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Embryonic cerebrospinal fluid nanovesicles carry evolutionarily conserved molecules and promote neural stem cell amplification.

ABSTRACT: During brain development, neural stem cells (NSCs) receive on-or-off signals important for regulating their amplification and reaching adequate neuron density. However, how a coordinated regulation of intracellular pathways and genetic programs is achieved has remained elusive. Here, we found that the embryonic (e) CSF contains 10¹² nanoparticles/ml (77 nm diameter), some of which were identified as exosome nanovesicles that contain evolutionarily conserved molecules important for coordinating intracellular pathways. eCSF nanovesicles collected from rodent and human embryos encapsulate protein and microRNA components of the insulin-like growth factor (IGF) signaling pathway. Supplementation of eCSF nanovesicles to a mixed culture containing eNSCs activated the IGF-mammalian target of rapamycin complex 1 (mTORC1) pathway in eNSCs and expanded the pool of proliferative eNSCs. These data show that the eCSF serves as a medium for the distribution of nanovesicles, including exosomes, and the coordinated transfer of evolutionary conserved molecules that regulate eNSC amplification during corticogenesis.

SUBMITTER: Feliciano DM

PROVIDER: S-EPMC3923048 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Embryonic cerebrospinal fluid nanovesicles carry evolutionarily conserved molecules and promote neural stem cell amplification.

Feliciano David M DM Zhang Shiliang S Nasrallah Carole M CM Lisgo Steven N SN Bordey Angélique A

PloS one 20140212 2

During brain development, neural stem cells (NSCs) receive on-or-off signals important for regulating their amplification and reaching adequate neuron density. However, how a coordinated regulation of intracellular pathways and genetic programs is achieved has remained elusive. Here, we found that the embryonic (e) CSF contains 10¹² nanoparticles/ml (77 nm diameter), some of which were identified as exosome nanovesicles that contain evolutionarily conserved molecules important for coordinating i ...[more]

PMID: 24533152

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Project description:BackgroundUnderstanding the molecular mechanisms controlling pluripotency in embryonic stem cells (ESCs) is of central importance towards realizing their potentials in medicine and science. Cross-species examination of transcriptional co-expression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation.Methodology/principal findingsWe examined transcriptional co-expression of ESCs from pathways to global networks under the framework of human-mouse comparisons. Using generalized singular value decomposition and comparative partition around medoids algorithms, evolutionarily conserved and divergent transcriptional co-expression regulating pluripotency were identified from ESC-critical pathways including ACTIVIN/NODAL, ATK/PTEN, BMP, CELL CYCLE, JAK/STAT, PI3K, TGFbeta and WNT. A set of transcription factors, including FOX, GATA, MYB, NANOG, OCT, PAX, SOX and STAT, and the FGF response element were identified that represent key regulators underlying the transcriptional co-expression. By transcriptional intervention conducted in silico, dynamic behavior of pathways was examined, which demonstrate how much and in which specific ways each gene or gene combination effects the behavior transition of a pathway in response to ESC differentiation or pluripotency induction. The global co-expression networks of ESCs were dominated by highly connected hub genes such as IGF2, JARID2, LCK, MYCN, NASP, OCT4, ORC1L, PHC1 and RUVBL1, which are possibly critical in determining the fate of ESCs.Conclusions/significanceThrough these studies, evolutionary conservation at genomic, transcriptomic, and network levels is shown to be an effective predictor of molecular factors and mechanisms controlling ESC development. Various hypotheses regarding mechanisms controlling ESC development were generated, which could be further validated by in vitro experiments. Our findings shed light on the systems-level understanding of how ESC differentiation or pluripotency arises from the connectivity or networks of genes, and provide a "road-map" for further experimental investigation.

Project description:ObjectiveTo develop and externally validate models to predict probabilities of alpha-synuclein (a-syn) positive or negative status in vivo in a mixture of people with and without Parkinson's disease (PD) using easily accessible clinical predictors.MethodsUni- and multi-variable logistic regression models were developed in a cohort of participants from the Parkinson Progression Marker Initiative (PPMI) study to predict cerebrospinal fluid (CSF) a-syn status as measured by seeding amplification assay (SAA). Models were externally validated in a cohort of participants from the Systemic Synuclein Sampling Study (S4) that had also measured CSF a-syn status using SAA.ResultsThe PPMI model training/testing cohort consisted of 1260 participants, of which 76% had manifest PD with a mean (± standard deviation) disease duration of 1.2 (±1.6) years. Overall, 68.7% of the overall PPMI cohort (and 88.0% with PD of those with manifest PD) had positive CSF a-syn SAA status results. Variables from the full multivariable model to predict CSF a-syn SAA status included age- and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) percentile values, sex, self-reported presence of constipation problems, leucine-rich repeat kinase 2 (LRRK2) genetic status and pathogenic variant, and GBA status. Internal performance of the model on PPMI data to predict CSF a-syn SAA status had an area under the receiver operating characteristic curve (AUROC) of 0.920, and sensitivity/specificity of 0.881/0.845. When this model was applied to the external S4 cohort, which included 71 participants (70.4% with manifest PD for a mean 5.1 (±4.8) years), it performed well, achieving an AUROC of 0.976, and sensitivity/specificity of 0.958/0.870. Models using only UPSIT percentile performed similarly well upon internal and external testing.ConclusionData-driven models using non-invasive clinical features can accurately predict CSF a-syn SAA positive and negative status in cohorts enriched for people living with PD. Scores from the UPSIT were highly significant in predicting a-syn SAA status.

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Embryonic cerebrospinal fluid nanovesicles carry evolutionarily conserved molecules and promote neural stem cell amplification.

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Embryonic cerebrospinal fluid nanovesicles carry evolutionarily conserved molecules and promote neural stem cell amplification.

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