Age-related changes in mesenchymal stem cells identified using a multi-omics approach.

Abstract

Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based treatments for many clinical diseases and injuries. Ageing is associated with various altered cellular phenotypes coupled with a variety of transcriptional, epigenetic and translational changes. Furthermore, the regeneration potential of MSCs is reduced with increasing age and is correlated with changes in cellular functions. This study used a systems biology approach to investigate the transcriptomic (RNASeq), epigenetic (miRNASeq and DNA methylation) and protein alterations in ageing MSCs in order to understand the age-related functional and biological variations, which may affect their applications to regenerative medicine. We identified no change in expression of the cellular senescence markers. Alterations were evident at both the transcriptional and post-transcriptional level in a number of transcription factors. There was enrichment in genes involved in developmental disorders at mRNA and differential methylated loci (DML) level. Alterations in energy metabolism were apparent at the DML and protein level. The microRNA miR-199b-5p, whose expression was reduced in old MSCs, had predicted gene targets involved in energy metabolism and cell survival. Additionally, enrichment of DML and proteins in cell survival was evident. Enrichment in metabolic processes was revealed at the protein level and in genes identified as undergoing alternate splicing. Overall, an altered phenotype in MSC ageing at a number of levels implicated roles for inflamm-ageing and mitochondrial ageing. Identified changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients.