epidermal-growth-factor and Down-Syndrome

Myelomeningocele (MMC) is a congenital disease without genetic abnormalities. Neurological symptoms are irreversibly impaired after birth, and no effective treatment has been reported to date. Only surgical repairs have been reported so far. In this study, we performed antenatal treatment of MMC with an artificial skin using induced pluripotent stem cells (iPSCs) generated from a patient with Down syndrome (AF-T21-iPSCs) and twin-twin transfusion syndrome (AF-TTTS-iPSCs) to a rat model. We manufactured three-dimensional skin with epidermis generated from keratinocytes derived from AF-T21-iPSCs and AF-TTTS-iPSCs and dermis of human fibroblasts and collagen type I. For generation of epidermis, we developed a protocol using Y-27632 and epidermal growth factor. The artificial skin was successfully covered over MMC defect sites during pregnancy, implying a possible antenatal surgical treatment with iPSC technology.

Topics: Amides; Amniotic Fluid; Animals; Cell Adhesion Molecules; Cell Culture Techniques; Cell Differentiation; Cells, Cultured; Cellular Reprogramming; Disease Models, Animal; Down Syndrome; Epidermal Cells; Epidermal Growth Factor; Epidermis; Exome Sequencing; Extracellular Matrix Proteins; Female; Fetal Therapies; Fetofetal Transfusion; Humans; Induced Pluripotent Stem Cells; Karyotyping; Keratin-14; Keratinocytes; Meningomyelocele; Polymorphism, Single Nucleotide; Pregnancy; Pyridines; Rats; Skin; Transcription Factors

Molecular pathogenesis of Down syndrome (DS) is still incompletely understood. Epigenetic mechanisms, including miRNAs gene expression regulation, belong to potential influencing factors. The aims of this study were to compare miRNAs expressions in placentas with normal and trisomic karyotype and to associate differentially expressed miRNAs with concrete biological pathways.. A total of 80 CVS samples - 41 with trisomy 21 and 39 with normal karyotype - were included in our study. Results obtained in the pilot study using real-time PCR technology and TaqMan Human miRNA Array Cards were subsequently validated on different samples using individual TaqMan miRNA Assays.. Seven miRNAs were verified as upregulated in DS placentas (miR-99a, miR-542-5p, miR-10b, miR-125b, miR-615, let-7c and miR-654); three of these miRNAs are located on chromosome 21 (miR-99a, miR-125b and let-7c). Many essential biological processes, transcriptional regulation or apoptosis, were identified as being potentially influenced by altered miRNA levels. Moreover, miRNAs overexpressed in DS placenta apparently regulate genes involved in placenta development (GJA1, CDH11, EGF, ERVW-1, ERVFRD-1, LEP or INHA).. These findings suggest the possible participation of miRNAs in Down syndrome impaired placentation and connected pregnancy pathologies. © 2016 John Wiley & Sons, Ltd.

Topics: Adult; Cadherins; Case-Control Studies; Chorionic Villi Sampling; Connexin 43; Down Syndrome; Epidermal Growth Factor; Epigenesis, Genetic; Female; Gene Expression Regulation, Developmental; Gene Products, env; Humans; Inhibins; Leptin; MicroRNAs; Pilot Projects; Placenta; Placentation; Pregnancy; Pregnancy Proteins; Real-Time Polymerase Chain Reaction; Transcriptome; Up-Regulation

Atrioventricular septal defects (AVSD) are common cardiovascular malformations, occurring in 3.5/10,000 births. Although frequently associated with trisomy 21, autosomal dominant AVSD has also been described. Recently we identified and characterized the cell adhesion molecule CRELD1 (previously known as "cirrin") as a candidate gene for the AVSD2 locus mapping to chromosome 3p25. Analysis of the CRELD1 gene from individuals with non-trisomy 21-associated AVSD identified heterozygous missense mutations in nearly 6% of this population, including mutations in isolated AVSD and AVSD associated with heterotaxy syndrome. CRELD1 is the first human gene to be implicated in the pathogenesis of isolated AVSD and AVSD in the context of heterotaxy, which provides an important step in unraveling the pathogenesis of AVSD.

Topics: Amino Acid Sequence; Animals; Cattle; Cell Adhesion Molecules; Chromosome Mapping; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 3; Down Syndrome; Epidermal Growth Factor; Exons; Extracellular Matrix Proteins; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Heterozygote; Humans; Mice; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Alignment; Sequence Homology, Amino Acid

The purpose of the present study was to determine whether skin fibroblasts from individuals, either with an inherited predisposition to cancer or with genetic disorders usually associated with a high risk of cancer, can be oncogenically transformed in vitro by a tumor promoter alone. The effects of chronic and limited applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on several properties that are associated with transformation were examined using skin fibroblasts from individuals with polyposis coli, a familial cancer syndrome, xeroderma pigmentosum, Fanconi's anemia, and trisomy 21. The results of this study show that TPA treatment induces similar changes on cellular morphology, growth rate, saturation density, epidermal growth factor binding, and cytoskeleton in fibroblasts from both normal and genetically predisposed individuals. None of these cell lines, however, acquired anchorage-independent growth or unlimited growth potential in culture after chronic application of TPA. These observations suggest clearly that skin fibroblasts from individuals with either a genetic predisposition to or a high risk of cancer may not exist in a preneoplastic or "initiated" state susceptible to oncogenic transformation by TPA alone and that the mechanism of genetically determined cancer induction may be different from that of chemical carcinogenesis.

Topics: Cell Adhesion; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cytoskeleton; Disease Susceptibility; Down Syndrome; Epidermal Growth Factor; Fanconi Anemia; Female; Fibroblasts; Humans; Intestinal Polyps; Male; Neoplasms; Phorbols; Tetradecanoylphorbol Acetate; Trypsin; Xeroderma Pigmentosum