Cell transplantation strategies for acquired and inherited disorders of peripheral myelin
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PROVIDER: PRJNA431661 | ENA |
REPOSITORIES: ENA
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Project description:Objective: To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage. Methods: Primary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells (NCSC), and subsequently toward a Schwann cell lineage via two different protocols. Protocol 1 = treated with MesenPRO with Heregulin. Protocol 2 = coculture with iPSC-derived Motor Neurons. Cell types were characterized using flow cytometry, immunocytochemistry and transcriptomics. Rat Schwann cells and human iPSC-derivatives were transplanted into (i) nude rats pretreated with lysolecithin to induce demyelination or (ii) a transgenic rat model of dysmyelination due to PMP22 overexpression. Results: Rat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migration. Transplanted Schwann cells engaged existing axons and displaced dysfunctional Schwann cells to form normal appearing myelin. Human iPSC-derived neural crest stem cells and their derivatives shared similar engraftment and migration characteristics to rat Schwann cells after transplantation, but did not further differentiate into Schwann cells or form myelin. Interpretation: These results indicate that cultured Schwann cells surgically delivered to peripheral nerve can engraft and form myelin in either acquired or inherited myelin injury, as proof of concept for pursuing cell therapy for diseases of peripheral nerve. However, lack of reliable technology for generating human iPSC-derived Schwann cells for transplantation therapy remains a barrier in the field.
2018-01-26 | GSE109686 | GEO
Project description: Not available
| S-EPMC5817839 | biostudies-literature
Project description: Not available
| S-EPMC5010953 | biostudies-literature
Project description:Acquired somatic variants in inherited myeloid malignancies
| PRJEB49554 | ENA
Project description:Molecular mechanisms underlying the neurological disorders of inherited diseases of cobalamin metabolism remain obscure. Transcriptome data from a cell model with impaired cobalamin metabolism implicated dysregulated RNA metabolism and endoplasmic reticulum stress. Evidence from the cell model, Cd320 knockout mice, and fibroblasts with inborn errors of cobalamin metabolism indeed supported the findings of transcriptome. These models allowed the demonstration of RNA binding proteins (RBP) mislocalized subcellularly due to failed nucleocytoplasmic shuttling. In the case of HuR, decreased RBP interaction with nuclear receptor CRM1/exportin accounted for the failure, and HuR hypomethylation and dephosphorylation were the causes of this. Our evidence further indicated that decreased SAM and CARM1 level and increased PP2A expression were partly responsible for the post translational modifications of HuR. The consequent HuR mislocalization to the nucleus in turn reduced the expression of SIRT1 and other genes involved in brain development, neuroplasticity, myelin formation, and brain aging. This mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key roles of cobalamin metabolism on HuR-mediated mRNA stability, which when disrupted produce genomic changes consistent with the effects of inborn errors of cobalamin on brain development, neuroplasticity and myelin formation.
2018-07-20 | GSE103417 | GEO
Project description:The Molecular Basis of Inherited Reproductive Disorders
| PRJNA89533 | ENA
Project description:The Genetic Basis of Inherited Reproductive Disorders
| PRJNA353732 | ENA
Project description:Many acquired traits related to fat metabolism are inherited, and nutritional factors can induce fatty liver in chickens. We found that the paternal fatty livers induced by high-fat diet in Jingxing-Huang chickens were inherited, but the molecular mechanisms of inherited fatty liver in chickens are far from clear. The goals of this study are to compare liver transcriptome profiling (RNA-seq) in F1 generation to screen candidate genes for acquired fatty liver. Compared to birds without fatty liver in the control group, the paternal group exhibited altered hepatic gene expression profiles, including up-regulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism (ACACA, FASN, SCD, ACSL5, FADS2, FABP1, APOA4 and ME1). This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers.
2018-04-09 | GSE111909 | GEO
Project description:Rapid nerve conduction in the CNS is facilitated by the insulation of axons with myelin, a specialized oligodendroglial compartment distant from the cell body. Myelin is turned over and adapted throughout life; however, the molecular and cellular basis of myelin dynamics is not well understood. Hypothesizing that only a fraction of all myelin-related mRNAs has been identified so far, we subjected myelin biochemically purified from mouse brains at various ages to RNA sequencing. We find a surprisingly large pool of transcripts abundant and/or enriched in myelin. Furthermore, a comprehensive analysis showed that the myelin transcriptome is closely related to the myelin proteome but clearly distinct from the transcriptomes of oligodendrocytes and brain tissues, suggesting that the incorporation of mRNAs into the myelin compartment is highly selective. The mRNA-pool in myelin displays maturation-dependent dynamic changes of composition, abundance, and functional associations; however ageing-dependent changes after 6 months of age were minor. We suggest that this transcript pool provides a basis for the local modulation of myelin turnover and adaptation, i.e. in the individual internode. A light-weight membrane fraction enriched for myelin was purified from mouse brains as described previously (Jahn et al., Neuromethods, 2013). For RNA-Seq, RNA was isolated from myelin of mice from indicated ages.
2016-06-24 | E-GEOD-78151 | biostudies-arrayexpress
Project description:Background: Inherited Platelet Disorders (IPDs) are a heterogeneous group of rare diseases that are caused by defects in early megakaryopoiesis, pro-platelet formation and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function, however insights into how variants that cause IPDs impact platelet proteomes is limited. Objectives: To profile the platelet proteomics signatures of inherited platelet disorders. Methods: We performed unbiased label free quantitative mass spectrometry (MS)-based proteome profiling on platelets of 34 IPD patients with variants in 13 ISTH TIER1 genes that affect different stages of platelet development. Results: In line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1 and WAS). Utilizing the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein-complexes. This analysis furthermore grouped proteins with similar cellular- function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins. Conclusions: With this study we demonstrate a MS-based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function.
2023-01-31 | PXD027463 | Pride