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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents

ID: 717295.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
DNA damage response in neonatal and adult stromal cells compared with induced pluripotent stem cells
Authors:Liedtke, S.; Biebernick, S.; Radke, T. F.; Stapelkamp, D.; Coenen, C.; Zaehres, H.; Fritz, G.; Kogler, G.
Date of Publication (YYYY-MM-DD):2015-06
Title of Journal:Stem Cells Transl Med
Issue / Number:6
Start Page:576
End Page:589
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Comprehensive analyses comparing individual DNA damage response (DDR) of induced pluripotent stem cells (iPSCs) with neonatal stromal cells with respect to their developmental age are limited. The imperative necessity of providing developmental age-matched cell sources for meaningful toxicological drug safety assessments in replacement of animal-based testing strategies is evident. Here, DDR after radiation or treatment with N-methyl-N-nitrosurea (MNU) was determined in iPSCs compared with neonatal and bone marrow stromal cells. Neonatal and adult stromal cells showed no significant morphologically detectable cytotoxicity following treatment with 1 Gy or 1 mM MNU, whereas iPSCs revealed a much higher sensitivity. Foci analyses revealed an effective DNA repair in stromal cell types and iPSCs, as reflected by a rapid formation and disappearance of phosphorylated ATM and gammaH2AX foci. Furthermore, quantitative polymerase chain reaction analyses revealed the highest basic expression level of DDR and repair-associated genes in iPSCs, followed by neonatal stromal cells and adult stromal cells with the lowest expression levels. In addition, the influence of genotoxic stress prior to and during osteogenic differentiation of neonatal and adult stromal cells was analyzed applying common differentiation procedures. Experiments presented here suggest a developmental age-dependent basic expression level of genes involved in the processing of DNA damage. In addition a differentiation-dependent downregulation of repair genes was observed during osteogenesis. These results strongly support the requirement to provide adequate cell sources for toxicological in vitro drug testing strategies that match to the developmental age and differentiation status of the presumptive target cell of interest. SIGNIFICANCE: The results obtained in this study advance the understanding of DNA damage processing in human neonatal stromal cells as compared with adult stromal cells and induced pluripotent stem cells (iPSCs). The data suggest developmental age-dependent differences in DNA damage repair capacity. In iPSCs (closest to embryonic stem cells), the highest expression level of DNA damage response and repair genes was found, followed by neonatal stromal cells and adult stromal cells with the lowest overall expression. In addition, a differentiation-dependent downregulation of repair capacity was observed during osteogenic differentiation in neonatal stromal cells. Notably, the impact of genotoxic stress on osteogenic differentiation depended on the time the genotoxic insult took place and, moreover, was agent-specific. These results strongly support the necessity of offering and establishing adequate cell sources for informative toxicological testing matching to the developmental age and differentiation status of the respective cell of interest.
Free Keywords:Adult; Alkylating Agents/*pharmacology; Ataxia Telangiectasia Mutated Proteins/metabolism; Cell Differentiation/*drug effects; *DNA Damage; Drug Evaluation, Preclinical/methods; Female; Histones/metabolism; Humans; Induced Pluripotent Stem Cells/cytology/*metabolism; Infant, Newborn; Male; Methylnitrosourea/*pharmacology; Osteogenesis/*drug effects; Phosphorylation/drug effects; Stromal Cells/cytology/metabolism; X-Rays; DNA Repair; DNA damage response; Ionizing radiation; Mnu; Msc; Neonatal and adult stromal cells; Osteogenesis; iPSC
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
Identifiers:ISSN:2157-6564 (Print) 2157-6564 (Linking) %R 10.5966/s... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/25900727 [ID No:2]
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