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Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1‐related genes and impairs DNA double‐strand break recognition
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Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1‐related genes and impairs DNA double‐strand break recognition
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Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1‐related genes and impairs DNA double‐strand break recognition
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Journal Article
Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1‐related genes and impairs DNA double‐strand break recognition
2020
Overview
Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell‐based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome‐based pathway analysis of in vitro‐expanded human bone marrow‐derived mesenchymal stem cell (hBM‐MSCs), supplemented with cellular assays focusing on DNA double‐strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (γ‐H2AX + 53BP1 foci) and repair (pBRCA1 + γ‐H2AX foci) of X‐ray‐induced DNA DSBs in hBM‐MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3‐ to fourfold reduction of their mRNA expression by qRT‐PCR. We conclude that the in vitro expansion of hMSCs can lead to aging‐related impairment of the recognition and repair of DNA breaks. During the process of their in vitro expansion, primary human BM‐MSCs experience a gradual impairment of their ability to recognize DNA double‐strand breaks. A reduced DNA damage response (fewer γ‐H2AX + 53BP1 foci) was associated with a downregulation of BRCA1‐related DNA repair by homologous recombination and chromosomal replication pathways, suggesting that in vitro aged hMSCs could be affected by reduced genetic stability.
