By 2030, one in six people will be over the age of 60. Globally, the prevalence of age-related diseases is escalating rapidly. The deterioration of organ function during ageing is thought to be correlated to the senescence of stem cells, which impedes the capacity of stem cells to maintain tissue integrity and repair tissue damage.
Although a decline in matrix integrity is evident in age-related pathologies such as skin laxity, fibrosis, and aortic stiffness, few studies have dissected the effects of extracellular matrix signals on cellular senescence. In particular, elastin loss and dysregulation are hallmarks of ageing mesodermal tissue of the skin and vasculature. Conversely, supplementation of the elastin monomer, tropoelastin, promotes mesenchymal stem cell (MSC) regenerative functions, such as proliferation, migration, and differentiation. Given its association with MSC youth and functionality, we posit that tropoelastin modulates MSC senescence.
To explore this hypothesis, we analysed the transcriptomes of cells grown briefly on a tropoelastin substrate. We also serially cultured MSCs with or without tropoelastin, either as a substrate or soluble media supplement, and investigated the functional and molecular changes of MSCs during replicative ageing. RNA sequencing revealed concurrent upregulation of proliferative genes and downregulation of genes implicated with cellular senescence by tropoelastin. Furthermore, we showed that these effects persist in continuous culture of MSCs. Cells expanded with tropoelastin retain greater youth-associated functions of differentiation and paracrine secretion, and maintain youthful phenotypes marked by low senescence-associated beta-galactosidase activity, small cell size, and decreased expression of ageing markers. Our results indicate that despite exerting strong mitogenic effects, tropoelastin protects against MSC senescence during replicative aging. This work sheds new light on the role structural matrix proteins play in driving fitness and preserving age-related loss in cellular functions.