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Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease[Mouse]

ABSTRACT: Patients with familial cerebral cavernous malformation (CCM) inherit germline loss of function mutations and are susceptible to progressive development of brain lesions and neurological sequelae during their lifetime. To date, no homologous circulat- ing molecules have been identified that can reflect the presence of germ line pathogenetic CCM mutations, either in animal models or patients. We hypothesize that homologous differentially expressed (DE) plasma miRNAs can reflect the CCM germline mutation in preclinical murine models and patients. Herein, homologous DE plasma miRNAs with mechanistic putative gene targets within the transcriptome of preclinical and human CCM lesions were identified. Several of these gene targets were additionally found to be associated with CCM-enriched pathways identified using the Kyoto Encyclopedia of Genes and Genomes. DE miRNAs were also identified in familial-CCM patients who developed new brain lesions within the year following blood sample collection. The miRNome results were then validated in an independent cohort of human subjects with real-time-qPCR quantification, a technique facilitating plasma assays. Finally, a Bayesian-informed machine learning approach showed that a combination of plasma levels of miRNAs and circulating proteins improves the associa- tion with familial-CCM disease in human subjects to 95% accuracy. These findings act as an important proof of concept for the future development of translatable circulating biomarkers to be tested in preclinical studies and human trials aimed at monitoring and restoring gene function in CCM and other diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE232009 | GEO | 2023/05/09

REPOSITORIES: GEO

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Project description:The developmental origins of adult disease are now recognized to reflect intrauterine conditions during embryonic and fetal life. Cell-cell communication between the maternal endometrium and the pre-implantation embryo can occur by several means. Here, we show that maternal miRNAs are secreted by the endometrial epithelium to the endometrial fluid. Microarray assessments revealed the presence of specific miRNAs that are associated with the window of implantation and therefore in direct contact with the human preimplantation embryo. These miRNAS are transported as free or exosome-associated molecules secreted to the endometrial fluid and then uptake into the pre-implantation embryo through the trophoectoderm. Finally, these maternal miRNAs were able to induce transcriptional and functional modifications of the embryo. Therefore, we propose an innovative model whereby endometrial maternal miRNAS may function as transcriptomic regulators during early embryo development offering a new perspective on the developmental origins of adult diseases such as obesity, type 2 diabetes, and others that are now recognized to reflect intrauterine conditions. The B6C3F1 mice strain was purchased. Female mice aged 6M-bM-^@M-^S8 weeks were primed to ovulate by administering 10 IU pregnant mare serum gonadotropin(Sigma-Aldrich, Irvine, UK), followed by administration of 10 IU hCG(Sigma-Aldrich, Irvine, UK), 48 hours later. Females were housed overnight with male breeders and examined the following morning for the presence of a vaginal plug (day 1 of pregnancy). On day 2 of pregnancy, mice were sacrificed by cervical dislocation, and embryos flushed with PBS from the oviduct using a blunt 30-gauge needle. Then, embryos were cultured in CCM-30 medium (Vitrolife, Lubeck, Germany) in presence or absence of 400nM of mir-30d MIMIC or Scramble-Alexa 488 for 72 hours. Then embryos are four times washed in fresh CCM. Experiment were carried out by triplicate and with 30 embryos/condition

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Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease[Mouse]

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