GDM). In a cross‐sectional study, we identified miRNAs expressed both in the placenta and circulating exosomes of pregnant women with GDM, and estimated their diagnostic value. Materials and Methods Next‐generation sequencing was used to identify miRNAs in the placenta that were differentially expressed between GDM and normal glucose tolerance pregnancies. Quantitative polymerase chain reaction was used to validate the identified targets. Western blot and transmission electron microscopy were used to validate exosomes. Univariate logistic regression analysis was used to establish diagnostic models based on miRNAs expression, and the diagnostic value was estimated using the receiver operator characteristic curve. Results We identified 157 dysregulated miRNAs in the placental tissue obtained from GDM pregnancies. Of these, miRNA‐125b was downregulated (P < 0.001), whereas miRNA‐144 was upregulated (P < 0.001). The patterns of these two miRNAs remained the same in circulating exosomes from GDM pregnancies (all P < 0.001). miRNA‐144 levels in the circulating exosomes negatively correlated with body mass index both before pregnancy (P = 0.018) and before delivery (P = 0.039), and positively correlated with blood glucose at 1 h, estimated using the oral glucose tolerance test (P = 0.044). The area under curve for the established diagnostic model was 0.898, which was higher than blood glucose levels at 0 h. Conclusions These findings suggest that miRNA‐125b and miRNA‐144 are consistently dysregulated in circulating exosomes and the placenta from GDM pregnancies, and are of excellent diagnostic value for GDM.
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Affiliation(s)
- Lei Zhang
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Ting Zhang
- Department of Pharmacy, Jinan Infectious Disease Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Daoxu Sun
- Office of Heze Health Association, Heze, China
| | - Guanghui Cheng
- Central Research Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Hanxiao Ren
- Department of Clinical Laboratory Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Haijie Hong
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Liyu Chen
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Xue Jiao
- School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Yijia Du
- School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Yuqing Zou
- School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Lina Wang
- Department of Clinical Laboratory Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
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12
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Guajardo L, Aguilar R, Bustos FJ, Nardocci G, Gutiérrez RA, van Zundert B, Montecino M. Downregulation of the Polycomb-Associated Methyltransferase Ezh2 during Maturation of Hippocampal Neurons Is Mediated by MicroRNAs Let-7 and miR-124. Int J Mol Sci 2020; 21:ijms21228472. [PMID: 33187138 PMCID: PMC7697002 DOI: 10.3390/ijms21228472] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/04/2022] Open
Abstract
Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was differentially expressed during maturation of hippocampal neurons; in immature neurons, Ezh2 was abundantly expressed, whereas in mature neurons the expression Ezh2 was significantly reduced. Here, we report that Ezh2 is downregulated by microRNAs (miRs) that are expressed during the hippocampal maturation process. We show that, in mature hippocampal neurons, lethal-7 (let-7) and microRNA-124 (miR-124) are robustly expressed and can target cognate motifs at the 3′-UTR of the Ezh2 gene sequence to downregulate Ezh2 expression. Together, these data demonstrate that the PRC2 repressive activity during hippocampal maturation is controlled through a post-transcriptional mechanism that mediates Ezh2 downregulation in mature neurons.
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Affiliation(s)
- Laura Guajardo
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; (L.G.); (R.A.); (F.J.B.); (G.N.)
- FONDAP Center for Genome Regulation, Santiago 8370186, Chile;
| | - Rodrigo Aguilar
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; (L.G.); (R.A.); (F.J.B.); (G.N.)
- FONDAP Center for Genome Regulation, Santiago 8370186, Chile;
| | - Fernando J. Bustos
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; (L.G.); (R.A.); (F.J.B.); (G.N.)
- FONDAP Center for Genome Regulation, Santiago 8370186, Chile;
- CARE Biomedical Research Center, Santiago 83370186, Chile
| | - Gino Nardocci
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; (L.G.); (R.A.); (F.J.B.); (G.N.)
- FONDAP Center for Genome Regulation, Santiago 8370186, Chile;
| | - Rodrigo A. Gutiérrez
- FONDAP Center for Genome Regulation, Santiago 8370186, Chile;
- Millennium Institute for Integrative Biology, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Brigitte van Zundert
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; (L.G.); (R.A.); (F.J.B.); (G.N.)
- CARE Biomedical Research Center, Santiago 83370186, Chile
- Correspondence: (B.v.Z.); (M.M.)
| | - Martin Montecino
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; (L.G.); (R.A.); (F.J.B.); (G.N.)
- FONDAP Center for Genome Regulation, Santiago 8370186, Chile;
- Correspondence: (B.v.Z.); (M.M.)
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13
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Bame M, McInnis MG, O'Shea KS. MicroRNA Alterations in Induced Pluripotent Stem Cell-Derived Neurons from Bipolar Disorder Patients: Pathways Involved in Neuronal Differentiation, Axon Guidance, and Plasticity. Stem Cells Dev 2020; 29:1145-1159. [PMID: 32438891 PMCID: PMC7469698 DOI: 10.1089/scd.2020.0046] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/21/2020] [Indexed: 12/17/2022] Open
Abstract
Bipolar disorder (BP) is a complex psychiatric condition characterized by severe fluctuations in mood for which underlying pathological mechanisms remain unclear. Family and twin studies have identified a hereditary component to the disorder, but a single causative gene (or set of genes) has not been identified. MicroRNAs (miRNAs) are small, noncoding RNAs ∼20 nucleotides in length, that are responsible for the posttranslational regulation of multiple genes. They have been shown to play important roles in neural development as well as in the adult brain, and several miRNAs have been reported to be dysregulated in postmortem brain tissue isolated from bipolar patients. Because there are no viable cellular models to study BP, we have taken advantage of the recent discovery that somatic cells can be reprogrammed to pluripotency then directed to form the full complement of neural cells. Analysis of RNAs extracted from Control and BP patient-derived neurons identified 58 miRNAs that were differentially expressed between the two groups. Using quantitative polymerase chain reaction we validated six miRNAs that were elevated and two miRNAs that were expressed at lower levels in BP-derived neurons. Analysis of the targets of the miRNAs indicate that they may regulate a number of cellular pathways, including axon guidance, Mapk, Ras, Hippo, Neurotrophin, and Wnt signaling. Many are involved in processes previously implicated in BP, such as cell migration, axon guidance, dendrite and synapse development, and function. We have validated targets of several different miRNAs, including AXIN2, BDNF, RELN, and ANK3 as direct targets of differentially expressed miRNAs using luciferase assays. Identification of pathways altered in patient-derived neurons suggests that disruption of these regulatory networks that may contribute to the complex phenotypes in BP.
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Affiliation(s)
- Monica Bame
- Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Melvin G. McInnis
- Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - K. Sue O'Shea
- Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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14
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Wen L, Sun J, Chen X, Du R. miR-135b-dependent downregulation of S100B promotes neural stem cell differentiation in a hypoxia/ischemia-induced cerebral palsy rat model. Am J Physiol Cell Physiol 2020; 319:C955-C966. [PMID: 32491925 DOI: 10.1152/ajpcell.00481.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cerebral palsy (CP) is frequently caused by brain injury during pregnancy, delivery, or the immediate postnatal period. The differentiation potential of neural stem cell (NSC) makes them effective in restoring injured tissues and organs with minimal risks of side effects. In this study, we identified a novel microRNA-135b (miR-135b) in CP and investigated its functional role in mediating NSC differentiation. CP models were established in Wistar rats and validated with the Y-maze test. Gain- and loss-of-function experimentation was performed on CP rats. Then NSCs were isolated and the expression patterns of miR-135b and S100B were altered in NSCs. S100B exhibited high expression in the hippocampus tissues of CP models, which was targeted by miR-135b. miR-135b elevation or S100B silencing resulted in promoted NSC differentiation, alleviated brain injury, and inhibited NSC apoptosis in hippocampus tissues of CP rats. S100B downregulation targeted by miR-135b overexpression contributed to the inactivation of the signal transducer and activator of transcription-3 (STAT3) pathway, which promoted NSC differentiation and proliferation but inhibited NSC apoptosis. Our results highlight the suppressor role played by miR-135b in CP by inducing NSC differentiation via inactivation of S100B-dependent STAT3 pathway.
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Affiliation(s)
- Linbao Wen
- Department of Neurosurgery, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, People's Republic of China
| | - Jingwei Sun
- Department of Neurosurgery, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, People's Republic of China
| | - Xionggao Chen
- Department of Neurosurgery, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, People's Republic of China
| | - Ruili Du
- Department of Radiology, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, People's Republic of China
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15
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MicroRNA-212-3p regulates early neurogenesis through the AKT/mTOR pathway by targeting MeCP2. Neurochem Int 2020; 137:104734. [PMID: 32246981 DOI: 10.1016/j.neuint.2020.104734] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/13/2020] [Accepted: 03/28/2020] [Indexed: 11/22/2022]
Abstract
Compelling evidence has implicated role of microRNAs (miRNAs) in neurogenesis. Methyl-CpG Binding Protein 2 (MeCP2) was a key contributor to neurological disease. This study investigated whether miR-212-3p affects early neurogenesis associated with MeCP2. Microarray-based gene expression profiling of neurogenesis was employed to identify differentially expressed genes. Next, miR-212-3p expression in neural progenitor cells (NPCs) was detected using in situ hybridization and immunofluorescence. Effect of miR-212-3p and MeCP2 on cell viability, β-tubulin III expression and the AKT/mammalian target of rapamycin (mTOR) pathway activity was examined with gain- and loss-of-function experiments. In vivo experiments were also performed to verify effects of miR-212-3p on nerve tube development. MiR-212-3p expression was decreased while MeCP2 expression was increased during differentiation of NPCs. MiR-212-3p targets MeCP2 and down-regulates its expression, which resulted in repressed cell differentiation, proliferation as well as blocked AKT/mTOR pathway activation, subsequently early neurogenesis was prevented. Furthermore, overexpression of miR-212-3p inhibited nerve tube development in vivo. Taken together, miR-212-3p could restrain early neurogenesis through the blockade of AKT/mTOR pathway activation by targeting MeCP2, suggesting a promising therapeutic target for neurogenic disorders.
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16
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Identification and functional analysis of specific MS risk miRNAs and their target genes. Mult Scler Relat Disord 2020; 41:102044. [PMID: 32179484 DOI: 10.1016/j.msard.2020.102044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/24/2020] [Accepted: 03/04/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND It has been widely acknowledged that abnormal expression of microRNAs (miRNAs) may lead to the occurrence and development of MS through regulating target genes. Currently, only few studies have comprehensively evaluated the function and relationship between MS-related miRNAs and their target genes. METHODS Differentially expressed miRNAs in MS patients' serum and plasma were selected by reviewing numerous literatures manually. Then, thousands of target genes were screened by several online databases, of which 899 MS-related genes were further identified. Gene ontology, protein-protein interaction and KEGG pathway analysis were used to determine high-risk pathways and MS risk genes. Transcriptomic datasets from GEO was analyzed to evaluate these risk genes. RESULTS 28 MS-related miRNAs were extracted. MiR-30e, miR-93, miR-155 were identified as the most crucial miRNAs through targeting hub genes: PIK3CA, PIK3R1, PIK3R2 and MAPK8. Seven immune pathways were screened out according to KEGG pathway analysis. Six transcriptomic datasets were used to evaluate results, and PIK3CA was differentially expressed in MS patients compared with healthy donors. CONCLUSIONS According to our research, MS-related miRNAs and their target genes of MS were identified and comprehensively evaluated. This work may provide a new insight for discovering pathogenesis and possible biomarkers of MS in future studies.
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17
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Bahmad HF, Darwish B, Dargham KB, Machmouchi R, Dargham BB, Osman M, Khechen ZA, El Housheimi N, Abou-Kheir W, Chamaa F. Role of MicroRNAs in Anesthesia-Induced Neurotoxicity in Animal Models and Neuronal Cultures: a Systematic Review. Neurotox Res 2020; 37:479-490. [PMID: 31707631 DOI: 10.1007/s12640-019-00135-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/15/2019] [Accepted: 10/28/2019] [Indexed: 12/27/2022]
Abstract
Exposure to anesthetic agents in early childhood or late intrauterine life might be associated with neurotoxicity and long-term neurocognitive decline in adulthood. This could be attributed to induction of neuroapoptosis and inhibition of neurogenesis by several mechanisms, with a pivotal role of microRNAs in this milieu. MicroRNAs are critical regulators of gene expression that are differentially expressed in response to internal and external environmental stimuli, including general anesthetics. Through this systematic review, we aimed at summarizing the current knowledge apropos of the roles and implications of deregulated microRNAs pertaining to anesthesia-induced neurotoxicity in animal models and derived neuronal cultures. OVID/Medline and PubMed databases were lastly searched on April 1st, 2019, using the Medical Subject Heading (MeSH) or Title/Abstract words ("microRNA" and "anesthesia"), to identify all published research studies on microRNAs and anesthesia. During the review process, data abstraction and methodological assessment was done by independent groups of reviewers. In total, 29 studies were recognized to be eligible and were thus involved in this systematic review. Anesthetic agents studied included sevoflurane, isoflurane, propofol, bupivacaine, and ketamine. More than 40 microRNAs were identified to have regulatory roles in anesthesia-induced neurotoxicity. This field of study still comprises several gaps that should be filled by conducting basic, clinical, and translational research in the future to decipher the exact role of microRNAs and their functions in the context of anesthesia-induced neurotoxicity.
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Affiliation(s)
- Hisham F Bahmad
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Batoul Darwish
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Karem Bou Dargham
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
- Department of Anesthesiology, Hammoud Hospital University Medical Center, Sidon, Lebanon
| | - Rabih Machmouchi
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
- Department of Anesthesiology, Hammoud Hospital University Medical Center, Sidon, Lebanon
| | - Bahaa Bou Dargham
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
- Department of Anesthesiology, Hammoud Hospital University Medical Center, Sidon, Lebanon
| | - Maarouf Osman
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
- Department of Anesthesiology, Hammoud Hospital University Medical Center, Sidon, Lebanon
| | - Zonaida Al Khechen
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
- Department of Anesthesiology, Hammoud Hospital University Medical Center, Sidon, Lebanon
| | - Nour El Housheimi
- Department of Anesthesiology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
| | - Farah Chamaa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
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18
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Ma R, Wang M, Gao S, Zhu L, Yu L, Hu D, Zhu L, Huang W, Zhang W, Deng J, Pan J, He H, Gao Z, Xu J, Han X. miR-29a Promotes the Neurite Outgrowth of Rat Neural Stem Cells by Targeting Extracellular Matrix to Repair Brain Injury. Stem Cells Dev 2020; 29:599-614. [PMID: 31885334 DOI: 10.1089/scd.2019.0174] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Neural stem cells (NSCs) can generate new neurons to repair brain injury and central nervous system disease by promoting neural regeneration. MicroRNAs (miRNAs) involve in neural development, brain damage, and neurological diseases repair. Recent reports show that several miRNAs express in NSCs and are important to neurogenesis. Neurites play a key role in NSC-related neurogenesis. However, the mechanism of NSC neurite generation is rarely studied. We surprisingly noticed that the neurites increased after bone morphogenetic protein (BMP) treatment in rat NSCs. This process was accompanied by the dynamic change of miRNA-29. Then we discovered that miR-29a regulated neural neurites in rat hippocampus NSCs. Overexpression of miR-29a reduced the cell soma area and promoted the neurite outgrowth of NSCs. Cell soma area became small, whereas the number of neurite increased. Moreover, neurite complexity increased dramatically, with more primary and secondary branches after miR-29a overexpression. In addition, miR-29a overexpression still maintained the stemness of NSCs. Besides, we identified that miR-29a can promote the neurite outgrowth by targeting extracellular matrix-related genes like Fibrillin 1 (Fbn1), Follistatin-like 1 (Fstl1), and laminin subunit gamma 2 (Lamc2). These findings may provide a novel role of miR-29a to regulate neurite outgrowth and development of NSCs. We also offered a possible theoretical basis to the migration mechanism of NSCs in brain development and damage repair.
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Affiliation(s)
- Rongjie Ma
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Min Wang
- School of Medicine, Jiaxing University, Jiaxing, China.,Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Shane Gao
- East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liang Zhu
- East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liming Yu
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Daiyu Hu
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Lifeng Institute of Regenerative Medicine, Tongji University, Shanghai, China
| | - Luying Zhu
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Wei Huang
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Weihua Zhang
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Jiajia Deng
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Jie Pan
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Hua He
- Department of Neurosurgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Zhengliang Gao
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Lifeng Institute of Regenerative Medicine, Tongji University, Shanghai, China
| | - Jun Xu
- East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinxin Han
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China
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19
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Lin Y, Jiang X, Yin G, Lin H. Syringic acid promotes proliferation and migration of Schwann cells via down-regulating miR-451-5p. Acta Biochim Biophys Sin (Shanghai) 2019; 51:1198-1207. [PMID: 31748779 DOI: 10.1093/abbs/gmz118] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Indexed: 12/21/2022] Open
Abstract
Schwann cells are the main force in spontaneous regeneration after peripheral nerve injury. The neurotrophic factors could promote the regeneration, but clinical applications of these factors are limited by some constraints. Hence, searching for new substances to elevate the function of Schwann cells and facilitate the regeneration of nerve is urgently needed. Syringic acid (SA) is a natural product with neuroprotective activity in vivo, but the role of SA on Schwann cells remains unclear. In this study, we for the first time found that SA was able to promote the proliferation and migration of Schwann cells, two important abilities in the process of regeneration. Then, microRNA (miRNA) microarray analysis was performed and 26 differentially expressed miRNAs (22 down-regulated and 4 up-regulated) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses found that the target genes of these miRNAs were mainly enriched in cellular response to chemical stimulus and cancer-related pathways, respectively. Subsequently, the levels of top 6 down-regulated miRNAs were validated by RT-qPCR and miR-451-5p was shown to be the most down-regulated one. Further experiments demonstrated that inhibition of miR-451-5p significantly promoted the proliferation and migration of Schwann cells. These results suggested that SA promoted the proliferation and migration of Schwann cells via down-regulation of miR-451-5p, and SA could be developed into a promising nutritional supplement to assist peripheral nerve regeneration.
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Affiliation(s)
- Yaofa Lin
- Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xin Jiang
- Department of Anesthesiology, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Gang Yin
- Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Haodong Lin
- Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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20
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Zhang H, Liu T, Zhou Z, Zhang A, Zhu Y, Zhang J, Pan L, Ma J. miR-137 Affects Vaginal Lubrication in Female Sexual Dysfunction by Targeting Aquaporin-2. Sex Med 2018; 6:339-347. [PMID: 30454615 PMCID: PMC6302129 DOI: 10.1016/j.esxm.2018.09.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/26/2018] [Accepted: 09/26/2018] [Indexed: 11/30/2022] Open
Abstract
Introduction Female sexual dysfunction (FSD) is a common disease with serious potential hazards, but it has not received much attention. The pathogenesis of FSD is urgently needed for the diagnosis and treatment of FSD. Aim To investigate the role of microribonucleic acid (mRNA, miR)-137 in FSD. Methods Vaginal epithelium tissues from 15 women with lubrication disorder and 15 women with normal function were collected for this study. The expression level of miR-137 in lubrication disorder and normal function women were measured by microarray analysis and Real-time Quantitative Polymerase Chain Reaction (PCR, qPCR). miR-137 was overexpressed in vaginal epithelial cells VK2/E6E7 by lentivirus infection. The cell water permeability was measured using the calcein-quenching method. Cell apoptosis was analyzed by flow cytometry. The potential target of miR-137 was predicted by bioinformatic analysis, then verified by luciferase reporter assays. Main Outcome Measure The expression level of miR-137 and aquaporin-2 (AQP2), cell water permeability, cell apoptosis, and luciferase reporter assays were examined. Results miR-137 was found to be highly expressed in vaginal epithelial tissues of women with lubrication disorder. Additionally, functional in vitro studies suggested that overexpression of miR-137 leads to a decrease in cell permeability. By combining target prediction and examination, we identified AQP2 as the direct mechanistic target of miR-137 that affected the water permeability of vaginal epithelial cells. Conclusion Our results point to a novel role for miR-137 and its downstream effector AQP2 in vaginal lubrication, which can be manipulated as therapeutic targets against lubrication disorder and its related disorders. Zhang H, Liu T, Zhou Z. miR-137 affects vaginal lubrication in female sexual dysfunction by targeting Aquaporin-2. Sex Med 2018;6:339–347.
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Affiliation(s)
- Hepeng Zhang
- Department of Urology, The People's Hospital of Yuyao, Zhejiang, China
| | - Tianjiao Liu
- Department of Women Health Care, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Ziyun Zhou
- Department of Children Health Care, Wuxi Children's Hospital, Wuxi, China
| | - Aixia Zhang
- The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Yuan Zhu
- The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jing Zhang
- Jiangsu Health Vocational College, Nanjing, China
| | - Lianjun Pan
- The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jiehua Ma
- The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China.
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21
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Shi Z, Zhou H, Lu L, Pan B, Wei Z, Liu J, Li J, Yuan S, Kang Y, Liu L, Yao X, Kong X, Feng S. MicroRNA‐29a regulates neural stem cell neuronal differentiation by targeting PTEN. J Cell Biochem 2018; 119:5813-5820. [DOI: 10.1002/jcb.26768] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 02/02/2018] [Indexed: 01/09/2023]
Affiliation(s)
- Zhongju Shi
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Hengxing Zhou
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Lu Lu
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Bin Pan
- Department of OrthopaedicsThe Affiliated Hospital of XuzhouMedical UniversityXuzhouJiangsuP. R. China
| | - Zhijian Wei
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Jun Liu
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Jiahe Li
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Shiyang Yuan
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Yi Kang
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Lu Liu
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Xue Yao
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
| | - Xiaohong Kong
- 221 LaboratorySchool of MedicineNankai UniversityTianjinP. R. China
| | - Shiqing Feng
- Department of OrthopaedicsTianjin Medical University General HospitalTianjinP. R. China
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22
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Lamadrid-Romero M, Solís KH, Cruz-Reséndiz MS, Pérez JE, Díaz NF, Flores-Herrera H, García-López G, Perichart O, Reyes-Muñoz E, Arenas-Huertero F, Eguía-Aguilar P, Molina-Hernández A. Central nervous system development-related microRNAs levels increase in the serum of gestational diabetic women during the first trimester of pregnancy. Neurosci Res 2017; 130:8-22. [PMID: 28803788 DOI: 10.1016/j.neures.2017.08.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 08/03/2017] [Accepted: 08/07/2017] [Indexed: 01/14/2023]
Abstract
MicroRNAs are heterochronic molecules important during brain development, which could be altered by gestational diabetes mellitus (GDM). To explore these molecules in maternal serum, we performed an RT-qPCR analysis. Our results revealed the heterochronic character of some neural development-related microRNA in serum samples of pregnant women. In relation to the first trimester, higher levels of miR-183-5p, -200b-3p, and -125-5p in the second trimester, and higher levels of miR-137 in the third trimester, were found. Furthermore, an insult such as GDM led to higher levels of miR-183-5p, -200b-3p, -125-5p, and -1290 relative to the control in the first trimester, which might be related to changes in neurogenesis and cell proliferation. An in silico analysis suggested that increased microRNAs in the second trimester in the control contributed to cell proliferation and neuron differentiation and that the rise in miR-137 in the third trimester led to neuron maturation. In the diabetic, higher levels of the microRNAs in the first trimester suggested alterations in cell proliferation and neuron differentiation. In conclusion, we showed that fetal-related microRNAs can be detected in the serum of pregnant woman and exhibit temporary regulation during pregnancy and that microRNAs involved in cell proliferation and neuron differentiation are upregulated under GDM.
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Affiliation(s)
- M Lamadrid-Romero
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico; Posgrado en Ciencias Biológicas, Facultad de Ciencias-UNAM, Ciudad de México, Mexico
| | - K H Solís
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - M S Cruz-Reséndiz
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico; Posgrado en Ciencias Biológicas, Facultad de Ciencias-UNAM, Ciudad de México, Mexico
| | - J E Pérez
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - N F Díaz
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - H Flores-Herrera
- Instituto Nacional de Perinatología "Isidro Espinosa de Los Reyes", Departamento de Inmunobioquímica, Mexico
| | - G García-López
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - O Perichart
- Instituto Nacional de Perinatología "Isidro Espinosa de Los Reyes", Departamento de Nutrición, Mexico
| | - E Reyes-Muñoz
- Instituto Nacional de Perinatología "Isidro Espinosa de Los Reyes", Departamento de Endocrionología, Mexico
| | - F Arenas-Huertero
- Hospital Infantil de México "Federico Gómez", Laboratorio de Investigación en Patología Experimental, Mexico
| | - P Eguía-Aguilar
- Hospital Infantil de México "Federico Gómez", Departamento de Patología, Mexico
| | - A Molina-Hernández
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico.
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23
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Alural B, Genc S, Haggarty SJ. Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: Past, present, and future. Prog Neuropsychopharmacol Biol Psychiatry 2017; 73:87-103. [PMID: 27072377 PMCID: PMC5292013 DOI: 10.1016/j.pnpbp.2016.03.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 03/28/2016] [Accepted: 03/30/2016] [Indexed: 12/12/2022]
Abstract
Neuropsychiatric disorders are common health problems affecting approximately 1% of the population. Twin, adoption, and family studies have displayed a strong genetic component for many of these disorders; however, the underlying pathophysiological mechanisms and neural substrates remain largely unknown. Given the critical need for new diagnostic markers and disease-modifying treatments, expanding the focus of genomic studies of neuropsychiatric disorders to include the role of non-coding RNAs (ncRNAs) is of growing interest. Of known types of ncRNAs, microRNAs (miRNAs) are 20-25-nucleotide, single-stranded, molecules that regulate gene expression through post-transcriptional mechanisms and have the potential to coordinately regulate complex regulatory networks. In this review, we summarize the current knowledge on miRNA alteration/dysregulation in neuropsychiatric disorders, with a special emphasis on schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). With an eye toward the future, we also discuss the diagnostic and prognostic potential of miRNAs for neuropsychiatric disorders in the context of personalized treatments and network medicine.
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Affiliation(s)
- Begum Alural
- Department of Neuroscience, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey; Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Turkey
| | - Sermin Genc
- Department of Neuroscience, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey; Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Turkey
| | - Stephen J Haggarty
- Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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24
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Yang P, Cai L, Zhang G, Bian Z, Han G. The role of the miR-17-92 cluster in neurogenesis and angiogenesis in the central nervous system of adults. J Neurosci Res 2016; 95:1574-1581. [PMID: 27869313 DOI: 10.1002/jnr.23991] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 10/23/2016] [Accepted: 10/24/2016] [Indexed: 02/03/2023]
Abstract
It is well known that neurogenesis is not the only concern for the fully functional recovery after brain or spinal cord injury, as it has been shed light on the critical role of angiogenesis in improving neurological functional recovery. Angiogenesis and neurogenesis coordinately interact with each other in the developing and adult brain, during which they may respond to similar mediators and receptors, in which they share a common posttranscriptional regulator: the miR-17-92 cluster. The miR-17-92 cluster was initially described as an oncogene and was later demonstrated to drive key physiological and pathological responses during development and diseases respectively. It has been reported that the miR-17-92 cluster regulates both neurogenesis and angiogenesis. The miR-17-92 cluster modulates neural progenitor cells proliferation not only during development but also during neurological disorders such as stroke. It has also been shown that the endothelial miR-17-92 cluster regulates angiogenesis during embryonic stage and adulthood. In this review, we have discussed the actions of the miR-17-92 cluster in neuronal and vascular plasticity, and its potential as a novel therapeutic strategy for CNS injury. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ping Yang
- Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, 400038, PR China
| | - Linghu Cai
- Cadet Brigade, Third Military Medical University, Chongqing, 400038, PR China
| | - Guan Zhang
- Cadet Brigade, Third Military Medical University, Chongqing, 400038, PR China
| | - Zhiqun Bian
- Cadet Brigade, Third Military Medical University, Chongqing, 400038, PR China
| | - Gaofeng Han
- Cadet Brigade, Third Military Medical University, Chongqing, 400038, PR China
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25
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Tsan YC, Morell MH, O'Shea KS. miR-410 controls adult SVZ neurogenesis by targeting neurogenic genes. Stem Cell Res 2016; 17:238-247. [PMID: 27591480 DOI: 10.1016/j.scr.2016.07.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/14/2016] [Accepted: 07/11/2016] [Indexed: 11/16/2022] Open
Abstract
Over-expression of the early neural inducer, Noggin, in nestin positive subventricular zone (SVZ), neural stem cells (NSC) promotes proliferation and neuronal differentiation of neural progenitors and inhibits the expression of a CNS-enriched microRNA-410 (miR-410) (Morell et al., 2015). When expressed in neurospheres derived from the adult SVZ, miR-410 inhibits neuronal and oligodendrocyte differentiation, and promotes astrocyte differentiation. miR-410 also reverses the increase in neuronal differentiation and decreased astroglial differentiation caused by Noggin over-expression. Conversely, inhibition of miR-410 activity promotes neuronal and decreases astroglial differentiation of NSC. Using computer prediction algorithms and luciferase reporter assays we identified multiple neurogenic genes including Elavl4 as downstream targets of miR-410 via the canonical miRNA-3'UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3'UTR rescued the decrease in neuronal differentiation caused by miR-410 overexpression. Interestingly, we also observed that miR-410 affected neurite morphology; over-expression of miR-410 resulted in the formation of short, unbranched neurites. We conclude that miR-410 expression provides a new link between BMP signaling and the crucial lineage choice of adult neural stem cells via its ability to bind and control the expression of neurogenic gene transcripts.
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Affiliation(s)
- Yao-Chang Tsan
- Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - Maria H Morell
- Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - K Sue O'Shea
- Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
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Lépinoux-Chambaud C, Barreau K, Eyer J. The Neurofilament-Derived Peptide NFL-TBS.40-63 Targets Neural Stem Cells and Affects Their Properties. Stem Cells Transl Med 2016; 5:901-13. [PMID: 27177578 DOI: 10.5966/sctm.2015-0221] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 02/23/2016] [Indexed: 01/18/2023] Open
Abstract
UNLABELLED Targeting neural stem cells (NSCs) in the adult brain represents a promising approach for developing new regenerative strategies, because these cells can proliferate, self-renew, and differentiate into new neurons, astrocytes, and oligodendrocytes. Previous work showed that the NFL-TBS.40-63 peptide, corresponding to the sequence of a tubulin-binding site on neurofilaments, can target glioblastoma cells, where it disrupts their microtubules and inhibits their proliferation. We show that this peptide targets NSCs in vitro and in vivo when injected into the cerebrospinal fluid. Although neurosphere formation was not altered by the peptide, the NSC self-renewal capacity and proliferation were reduced and were associated with increased adhesion and differentiation. These results indicate that the NFL-TBS.40-63 peptide represents a new molecular tool to target NSCs to develop new strategies for regenerative medicine and the treatment of brain tumors. SIGNIFICANCE In the present study, the NFL-TBS.40-63 peptide targeted neural stem cells in vitro when isolated from the subventricular zone and in vivo when injected into the cerebrospinal fluid present in the lateral ventricle. The in vitro formation of neurospheres was not altered by the peptide; however, at a high concentration of the peptide, the neural stem cell (NSC) self-renewal capacity and proliferation were reduced and associated with increased adhesion and differentiation. These results indicate that the NFL-TBS.40-63 peptide represents a new molecular tool to target NSCs to develop new strategies for regenerative medicine and the treatment of brain tumors.
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Affiliation(s)
- Claire Lépinoux-Chambaud
- Laboratoire Neurobiologie et Transgenese, Université Nantes, Angers, Le Mans, Unité Propre de Recherche de l'Enseignement Supérieur EA-3143, Institut de Biologie en Santé, L'Université d'Angers, Centre Hospitalier Universitaire, Angers, France
| | - Kristell Barreau
- Laboratoire Neurobiologie et Transgenese, Université Nantes, Angers, Le Mans, Unité Propre de Recherche de l'Enseignement Supérieur EA-3143, Institut de Biologie en Santé, L'Université d'Angers, Centre Hospitalier Universitaire, Angers, France
| | - Joël Eyer
- Laboratoire Neurobiologie et Transgenese, Université Nantes, Angers, Le Mans, Unité Propre de Recherche de l'Enseignement Supérieur EA-3143, Institut de Biologie en Santé, L'Université d'Angers, Centre Hospitalier Universitaire, Angers, France
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27
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Decoding the ubiquitous role of microRNAs in neurogenesis. Mol Neurobiol 2016; 54:2003-2011. [PMID: 26910816 DOI: 10.1007/s12035-016-9797-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 02/16/2016] [Indexed: 12/21/2022]
Abstract
Neurogenesis generates fledgling neurons that mature to form an intricate neuronal circuitry. The delusion on adult neurogenesis was far resolved in the past decade and became one of the largely explored domains to identify multifaceted mechanisms bridging neurodevelopment and neuropathology. Neurogenesis encompasses multiple processes including neural stem cell proliferation, neuronal differentiation, and cell fate determination. Each neurogenic process is specifically governed by manifold signaling pathways, several growth factors, coding, and non-coding RNAs. A class of small non-coding RNAs, microRNAs (miRNAs), is ubiquitously expressed in the brain and has emerged to be potent regulators of neurogenesis. It functions by fine-tuning the expression of specific neurogenic gene targets at the post-transcriptional level and modulates the development of mature neurons from neural progenitor cells. Besides the commonly discussed intrinsic factors, the neuronal morphogenesis is also under the control of several extrinsic temporal cues, which in turn are regulated by miRNAs. This review enlightens on dicer controlled switch from neurogenesis to gliogenesis, miRNA regulation of neuronal maturation and the differential expression of miRNAs in response to various extrinsic cues affecting neurogenesis.
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28
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Heterochronic microRNAs in temporal specification of neural stem cells: application toward rejuvenation. NPJ Aging Mech Dis 2016; 2:15014. [PMID: 28721261 PMCID: PMC5514991 DOI: 10.1038/npjamd.2015.14] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/29/2015] [Accepted: 11/01/2015] [Indexed: 12/27/2022] Open
Abstract
Plasticity is a critical factor enabling stem cells to contribute to the development and regeneration of tissues. In the mammalian central nervous system (CNS), neural stem cells (NSCs) that are defined by their capability for self-renewal and differentiation into neurons and glia, are present in the ventricular neuroaxis throughout life. However, the differentiation potential of NSCs changes in a spatiotemporally regulated manner and these cells progressively lose plasticity during development. One of the major alterations in this process is the switch from neurogenesis to gliogenesis. NSCs initiate neurogenesis immediately after neural tube closure and then turn to gliogenesis from midgestation, which requires an irreversible competence transition that enforces a progressive reduction of neuropotency. A growing body of evidence indicates that the neurogenesis-to-gliogenesis transition is governed by multiple layers of regulatory networks consisting of multiple factors, including epigenetic regulators, transcription factors, and non-coding RNA (ncRNA). In this review, we focus on critical roles of microRNAs (miRNAs), a class of small ncRNA that regulate gene expression at the post-transcriptional level, in the regulation of the switch from neurogenesis to gliogenesis in NSCs in the developing CNS. Unraveling the regulatory interactions of miRNAs and target genes will provide insights into the regulation of plasticity of NSCs, and the development of new strategies for the regeneration of damaged CNS.
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29
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Effects of addictive drugs on adult neural stem/progenitor cells. Cell Mol Life Sci 2015; 73:327-48. [PMID: 26468052 DOI: 10.1007/s00018-015-2067-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 10/04/2015] [Accepted: 10/08/2015] [Indexed: 12/18/2022]
Abstract
Neural stem/progenitor cells (NSPCs) undergo a series of developmental processes before giving rise to newborn neurons, astrocytes and oligodendrocytes in adult neurogenesis. During the past decade, the role of NSPCs has been highlighted by studies on adult neurogenesis modulated by addictive drugs. It has been proven that these drugs regulate the proliferation, differentiation and survival of adult NSPCs in different manners, which results in the varying consequences of adult neurogenesis. The effects of addictive drugs on NSPCs are exerted via a variety of different mechanisms and pathways, which interact with one another and contribute to the complexity of NSPC regulation. Here, we review the effects of different addictive drugs on NSPCs, and the related experimental methods and paradigms. We also discuss the current understanding of major signaling molecules, especially the putative common mechanisms, underlying such effects. Finally, we review the future directions of research in this area.
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30
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31
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MicroRNA delivery for regenerative medicine. Adv Drug Deliv Rev 2015; 88:108-22. [PMID: 26024978 DOI: 10.1016/j.addr.2015.05.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 05/13/2015] [Accepted: 05/21/2015] [Indexed: 12/26/2022]
Abstract
MicroRNA (miRNA) directs post-transcriptional regulation of a network of genes by targeting mRNA. Although relatively recent in development, many miRNAs direct differentiation of various stem cells including induced pluripotent stem cells (iPSCs), a major player in regenerative medicine. An effective and safe delivery of miRNA holds the key to translating miRNA technologies. Both viral and nonviral delivery systems have seen success in miRNA delivery, and each approach possesses advantages and disadvantages. A number of studies have demonstrated success in augmenting osteogenesis, improving cardiogenesis, and reducing fibrosis among many other tissue engineering applications. A scaffold-based approach with the possibility of local and sustained delivery of miRNA is particularly attractive since the physical cues provided by the scaffold may synergize with the biochemical cues induced by miRNA therapy. Herein, we first briefly cover the application of miRNA to direct stem cell fate via replacement and inhibition therapies, followed by the discussion of the promising viral and nonviral delivery systems. Next we present the unique advantages of a scaffold-based delivery in achieving lineage-specific differentiation and tissue development.
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32
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Wang B, Ricardo S. Role of microRNA machinery in kidney fibrosis. Clin Exp Pharmacol Physiol 2015; 41:543-50. [PMID: 24798583 DOI: 10.1111/1440-1681.12249] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 04/10/2014] [Accepted: 04/25/2014] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that are critical regulators of gene expression at the post-transcriptional level. The miRNAs constitute an abundant class of RNAs conserved from plants to animals and, as such, play key roles in diverse biological processes, including inflammation, development, differentiation and apoptosis. More recently, it has become apparent that changes in miRNA expression contribute to a wide spectrum of human pathologies, including heart and kidney disease, organ developmental abnormalities and neuronal degeneration. Moreover, inflammation and the development of kidney fibrosis is accompanied by changes in miRNA expression. This review summarizes the emerging field deciphering the complex connections between human miRNA biology and different aspects of kidney injury, focusing on kidney fibrosis. The miRNA-regulated fibrosis is discussed based on the classification of pivotal mechanisms, notably involving the transforming growth factor-β1 signalling pathway. In addition, the challenge of miRNA delivery vehicles as mechanisms of cellular transfer are reviewed, as is the use of miRNA as a potential biomarker for disease.
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Affiliation(s)
- Bo Wang
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
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33
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Shimizu S, Tanaka T, Tohyama M, Miyata S. Yokukansan normalizes glucocorticoid receptor protein expression in oligodendrocytes of the corpus callosum by regulating microRNA-124a expression after stress exposure. Brain Res Bull 2015; 114:49-55. [PMID: 25857947 DOI: 10.1016/j.brainresbull.2015.03.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/24/2015] [Accepted: 03/30/2015] [Indexed: 12/29/2022]
Abstract
Stressful events are known to down-regulate expression levels of glucocorticoid receptors (GRs) in the brain. Recently, we reported that stressed mice with elevated plasma levels of corticosterone exhibit morphological changes in the oligodendrocytes of nerve fiber bundles, such as those in the corpus callosum. However, little is known about the molecular mechanism of GR expression regulation in oligodendrocytes after stress exposure. A previous report has suggested that GR protein levels might be regulated by microRNA (miR)-18 and/or -124a in the brain. In this study, we aimed to elucidate the GR regulation mechanism in oligodendrocytes and evaluate the effects of yokukansan (YKS), a Kampo medicine, on GR protein regulation. Acute exposure to stress increased plasma corticosterone levels, decreased GR protein expression, and increased miR-124a expression in the corpus callosum of adult male mice, though the GR mRNA and miR-18 expression levels were not significant changes. YKS normalized the stress-induced changes in the plasma corticosterone, GR protein, and miR124a expression levels. An oligodendrocyte primary culture study also showed that YKS down-regulated miR-124a, but not miR-18, expression levels in dexamethasone-treated cells. These results suggest that the down-regulation of miR124a expression might be involved in the normalization of stress-induced decreases in GR protein in oligodendrocytes by YKS. This effect may imply the molecular mechanisms underlying the ameliorative effects of YKS on psychological symptoms and stress-related behaviors.
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Affiliation(s)
- Shoko Shimizu
- Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Osaka-sayama, Osaka 589-8511, Japan
| | - Takashi Tanaka
- Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Osaka-sayama, Osaka 589-8511, Japan
| | - Masaya Tohyama
- Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Osaka-sayama, Osaka 589-8511, Japan; Osaka Prefectural Hospital Organization, Osaka 558-8558, Japan
| | - Shingo Miyata
- Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Osaka-sayama, Osaka 589-8511, Japan.
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McAdams RM, McPherson RJ, Beyer RP, Bammler TK, Farin FM, Juul SE. Dose-dependent effects of morphine exposure on mRNA and microRNA (miR) expression in hippocampus of stressed neonatal mice. PLoS One 2015; 10:e0123047. [PMID: 25844808 PMCID: PMC4386824 DOI: 10.1371/journal.pone.0123047] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 02/18/2015] [Indexed: 12/02/2022] Open
Abstract
Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05) from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated), and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine–mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine-related impairment of adult learning.
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Affiliation(s)
- Ryan M. McAdams
- Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, Washington, United States of America
- * E-mail:
| | - Ronald J. McPherson
- Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, Washington, United States of America
| | - Richard P. Beyer
- Dept of Environmental & Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - Theo K. Bammler
- Dept of Environmental & Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - Frederico M. Farin
- Dept of Environmental & Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - Sandra E. Juul
- Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, Washington, United States of America
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35
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Swaminathan A, Kumar M, Halder Sinha S, Schneider-Anthony A, Boutillier AL, Kundu TK. Modulation of neurogenesis by targeting epigenetic enzymes using small molecules: an overview. ACS Chem Neurosci 2014; 5:1164-77. [PMID: 25250644 DOI: 10.1021/cn500117a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Neurogenesis consists of a plethora of complex cellular processes including neural stem cell (NSC) proliferation, migration, maturation or differentiation to neurons, and finally integration into the pre-existing neural circuits in the brain, which are temporally regulated and coordinated sequentially. Mammalian neurogenesis begins during embryonic development and continues in postnatal brain (adult neurogenesis). It is now evident that adult neurogenesis is driven by extracellular and intracellular signaling pathways, where epigenetic modifications like reversible histone acetylation, methylation, as well as DNA methylation play a vital role. Epigenetic regulation of gene expression during neural development is governed mainly by histone acetyltransferases (HATs), histone methyltransferase (HMTs), DNA methyltransferases (DNMTs), and also the enzymes for reversal, like histone deacetylases (HDACs), and many of these have also been shown to be involved in the regulation of adult neurogenesis. The contribution of these epigenetic marks to neurogenesis is increasingly being recognized, through knockout studies and small molecule modulator based studies. These small molecules are directly involved in regeneration and repair of neurons, and not only have applications from a therapeutic point of view, but also provide a tool to study the process of neurogenesis itself. In the present Review, we will focus on small molecules that act predominantly on epigenetic enzymes to enhance neurogenesis and neuroprotection and discuss the mechanism and recent advancements in their synthesis, targeting, and biology.
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Affiliation(s)
- Amrutha Swaminathan
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Manoj Kumar
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Sarmistha Halder Sinha
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Anne Schneider-Anthony
- Laboratoire de Neurosciences
Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS,
GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Anne-Laurence Boutillier
- Laboratoire de Neurosciences
Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS,
GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Tapas K Kundu
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
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Characterization of paraquat-induced miRNA profiling response in hNPCs undergoing proliferation. Int J Mol Sci 2014; 15:18422-36. [PMID: 25314302 PMCID: PMC4227223 DOI: 10.3390/ijms151018422] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 09/26/2014] [Accepted: 09/29/2014] [Indexed: 01/03/2023] Open
Abstract
Aberration during the development of the central nervous system (CNS) due to environmental factors underlies a variety of adverse developmental outcomes. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. Yet, the impacts of PQ exposure on the developing CNS remain unclear. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development. Thus in the present study, we analyzed the impacts of PQ on the miRNome of human neural progenitor cells (hNPCs) during proliferation by using the Exiqon miRCURY™ LNA Array. A total of 66 miRNAs were identified as differentially expressed in proliferating hNPCs upon PQ treatment. miRTarBase prediction identified 1465 mRNAs, including several genes (e.g., nestin, sox1, ngn1) previously proved to be associated with the neural proliferation and differentiation, as target genes of PQ-induced differentially expressed miRNAs. The database for annotation, visualization and integrated discovery (DAVID) bioinformatics analysis showed that target genes were enriched in regulation of cell proliferation and differentiation, cell cycle and apoptosis as well as tumor protein 53 (p53), Wnt, Notch and mitogen-activated protein kinases (MAPK) signaling pathways (p < 0.001). These findings were confirmed by real-time RT-PCR. Based on our results we conclude that PQ-induced impacts on the miRNA profiling of hNPCs undergoing proliferation may underlie the developmental neurotoxicity of PQ.
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Hardwick LJA, Philpott A. Nervous decision-making: to divide or differentiate. Trends Genet 2014; 30:254-61. [PMID: 24791612 PMCID: PMC4046230 DOI: 10.1016/j.tig.2014.04.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 03/31/2014] [Accepted: 04/01/2014] [Indexed: 01/07/2023]
Abstract
Multiple mechanisms coordinate the cell cycle and neuronal differentiation. Lengthening of G1 phase is functionally important for differentiation. Cell cycle components can directly and independently affect neurogenesis. Differentiation factors can directly affect the cell cycle structure and machinery. The intricate balance between proliferation and differentiation is of fundamental importance in the development of the central nervous system (CNS). The division versus differentiation decision influences both the number and identity of daughter cells produced, thus critically shaping the overall microstructure and function of the CNS. During the past decade, significant advances have been made to characterise the changes in the cell cycle during differentiation, and to uncover the multiple bidirectional links that coordinate these two processes. Here, we explore the nature and mechanistic basis of these links in the context of the developing CNS, highlighting new insights into transcriptional, post-translational, and epigenetic levels of interaction.
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Affiliation(s)
- Laura J A Hardwick
- Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Anna Philpott
- Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
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Adyshev DM, Elangovan VR, Moldobaeva N, Mapes B, Sun X, Garcia JGN. Mechanical stress induces pre-B-cell colony-enhancing factor/NAMPT expression via epigenetic regulation by miR-374a and miR-568 in human lung endothelium. Am J Respir Cell Mol Biol 2014; 50:409-18. [PMID: 24053186 DOI: 10.1165/rcmb.2013-0292oc] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Increased lung vascular permeability and alveolar edema are cardinal features of inflammatory conditions such as acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). We previously demonstrated that pre-B-cell colony-enhancing factor (PBEF)/NAMPT, the proinflammatory cytokine encoded by NAMPT, participates in ARDS and VILI inflammatory syndromes. The present study evaluated posttranscriptional regulation of PBEF/NAMPT gene expression in human lung endothelium via 3'-untranslated region (UTR) microRNA (miRNA) binding. In silico analysis identified hsa-miR-374a and hsa-miR-568 as potential miRNA candidates. Increased PBEF/NAMPT transcription (by RT-PCR) and expression (by Western blotting) induced by 18% cyclic stretch (CS) (2 h: 3.4 ± 0.06 mRNA fold increase (FI); 10 h: 1.5 ± 0.06 protein FI) and by LPS (4 h: 3.8 ± 0.2 mRNA FI; 48 h: 2.6 ± 0.2 protein FI) were significantly attenuated by transfection with mimics of hsa-miR-374a or hsa-miR-568 (40-60% reductions each). LPS and 18% CS increased the activity of a PBEF/NAMPT 3'-UTR luciferase reporter (2.4-3.25 FI) with induction reduced by mimics of each miRNA (44-60% reduction). Specific miRNA inhibitors (antagomirs) for each PBEF/NAMPT miRNA significantly increased the endogenous PBEF/NAMPT mRNA (1.4-3.4 ± 0.1 FI) and protein levels (1.2-1.4 ± 0.1 FI) and 3'-UTR luciferase activity (1.4-1.7 ± 0.1 FI) compared with negative antagomir controls. Collectively, these data demonstrate that increased PBEF/NAMPT expression induced by bioactive agonists (i.e., excessive mechanical stress, LPS) involves epigenetic regulation with hsa-miR-374a and hsa-miR-568, representing novel therapeutic strategies to reduce inflammatory lung injury.
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Affiliation(s)
- Djanybek M Adyshev
- Institute for Personalized Respiratory Medicine, Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, Illinois
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Jamali AA, Pourhassan-Moghaddam M, Dolatabadi JEN, Omidi Y. Nanomaterials on the road to microRNA detection with optical and electrochemical nanobiosensors. Trends Analyt Chem 2014. [DOI: 10.1016/j.trac.2013.10.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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40
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Green HF, Nolan YM. Inflammation and the developing brain: Consequences for hippocampal neurogenesis and behavior. Neurosci Biobehav Rev 2014; 40:20-34. [DOI: 10.1016/j.neubiorev.2014.01.004] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 01/12/2014] [Accepted: 01/13/2014] [Indexed: 02/06/2023]
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Li H, Mao S, Wang H, Zen K, Zhang C, Li L. MicroRNA-29a modulates axon branching by targeting doublecortin in primary neurons. Protein Cell 2014; 5:160-9. [PMID: 24535747 PMCID: PMC3956970 DOI: 10.1007/s13238-014-0022-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 12/20/2013] [Indexed: 02/02/2023] Open
Abstract
MicroRNAs (miRNAs) are endogenously expressed small, non-coding transcripts that regulate protein expression. Substantial evidences suggest that miRNAs are enriched in central nervous system, where they are hypothesized to play pivotal roles during neural development. In the present study, we analyzed miRNAs expression in mice cerebral cortex and hippocampus at different developmental stages and found miR-29a increased dramatically at postnatal stages. In addition, we provided strong evidences that miR-29a is enriched in mature neurons both in vitro and in vivo. Further investigation demonstrated that the activation of glutamate receptors induced endogenous miR-29a level in primary neurons. Moreover, we showed that miR-29a directly regulated its target protein Doublecortin (DCX) expression, which further modulated axon branching in primary culture. Together, our results suggested that miR-29a play an important role in neuronal development of mice cerebrum.
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Affiliation(s)
- Hanqin Li
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences, Nanjing, 210093, China
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Choi E, Choi E, Hwang KC. MicroRNAs as novel regulators of stem cell fate. World J Stem Cells 2013; 5:172-187. [PMID: 24179605 PMCID: PMC3812521 DOI: 10.4252/wjsc.v5.i4.172] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/13/2013] [Accepted: 08/17/2013] [Indexed: 02/06/2023] Open
Abstract
Mounting evidence in stem cell biology has shown that microRNAs (miRNAs) play a crucial role in cell fate specification, including stem cell self-renewal, lineage-specific differentiation, and somatic cell reprogramming. These functions are tightly regulated by specific gene expression patterns that involve miRNAs and transcription factors. To maintain stem cell pluripotency, specific miRNAs suppress transcription factors that promote differentiation, whereas to initiate differentiation, lineage-specific miRNAs are upregulated via the inhibition of transcription factors that promote self-renewal. Small molecules can be used in a similar manner as natural miRNAs, and a number of natural and synthetic small molecules have been isolated and developed to regulate stem cell fate. Using miRNAs as novel regulators of stem cell fate will provide insight into stem cell biology and aid in understanding the molecular mechanisms and crosstalk between miRNAs and stem cells. Ultimately, advances in the regulation of stem cell fate will contribute to the development of effective medical therapies for tissue repair and regeneration. This review summarizes the current insights into stem cell fate determination by miRNAs with a focus on stem cell self-renewal, differentiation, and reprogramming. Small molecules that control stem cell fate are also highlighted.
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