Cell Therapy and Molecular Medicine

Biography

Biography: Marianna Kapetanou

Abstract

Proteostasis is a fundamental process, essential for the majority of cellular functions. Numerous studies have demonstrated that ageing is accompanied by a failure of proteostasis, while chronic exposure to denatured or aggregated proteins contributes to the development of age-related diseases. The proteasome, being the main proteolytic cellular system, plays a pivotal role in maintaining proteostasis. Essentially, we have established a direct link between the proteasome mediated protein degradation and aging. In detail, we have revealed that senescent human mesenchymal stem cells (hMSCs) exhibit a decrease in expression of proteasome subunits, proteasome content and peptidase activities, accompanied by alterations of proteasomal complexes. Additionally, we show that senescence and the concomitant failure of proteostasis negatively affects stemness. Remarkably, the genetic activation of the proteasome through the overxpression of the catalytic β5 subunit, doubled the lifespan, induced the expression of the core pluripotency factors and enhanced the differentiation capability of hMSCs. Based on these observations, we postulated that the molecular factors and mechanisms that regulate the expression of proteasome subunits can be critical determinants of both aging and stem cell function. Shedding light on the limited data regarding the regulation of proteasome subunits’ expression and the mechanisms underlying its age-related decrease, we demontrated that the transcription factors Oct4 and FoxO1 bind at the promoter region of catalytic proteasome subunits and thus possibly regulate their expression. A firm understanding of the mechanisms regulating proteostasis in stem cells will pave the way to innovative stem cell-based interventions to improve healthspan and lifespan.