Replicative Senescence of Mesenchymal Stem Cells: A Continuous and Organized Process

By W. Wagner, P. Horn, M. Castoldi, A. Diehlmann, S. Bork, R. Saffrich, Vladimir Benes, Jonathon Blake, S. Pfister, V. Eckstein and 1 more. PLoS ONE, 2008

1,118 citations recorded by the source corpus.

Mesenchymal stem cells (MSC) comprise a promising tool for cellular therapy. These cells are usually culture expanded prior to their application. However, a precise molecular definition of MSC and the sequel of long-term in vitro culture are yet unknown. In this study, we have addressed the impact of replicative senescence on human MSC preparations. Within 43 to 77 days of cultivation (7 to 12 passages), MSC demonstrated morphological abnormalities, enlargement, attenuated expression of specific surface markers, and ultimately proliferation arrest. Adipogenic differentiation potential decreased whereas the propensity for osteogenic differentiation increased. mRNA expression profiling revealed a consistent pattern of alterations in the global gene expression signature of MSC at different passages. These changes are not restricted to later passages, but are continuously acquired with increasing passages. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages. Genes from chromosome 4q21 were over-represented among differentially regulated transcripts. Differential expression of 10 genes has been verified in independent donor samples as well as in MSC that were isolated under different culture conditions. Furthermore, miRNA expression profiling revealed an up-regulation of hsa-mir-371, hsa-mir-369-5P, hsa-mir-29c, hsa-mir-499 and hsa-let-7f upon in vitro propagation. Our studies indicate that replicative senescence of MSC preparations is a continuous process starting from the first passage onwards. This process includes far reaching alterations in phenotype, differentiation potential, global gene expression patterns, and miRNA profiles that need to be considered for therapeutic application of MSC preparations.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8fb928a26a26b369fe7646a7aa5d25a5094d5117

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Citations in the corpus

Comparative Analysis of Human Mesenchymal Stem Cells from Bone Marrow, Adipose Tissue, and Umbilical Cord Blood as Sources of Cell Therapy (2013, positive): “According to the literature, higher passages, namely p12, are considered “late” passage [28].”
Tissue Engineering for Clean Meat Production (2019, background): “MSCs undergo senescence in-vitro (Bonab et al., 2006; Wagner et al., 2008), however, under appropriate culture conditions, certain MSC subtypes can expand and maintain their differentiation potential (King and Miller, 2007; Nekanti et al.”
Bone regeneration strategies: engineered scaffolds, bioactive molecules and stem cells Current stage and future perspectives (2018, positive): “As a consequence, it is unclear whether in vitro expanded progenitor cells fully or only partly represent the native population [185].”
Silk fibroin as biomaterial for bone tissue engineering. (2016, background): “BMSCs can be expanded in vitro to 50 population doublings [35] which allows to increase their number such that a sufficient amount can be prepared for terminal differentiation and tissue regeneration.”
Circulating microRNAs are new and sensitive biomarkers of myocardial infarction (2010, background): “34 miR-499-5p is highly expressed in the myocardium(25,35) and its up-regulation is associated with cell senescence, suggesting that it may play a role in terminal differentiation.(36,37) Further, miR-499 has also been shown to promote the differentiation of cardiac progenitor cells into myocytes;(3”
The role of let-7 in cell differentiation and cancer. (2010, background): “2009), and let-7f was found to be up-regulated during replicative senescence of mesenchymal stem cells (Wagner et al. 2008).”