MicroRNA Profiling Reveals Unique miRNA Signatures in IGF-1 Treated Embryonic Striatal Stem Cell Fate Decisions in Striatal Neurogenesis In Vitro
01 Sep 2014-BioMed Research International (Hindawi Publishing Corporation)-Vol. 2014, pp 503162-503162
TL;DR: In order to decipher the underlying regulatory microRNA (miRNA)s in IGF-1/LIF-treated ESSC-derived neurogenesis, in-depth miRNA profiling at 12 days in vitro was performed and the important mRNA targets of the miRNAs were revealed and suggested specific interactomes were suggested.
Abstract: The striatum is considered to be the central processing unit of the basal ganglia in locomotor activity and cognitive function of the brain. IGF-1 could act as a control switch for the long-term proliferation and survival of EGF + bFGF-responsive cultured embryonic striatal stem cell (ESSC), while LIF imposes a negative impact on cell proliferation. The IGF-1-treated ESSCs also showed elevated hTERT expression with demonstration of self-renewal and trilineage commitment (astrocytes, oligodendrocytes, and neurons). In order to decipher the underlying regulatory microRNA (miRNA)s in IGF-1/LIF-treated ESSC-derived neurogenesis, we performed in-depth miRNA profiling at 12 days in vitro and analyzed the candidates using the Partek Genome Suite software. The annotated miRNA fingerprints delineated the differential expressions of miR-143, miR-433, and miR-503 specific to IGF-1 treatment. Similarly, the LIF-treated ESSCs demonstrated specific expression of miR-326, miR-181, and miR-22, as they were nonsignificant in IGF-treated ESSCs. To elucidate the possible downstream pathways, we performed in silico mapping of the said miRNAs into ingenuity pathway analysis. Our findings revealed the important mRNA targets of the miRNAs and suggested specific interactomes. The above studies introduced a new genre of miRNAs for ESSC-based neuroregenerative therapeutic applications.
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TL;DR: The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs and address key factors in cell preparation and approaches of cell delivery that affect the outcomes of cell therapy.
Abstract: Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.
97 citations
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TL;DR: Some of the latest findings regarding the impact of stress in the biology of the neurogenic niche are addressed, and how astrocytic exosomes (and miRNAs) may play a fundamental role in such phenomenon are postulated.
Abstract: Repetitive stress negatively affects several brain functions and neuronal networks. Moreover, adult neurogenesis is consistently impaired in chronic stress models and in associated human diseases such as unipolar depression and bipolar disorder, while it is restored by effective antidepressant treatments. The adult neurogenic niche contains neural progenitor cells in addition to amplifying progenitors, neuroblasts, immature and mature neurons, pericytes, astrocytes, and microglial cells. Because of their particular and crucial position, with their end feet enwrapping endothelial cells and their close communication with the cells of the niche, astrocytes might constitute a nodal point to bridge or transduce systemic stress signals from peripheral blood, such as glucocorticoids, to the cells involved in the neurogenic process. It has been proposed that communication between astrocytes and niche cells depends on direct cell-cell contacts and soluble mediators. In addition, new evidence suggests that this communication might be mediated by extracellular vesicles such as exosomes, and in particular, by their miRNA cargo. Here, we address some of the latest findings regarding the impact of stress in the biology of the neurogenic niche, and postulate how astrocytic exosomes (and miRNAs) may play a fundamental role in such phenomenon.
42 citations
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TL;DR: Ass associations between miRNAs and MRIs were both protective and pathogenic, and a topographic specificity differed for the brain vs the spinal cord, and the signature differed between T2LV and atrophy/destructive measures.
Abstract: Importance MicroRNAs (miRNAs) are promising multiple sclerosis (MS) biomarkers. Establishing the association between miRNAs and magnetic resonance imaging (MRI) measures of disease severity will help define their significance and potential impact. Objective To correlate circulating miRNAs in the serum of patients with MS to brain and spinal MRI. Design, Setting, and Participants A cross-sectional study comparing serum miRNA samples with MRI metrics was conducted at a tertiary MS referral center. Two independent cohorts (41 and 79 patients) were retrospectively identified from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital. Expression of miRNA was determined by locked nucleic acid–based quantitative real-time polymerase chain reaction. Spearman correlation coefficients were used to test the association between miRNA and brain lesions (T2 hyperintense lesion volume [T2LV]), the ratio of T1 hypointense lesion volume [T1LV] to T2LV [T1:T2]), brain atrophy (whole brain and gray matter), and cervical spinal cord lesions (T2LV) and atrophy. The study was conducted from December 2013 to April 2016. Main Outcomes and Measures miRNA expression. Results Of the 120 patients included in the study, cohort 1 included 41 participants (7 [17.1%] men), with mean (SD) age of 47.7 (9.5) years; cohort 2 had 79 participants (26 [32.9%] men) with a mean (SD) age of 43.0 (7.5) years. Associations between miRNAs and MRIs were both protective and pathogenic. Regarding miRNA signatures, a topographic specificity differed for the brain vs the spinal cord, and the signature differed between T2LV and atrophy/destructive measures. Four miRNAs showed similar significant protective correlations with T1:T2 in both cohorts, with the highest for hsa.miR.143.3p (cohort 1: Spearman correlation coefficient r s = −0.452, P = .003; cohort 2: r s = −0.225, P = .046); the others included hsa.miR.142.5p (cohort 1: r s = −0.424, P = .006; cohort 2: r s = −0.226, P = .045), hsa.miR.181c.3p (cohort 1: r s = −0.383, P = .01; cohort 2: r s = −0.222, P = .049), and hsa.miR.181c.5p (cohort 1: r s = −0.433, P = .005; cohort 2: r s = −0.231, P = .04). In the 2 cohorts, hsa.miR.486.5p (cohort 1: r s = 0.348, P = .03; cohort 2: r s = 0.254, P = .02) and hsa.miR.92a.3p (cohort 1: r s = 0.392, P = .01; cohort 2: r s = 0.222, P = .049) showed similar significant pathogenic correlations with T1:T2; hsa.miR.375 (cohort 1: r s = −0.345, P = .03; cohort 2: r s = −0.257, P = .022) and hsa.miR.629.5p (cohort 1: r s = −0.350, P = .03; cohort 2: r s = −0.269, P = .02) showed significant pathogenic correlations with brain atrophy. Although we found several miRNAs associated with MRI outcomes, none of these associations remained significant when correcting for multiple comparisons, suggesting that further validation of our findings is needed. Conclusions and Relevance Serum miRNAs may serve as MS biomarkers for monitoring disease progression and act as surrogate markers to identify underlying disease processes.
42 citations
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TL;DR: The evidence obtained herein supports the occurrence of significant neurobiological differences in the hippocampus, not only between adult and elderly individuals, but between old- healthy women and old-healthy men.
Abstract: Motivation: In the brain of elderly-healthy individuals, the effects of sexual dimorphism and those due to normal ageing appear overlapped. Discrimination of these two dimensions would powerfully contribute to a better understanding of the aetiology of some neurodegenerative diseases, such as “sporadic” Alzheimer. Methods: Following a system biology approach, top-down and bottom-up strategies were combined. First, public transcriptome data corresponding to the transition from adulthood to the ageing stage in normal, human hippocampus were analysed through an optimized microarray post-processing (Q-GDEMAR method) together with a proper experimental design (full factorial analysis). Second, the identified genes were placed in context by building compatible networks. The subsequent ontology analyses carried out on these networks clarify the main functionalities involved. Results: Noticeably we could identify large sets of genes according to three groups: those that exclusively depend on the sex, those that exclusively depend on the age, and those that depend on the particular combinations of sex and age (interaction). The genes identified were validated against three independent sources (a proteomic study of ageing, a senescence database, and a mitochondrial genetic database). We arrived to several new inferences about the biological functions compromised during ageing in two ways: by taking into account the sex-independent effects of ageing, and considering the interaction between age and sex where pertinent. In particular, we discuss the impact of our findings on the functions of mitochondria, autophagy, mitophagia, and microRNAs. Conclusions: The evidence obtained herein supports the occurrence of significant neurobiological differences in the hippocampus, not only between adult and elderly individuals, but between old-healthy women and old-healthy men. Hence, to obtain realistic results in further analysis of the transition from the normal ageing to incipient Alzheimer, the features derived from the sexual dimorphism in hippocampus should be explicitly considered.
29 citations
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TL;DR: A better understanding of the miR-181 family in pathological conditions may open new therapeutic avenues for devasting disorders such as neurodegenerative diseases and cancer.
Abstract: MicroRNAs (miRNAs) are small noncoding RNAs playing a fundamental role in the regulation of gene expression. Evidence accumulating in the past decades indicate that they are capable of simultaneously modulating diverse signaling pathways involved in a variety of pathophysiological processes. In the present review, we provide a comprehensive overview of the function of a highly conserved group of miRNAs, the miR-181 family, both in physiological as well as in pathological conditions. We summarize a large body of studies highlighting a role for this miRNA family in the regulation of key biological processes such as embryonic development, cell proliferation, apoptosis, autophagy, mitochondrial function, and immune response. Importantly, members of this family have been involved in many pathological processes underlying the most common neurodegenerative disorders as well as different solid tumors and hematological malignancies. The relevance of this miRNA family in the pathogenesis of these disorders and their possible influence on the severity of their manifestations will be discussed. A better understanding of the miR-181 family in pathological conditions may open new therapeutic avenues for devasting disorders such as neurodegenerative diseases and cancer.
29 citations
References
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TL;DR: It is suggested that EGF and/or TGF alpha may act on a multipotent progenitor cell in the striatum to generate both neurons and astrocytes.
Abstract: The mitogenic actions of epidermal growth factor (EGF) were examined in low-density, dissociated cultures of embryonic day 14 mouse striatal primordia, under serum-free defined conditions. EGF induced the proliferation of single progenitor cells that began to divide between 5 and 7 d in vitro, and after 13 d in vitro had formed a cluster of undifferentiated cells that expressed nestin, an intermediate filament present in neuroepithelial stem cells. In the continued presence of EGF, cells migrated from the proliferating core and differentiated into neurons and astrocytes. The actions of EGF were mimicked by the homolog transforming growth factor alpha (TGF alpha), but not by NGF, basic fibroblast growth factor, platelet-derived growth factor, or TGF beta. In EGF-generated cultures, cells with neuronal morphology contained immunoreactivity for GABA, substance P, and methionine-enkephalin, three neurotransmitters of the adult striatum. Amplification of embryonic day 14 striatal mRNA by using reverse transcription/PCR revealed mRNAs for EGF, TGF alpha, and the EGF receptor. These findings suggest that EGF and/or TGF alpha may act on a multipotent progenitor cell in the striatum to generate both neurons and astrocytes.
1,575 citations
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TL;DR: The first cellular and molecular elements of the stem cell niche in the adult brain have been identified and include cell-cell interactions and somatic cell signaling, the vasculature, the extracellular matrix and basal lamina.
Abstract: The adult mammalian brain harbors multipotent stem cells, which reside and participate in specialized niches that support self-renewal and differentiation. The first cellular and molecular elements of the stem cell niche in the adult brain have been identified and include cell-cell interactions and somatic cell signaling, the vasculature, the extracellular matrix and basal lamina. Furthermore, regulation at the epigenetic level via chromatin modification and remodeling is an integral aspect of stem cell biology. Understanding the in vivo stem cell niche will provide a framework for the elucidation of stem cell function in the adult brain.
639 citations
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TL;DR: It was striking that several age-related gene expression changes in both MSC and HPC were also differentially expressed upon replicative senescence of MSC in vitro, indicating that the authors' stem and progenitor cells undergo a similar process also in vivo.
Abstract: The regenerative potential diminishes with age and this has been ascribed to functional impairments of adult stem cells. Cells in culture undergo senescence after a certain number of cell divisions whereby the cells enlarge and finally stop proliferation. This observation of replicative senescence has been extrapolated to somatic stem cells in vivo and might reflect the aging process of the whole organism. In this study we have analyzed the effect of aging on gene expression profiles of human mesenchymal stromal cells (MSC) and human hematopoietic progenitor cells (HPC). MSC were isolated from bone marrow of donors between 21 and 92 years old. 67 genes were age-induced and 60 were age-repressed. HPC were isolated from cord blood or from mobilized peripheral blood of donors between 27 and 73 years and 432 genes were age-induced and 495 were age-repressed. The overlap of age-associated differential gene expression in HPC and MSC was moderate. However, it was striking that several age-related gene expression changes in both MSC and HPC were also differentially expressed upon replicative senescence of MSC in vitro. Especially genes involved in genomic integrity and regulation of transcription were age-repressed. Although telomerase activity and telomere length varied in HPC particularly from older donors, an age-dependent decline was not significant arguing against telomere exhaustion as being causal for the aging phenotype. These studies have demonstrated that aging causes gene expression changes in human MSC and HPC that vary between the two different cell types. Changes upon aging of MSC and HPC are related to those of replicative senescence of MSC in vitro and this indicates that our stem and progenitor cells undergo a similar process also in vivo.
392 citations
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TL;DR: Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway.
Abstract: The Notch pathway is often regarded as a developmental pathway, but components of Notch signalling are expressed and active in the adult brain. With the advent of more sophisticated genetic manipulations, evidence has emerged that suggests both conserved and novel roles for Notch signalling in the adult brain. Not surprisingly, Notch is a key regulator of adult neural stem cells, but it is increasingly clear that Notch signalling also has roles in the regulation of migration, morphology, synaptic plasticity and survival of immature and mature neurons. Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway.
347 citations
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TL;DR: It is shown that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes, and the existence of a single molecule, IGF- I, that can influence the fate choice of multipotential adult neural progensitor cells to an oligod endodendroglial lineage is demonstrated.
Abstract: Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.
317 citations
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