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  • 1
    Keywords: CELLS ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; CELL ; Germany ; human ; POPULATION ; GENE-EXPRESSION ; DIFFERENTIATION ; MECHANISM ; CARCINOGENESIS ; TISSUES ; SKIN ; BIOLOGY ; CYCLE ; fibroblasts ; IN-SITU ; REVERSE-TRANSCRIPTASE ; PROMOTER ; AGE ; LENGTH ; NETHERLANDS ; REPLICATION ; HEMATOPOIETIC STEM-CELLS ; histone deacetylase inhibitor ; HaCaT ; organotypic culture ; molecular biology ; SKIN KERATINOCYTES ; telomere length ; STRAINS ; HTERT GENE ; HISTONE ACETYLATION ; regeneration ; GROWTH-FACTORS ; CULTURES ; Age-dependent telomere attrition ; COCULTURES ; HTERT ; In situ telomere length analysis ; Melanocyte ; Telomere length heterogeneity
    Abstract: Telomerase- and telomere length regulation in normal human tissues is still poorly understood. We show here that telomerase is expressed in the epidermis in situ independent of age but was repressed upon the passaging of keratinocytes in monolayer culture. However, when keratinocytes were grown in organotypic cultures (OTCs), telomerase was re-established, indicating that telomerase activity is not merely proliferation-associated but is regulated in a tissue context-dependent manner in human keratinocytes. While not inducible by growth factors, treatment with the histone deacetylation inhibitor FK228 restored telomerase activity in keratinocytes grown in monolayer cultures. Accordingly, CHIP analyses demonstrated an acetylated, active hTERT promoter in the epidermis in situ and in the epidermis of OTCs but a deacetylated, silenced hTERT promoter with subsequent propagation in monolayer culture suggesting that histone acetylation is part of the regulatory program to guarantee hTERT expression/telomerase activity in the epidermis. In agreement with the loss of telomerase activity, telomeres shortened during continuous propagation in monolayer culture by an average of similar to 70 base pairs (bp) per population doubling (pd). However, telomere erosion varied strongly between different keratinocyte strains and even between individual cells within the same culture, thereby arguing against a defined rate of telomere loss per replication cycle. In the epidermis in situ, as determined from early-passage keratinocytes and tissue sections from different age donors, we calculated a telomere loss of only similar to 25 bp per year. Since we determined the same rate for the non-regenerating melanocytes and dermal fibroblasts, our data suggest that in human epidermis telomerase is a protective mechanism against excessive telomere loss during the life-long regeneration. (C) 2009 Published by Elsevier B.V
    Type of Publication: Journal article published
    PubMed ID: 19419690
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  • 2
    Keywords: brain ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; CELL ; Germany ; MODEL ; MODELS ; VITRO ; SYSTEM ; SITE ; PROTEIN ; ACCUMULATION ; FAMILY ; SIMULATION ; BIOLOGY ; ACID ; TRANSPORT ; EPITHELIAL-CELLS ; organic anion transporters ; NETHERLANDS ; MOUSE MODEL ; specificity ; CHILDREN ; NATURAL-HISTORY ; EFFLUX ; endothelial cells ; TRANSPORTER ; SCIENCE ; blood-brain barrier ; BARRIER ; CAPILLARY ENDOTHELIAL-CELLS ; CELL BIOLOGY ; TRANSPORTERS ; Type ; ACIDEMIA ; COA DEHYDROGENASE-DEFICIENCY ; Dicarboxylic acids ; ENCEPHALOPATHIC CRISES ; Glutaric aciduria type I ; Methylmalonic aciduria ; Organic acid transporter ; Plexus choroideus
    Abstract: Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the choroid plexus respectively. We identified expression of organic acid transporters 1 (OAT1) and 3 (OAT3) in pBCEC on mRNA and protein level. For DCAs tested, transport from the basolateral to the apical site (i.e. efflux) was higher than influx. Efflux transport of GA, 3-OH-GA, and MMA across pBCEC was Na+-dependent. ATP-independent, and was inhibited by the OAT substrates para-aminohippuric acid (PAH), estrone sulfate, and taurocholate, and the OAT inhibitor probenecid. Members of the ATP-binding cassette transporter family or the organic anion transporting polypeptide family, namely MRP2, P-gp, BCRP, and OATP1B3, did not mediate transport of GA, 3-OH-GA or MMA confirming the specificity of efflux transport via OATs. In hCPEC, cellular import of GA was dependent on Na+-gradient, inhibited by NaCN, and unaffected by probenecid suggesting a Na+-dependent DCA transporter. Specific transport of GA across hCPEC, however, was not found. In conclusion, our results indicate a low but specific efflux transport for GA, 3-OH-GA, and MMA across pBCEC, an in vitro model of the BBB, via OAT1 and OAT3 but not across hCPEC, an in vitro model of the choroid plexus. (C) 2010 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20302929
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