Transplantation of Embryonic Neural Stem/Precursor Cells Overexpressing BM88/Cend1 Enhances the Generation of Neuronal Cells in the Injured Mouse Cortex

Makri, Georgia; Lavdas, Alexandros A.; Katsimpardi, Lida; Charneau, Pierre; Thomaidou, Dimitra; Matsas, Rebecca

doi:10.1002/stem.258

Cited by 36 publications

(39 citation statements)

References 58 publications

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“…CYP2W1 [29], GPR146 [30] and TOP1MT [31] are important for nutrient metabolism in the intestine. CEND1 plays a role in neuronal differentiation [32], thus in development of the enteric nervous system. The down-regulation of these genes due to promoter hypermethylation may significantly affect intestinal metabolism and development, which may help to explain the difficulties of preterm neonates to tolerate enteral feeding and the down-regulation of proteins involved in intestinal metabolism and motility [8].…”

Section: Resultsmentioning

confidence: 99%

Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

et al. 2014

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BackgroundThe serious feeding- and microbiota-associated intestinal disease, necrotizing enterocolitis (NEC), occurs mainly in infants born prematurely (5-10% of all newborns) and most frequently after formula-feeding. We hypothesized that changes in gene methylation is involved in the prenatal maturation of the intestine and its response to the first days of formula feeding, potentially leading to NEC in preterm pigs used as models for preterm infants.ResultsReduced Representation Bisulfite Sequencing (RRBS) was used to assess if changes in intestinal DNA methylation are associated with formula-induced NEC outbreak and advancing age from 10 days before birth to 4 days after birth. Selected key genes with differentially methylated gene regions (DMRs) between groups were further validated by HiSeq-based bisulfite sequencing PCR and RT-qPCR to assess methylation and expression levels. Consistent with the maturation of many intestinal functions in the perinatal period, methylation level of most genes decreased with advancing pre- and postnatal age. The highest number of DMRs was identified between the newborn and 4 d-old preterm pigs. There were few intestinal DMR differences between unaffected pigs and pigs with initial evidence of NEC. In the 4 d-old formula-fed preterm pigs, four genes associated with intestinal metabolism (CYP2W1, GPR146, TOP1MT, CEND1) showed significant hyper-methylation in their promoter CGIs, and thus, down-regulated transcription. Methylation-driven down-regulation of such genes may predispose the immature intestine to later metabolic dysfunctions and severe NEC lesions.ConclusionsPre- and postnatal changes in intestinal DNA methylation may contribute to high NEC sensitivity in preterm neonates. Optimizing gene methylation changes via environmental stimuli (e.g. diet, nutrition, gut microbiota), may help to make immature newborn infants more resistant to gut dysfunctions, both short and long term.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-716) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

et al. 2014

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“…It is well known that increased neuronal differentiation is helpful to the functional recovery after CNS insults [3]. Besides, another potentially beneficial effect of miR-17-92 cluster-overexpressing NSCs is the significant inhibition of astrogliosis since reactive astrocyte as well as glial scar may have detrimental consequences after CNS damage [48, 49].…”

Section: Discussionmentioning

confidence: 99%

“…Traumatic brain injury was performed as previously described [3]. Female C57BL/6 mice 10–12 weeks old were deeply anesthetized and positioned in a stereotaxic frame.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies suggest that transplantation of NSCs has become a promising therapy for various neurological disorders including ischemia, traumatic brain injury, and several neurodegenerative diseases of CNS [3, 4]. The tightly regulated cellular processes, especially the neural differentiation, are essential for grafted NSCs to produce enough neurons to restore neural damage in CNS [5].…”

Section: Introductionmentioning

confidence: 99%

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miR-17-92 facilitates neuronal differentiation of transplanted neural stem/precursor cells under neuroinflammatory conditions

Mao

Wang

et al. 2016

J Neuroinflammation

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BackgroundNeural stem/precursor cells (NSCs) are of particular interest because of their potential application in cell therapy for brain damage. However, most brain injury cases are followed with neuroinflammatory stress, which affects the lineage selection of grafted NSCs by promoting astrocytogenesis, thus hampering the potential for neural replacement. The present study investigated the role of miR-17-92 in protecting against detrimental effects of neuroinflammation on NSC differentiation in cell therapy.MethodsNSCs were treated with conditioned medium from lesioned astrocytes with/without neutralizing antibodies of leukemia inhibitory factor (LIF) or/and ciliary neurotrophic factor (CNTF), respectively. Afterward, the levels of p-STAT3 and p-JAK2 were determined by western blotting while expression of glial fibrillary acidic protein (GFAP) and β-tubulin III was assessed by immunostaining. The activation of JAK-STAT pathway and cell differentiation were also evaluated after we overexpressed miR-17-92 in NSCs under different neuroinflammatory conditions. After the transplantation of miR-17-92-overexpressing NSCs into injured mouse cortex, PH3, nestin, GFAP, and NeuN were analyzed by immunostaining. In addition, motor coordination of mice was evaluated by rotarod test.ResultsConditioned medium from lesioned astrocytes activated JAK-STAT pathway and facilitated astrocytic differentiation in NSCs while neutralizing antibodies of LIF and CNTF remarkably attenuated such effects. miR-17-92 cluster repressed the expression of multiple proteins including GP130, CNTFR, JAK2, and STAT3 in JAK-STAT pathway. Overexpression of miR-17-92 in NSCs systematically blocked the activation of JAK-STAT pathway mediated by LIF and CNTF, which facilitated neuronal differentiation in vitro. Furthermore, miR-17-92 increased neuronal generation of grafted NSCs and reduced astrogliosis, which resulted in the improvement of motor coordination of brain-injured mice.ConclusionsOur results suggest that miR-17-92 promotes neuronal differentiation of grafted NSCs under neuroinflammatory condition via inhibition of multiple proteins in JAK-STAT pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0685-5) contains supplementary material, which is available to authorized users.

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“…They play essential roles in repairing and maintaining normal CNS cells. Besides, tissue engineering by normal NSCs transplantation also enables the clinical therapeutic applications for CNS regressive diseases, such as Alzheimer's, Parkinson's, Huntington's disease and other CNS disorders (Storch and Schwarz, 2002;Lee et al, 2005;Oliveira and Hodges, 2005;Sanberg, 2007;Tang et al, 2008;Moghadam et al, 2009;Zhongling et al, 2009;Makri et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

System approaches reveal the molecular networks involved in neural stem cell differentiation

Wang

et al. 2012

Protein Cell

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The self-renewal and multipotent potentials in neural stem cells (NSCs) maintain the normal physiological functions of central nervous system (CNS). The abnormal differentiation of NSCs would lead to CNS disorders. However, the mechanisms of how NSCs differentiate into astrocytes, oligodendrocytes (OLs) and neurons are still unclear, which is mainly due to the complexity of differentiation processes and the limitation of the cell separation method. In this study, we modeled the dynamics of neural cell interactions in a systemic approach by mining the high-throughput genomic and proteomic data, and identified 8615 genes that are involved in various biological processes and functions with significant changes during the differentiation processes. A total of 1559 genes are specifically expressed in neural cells, in which 242 genes are NSC specific, 215 are astrocyte specific, 551 are OL specific, and 563 are neuron specific. In addition, we proposed 57 transcriptional regulators specifically expressed in NSCs may play essential roles in the development courses. These findings provide more comprehensive analysis for better understanding the endogenous mechanisms of NSC fate determination.

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Transplantation of Embryonic Neural Stem/Precursor Cells Overexpressing BM88/Cend1 Enhances the Generation of Neuronal Cells in the Injured Mouse Cortex

Cited by 36 publications

References 58 publications

Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

miR-17-92 facilitates neuronal differentiation of transplanted neural stem/precursor cells under neuroinflammatory conditions

System approaches reveal the molecular networks involved in neural stem cell differentiation

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