Senescence-associated metabolomic phenotype in primary and iPSC-derived mesenchymal stromal cells

Long-term culture of primary cells is reflected by functional and secretory changes, which ultimately result in replicative senescence. In contrast, induced pluripotent stem cells (iPSCs) do not reveal any signs of cellular aging while in the pluripotency state, whereas little is known how they sene...

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Published inbioRxiv
Main Authors Fernandez-Rebollo, Eduardo, Franzen, Julia, Hollmann, Jonathan, Ostrowska, Alina, Oliverio, Matteo, Sieben, Torsten, Rath, Bjorn, Jan-Wilhelm Kornfeld, Wagner, Wolfgang
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.02.2019
Subjects
Aging
Cell culture
Cytology
DNA methylation
Gene expression
Glycolysis
Mesenchymal stem cells
Mesenchyme
Metabolism
Metabolomics
Nicotinamide
Orotic acid
Phenotypes
Pluripotency
Senescence
Stromal cells
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Summary:Long-term culture of primary cells is reflected by functional and secretory changes, which ultimately result in replicative senescence. In contrast, induced pluripotent stem cells (iPSCs) do not reveal any signs of cellular aging while in the pluripotency state, whereas little is known how they senesce upon differentiation. Furthermore, it is largely unclear how the metabolome of cells changes during replicative senescence and if such changes are consistent across different cell types. In this study, we have directly compared culture expansion of primary mesenchymal stromal cells (MSCs) and iPSC-derived MSCs (iMSCs) until they reached growth arrest after a mean of 21 and 17 cumulative population doublings, respectively. Both cell types acquired similar changes in morphology, in vitro differentiation potential, up-regulation of senescence-associated beta-galactosidase, and senescence-associated DNA methylation changes. Furthermore, MSCs and iMSCs revealed overlapping gene expression changes during culture expansion, particularly in functional categories related to metabolic processes. We subsequently compared the metabolome of MSCs and iMSCs at early and senescent passages and observed various significant and overlapping senescence-associated changes in both cell types, including down-regulation of nicotinamide ribonucleotide and up-regulation of orotic acid. Replicative senescence of both cell types was consistently reflected by the metabolic switch from oxidative to glycolytic pathways. Taken together, long-term culture of iPSC-derived MSCs evokes very similar molecular and functional changes as observed in primary MSCs. Replicative senescence is associated with a highly reproducible senescence-associated metabolomics phenotype, which may be used to monitor the state of cellular aging.
DOI:10.1101/542357