Senescence-Associated Metabolomic Phenotype in Primary and iPSC-Derived Mesenchymal Stromal Cells

Abstract

Summary: Long-term culture of primary cells is characterized by functional and secretory changes, which ultimately result in replicative senescence. It is largely unclear how the metabolome of cells changes during replicative senescence and if such changes are consistent across different cell types. We have directly compared culture expansion of primary mesenchymal stromal cells (MSCs) and induced pluripotent stem cell-derived MSCs (iMSCs) until they reached growth arrest. Both cell types acquired similar changes in morphology, in vitro differentiation potential, senescence-associated β-galactosidase, and DNA methylation. Furthermore, MSCs and iMSCs revealed overlapping gene expression changes, particularly in functional categories related to metabolic processes. We subsequently compared the metabolomes of MSCs and iMSCs and observed overlapping senescence-associated changes in both cell types, including downregulation of nicotinamide ribonucleotide and upregulation of orotic acid. Taken together, replicative senescence is associated with a highly reproducible senescence-associated metabolomics phenotype, which may be used to monitor the state of cellular aging. : Wagner and colleagues show that expansion of iPSC-derived MSCs evokes molecular, functional, and metabolic changes similar to those observed in their primary counterparts. The highly consistent changes indicate that the metabolic phenotype can be used as a biomarker to assess the state of cellular aging, and this is relevant for regenerative medicine. Key words: replicative senescence, metabolomics, mesenchymal stromal cells, induced pluripotent stem cells, transcriptomics, DNA methylation