RT Journal Article
SR Electronic
T1 Senescence-associated metabolomic phenotype in primary and iPSC-derived mesenchymal stromal cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 542357
DO 10.1101/542357
A1 Fernandez-Rebollo, Eduardo
A1 Franzen, Julia
A1 Hollmann, Jonathan
A1 Ostrowska, Alina
A1 Oliverio, Matteo
A1 Sieben, Torsten
A1 Rath, Bjorn
A1 Kornfeld, Jan-Wilhelm
A1 Wagner, Wolfgang
YR 2019
UL http://biorxiv.org/content/early/2019/02/06/542357.abstract
AB 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.