Regulatory role of Sirtuin 1 (SIRT1), one of the most extensively studied members of its kind in histone deacetylase family in governing multiple cellular fates, is predominantly linked to p53 activity. SIRT1 deacetylates p53 in a NAD+-dependent manner to inhibit transcription activity of p53, in turn modulate pathways that are implicated in regulation of tissue homoeostasis and many disease states. In this review, we discuss the role of SIRT1-p53 pathway and its regulatory axis in the cellular events which are implicated in cellular aging, cancer and reprogramming. It is noteworthy that these cellular events share few common regulatory pathways, including SIRT1-p53-LDHA-Myc, miR-34a,-Let7 regulatory network, which forms a positive feedback loop that controls cell cycle, metabolism, proliferation, differentiation, epigenetics and many others. In the context of aging, SIRT1 expression is reduced as a protective mechanism against oncogenesis and for maintenance of tissue homeostasis. Interestingly, its activation in aged cells is evidenced in response to DNA damage to protect the cells from p53-dependent apoptosis or senescence, predispose these cells to neoplastic transformation. Importantly, the dual roles of SIRT1-p53 axis in aging and tumourigenesis, either as tumour suppressor or tumour promoter are determined by SIRT1 localisation and type of cells. Conceptualising the distinct similarity between tumorigenesis and cellular reprogramming, this review provides a perspective discussion on involvement of SIRT1 in improving efficiency in the induction and maintenance of pluripotent state. Further research in understanding the role of SIRT1-p53 pathway and their associated regulators and strategies to manipulate this regulatory axis very likely foster the development of therapeutics and strategies for treating cancer and aging-associated degenerative diseases.
Generation of functional hepatocytes from human pluripotent stem cells (hPSCs) is a vital tool to produce large amounts of human hepatocytes, which hold a great promise for biomedical and regenerative medicine applications. Despite a tremendous progress in developing the differentiation protocols recapitulating the developmental signalling and stages, these resulting hepatocytes from hPSCs yet achieve maturation and functionality comparable to those primary hepatocytes. The absence of 3D milieu in the culture and differentiation of these hepatocytes may account for this, at least partly, thus developing an optimal 3D culture could be a step forward to achieve this aim. Hence, review focuses on current development of 3D culture systems for hepatic differentiation and maturation and the future perspectives of its application.
Successful outcomes of cell-based therapeutic is highly-dependent on quality and quantity of the cells. Epigenetic modifiers are known to modulate cell fates via reprogramming, hence it is plausible to use them in enhancing the plasticity of mesenchymal stem cells. In this study, we aimed to study the effects of 5-Azacytidine (5-AzaCR), an epigenetic modifier, pretreatment on mesenchymal stem cells-derived from Wharton's Jelly (WJMSCs) fates. WJMSCs were pretreated with 5-AzaCR for 24 h and subsequently cultured in culture media mixtures. The proliferative and stemness characteristics of the pretreated WJMSCs were assessed through morphological and gene expression analyses. Results showed that cells pretreated with 5 μM to 20 μM of 5-AzaCR showed to acquire higher proliferative state transiently when cultured in embryonic-mesenchymal stem cell (ESC-MSC) media, but not in MSC medium alone, and this coincides with significant transitional upregulation of stemness transcription factors. 5-AzaCR pretreatment has potential to confer initial induction of higher state of stemness and proliferation in WJMSCs, influenced by the culture media.