Proteostasis as a post-transcriptional mechanism of pluripotency maintenance: the role of STI1 in human induced pluripotent stem cells

Abstract

Induced pluripotent stem cells (iPSCs) are one of the most important biological tools for the study of human development, cellular senescence, and neurodegenerative diseases, with a great appeal for patient-specific research and therapy. iPSCs, like embryonic stem cells (ESCs), present increased mechanisms for protein homeostasis (proteostasis) regulation, that added to the other know pathways of pluripotency and self-renewal control: the core of transcriptions factors OCT4, SOX2, and NANOG, epigenetic and metabolic specifications, helps to understand the overall regulation of these important cells. Although proteostasis is indisputably an important mechanism of pluripotency control, this topic has been neglected for a long time in research. Consequently, many aspects regulating the control of proteostasis in pluripotent cells, as well as the importance of these mechanisms for the maintenance of pluripotency and absence of cellular senescence remain unknown. Therefore, identifying molecules that can act directly or indirectly modulating this complex regulatory network is essential to explore the potential of pluripotent cells in regenerative medicine, assisted reproduction, and research. STI1 is a fundamental cochaperone in the maintenance of proteostasis, which has an essential role in early embryonic development. Preliminary data from our group show that STI1 expression is fundamental for maintaining pluripotency in mouse ESCs. Thus, we sought to understand whether STI1 and associated factors play a role in maintaining the pluripotency of human iPSCs, possibly reproducing some of the findings we obtained in mouse cells. In order words, we seek to shed light on the long-neglected importance of proteostasis mechanisms in human pluripotent cells, and the consequence of the disturbance of this mechanism in these cells. (AU)