Leukemia Inhibitory Factor (LIF)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway maintains the stemness and pluripotency of mouse embryonic stem cells (mESCs). Detailed knowledge on key intermediates in this pathway as well as any parallel pathways is largely missing. We initiated our study by investigating the effect of small molecule Curcumin on various signalling pathways essential for self-renewal. Curcumin sustained the LIF independent self-renewal of mESCs and induced pluripotent stem cells (miPSCs) in a STAT3 activity dependent manner. Gene expression analysis showed LIF/STAT3 and redox signaling components to be majorly modulated. Amongst ROS genes, expression of Manganese Superoxide Dismutase (MnSOD) specifically relied on STAT3 signaling as evidenced by STAT3 inhibition and reporter assay. The silencing of MnSOD, but not Cu-ZnSOD expression, resulted in the loss of mESC pluripotency in presence of LIF, and the overexpression of MnSOD is sufficient for maintaining the expression of pluripotent genes in the absence of STAT3 signaling. Finally, we demonstrate MnSOD to stabilize the turnover of pluripotent proteins at the post-translational level by modulating proteasomal activity. In conclusion, our findings unravel a novel role of STAT3 mediated MnSOD in the self-renewal of mESCs.

Distinct molecular processes are engaged during histogenesis and epithelial to mesenchymal transition (EMT) is the key evolutionarily conserved process that facilitate the organ developmental processes. Molecular programs governing EMT are embedded within the developmental programs and operate in cells of different tissues. Among different cell types, EMT in pancreatic β-cells is of larger interest as the existence of EMT in these cell types is highly debated. Although, in vitro generation of human islet derived mesenchymal progenitor cells has been proved beyond doubt, the in vivo occurrence of EMT in pancreatic β cells remain enigmatic. Understanding the in-depth process of EMT in in vivo human β cells is challenged by the limited application of lineage-tracing studies, which is otherwise feasible in mice. Understanding the EMT of β-cells would greatly facilitate the generation of clinically relevant β-cells either by enhancing endogenous β-cells, by long term in vitro islet culture or by differentiation of pluripotent stem cells to functional β-cells. In this review we update on the recent progress in understanding the EMT of β-cells and to what extent the investigation has helped in resolving the mystery of existence of EMT in pancreatic β-cells.

In the present review, we will overview the studies on stem cell and their effects in the treatment of diabetes in order to discuss the questions generated about their origin and the mechanisms that are involved in their reparative properties.

Differentiation of pluripotent stem cells (PSCs) to neural lineages has gathered huge attention in both basic research and regenerative medicine. The major hurdle lies in the efficiency of differentiation and identification of small molecules that facilitate neurogenesis would partly circumvent this limitation. The small molecule Cyclosporine A (CsA), a commonly used immunosuppressive drug, has been shown to enhance in vivo neurogenesis. To extend the information to in vitro neurogenesis, we examined the effect of CsA on neural differentiation of PSCs. We found CsA to increase the expression of neural progenitor genes during early neural differentiation. Gene silencing approach revealed CsA-mediated neural induction to be dependent on blocking the Ca-activated phosphatase calcineurin (Cn) signaling. Similar observation with FK506, an independent inhibitor of Cn, further strengthened the necessity of blocking Cn for enhanced neurogenesis. Surprisingly, mechanistic insight revealed Cn-inhibition dependent upregulation of IL-6 protein to be necessary for CsA-mediated neurogenesis. Together, these findings provide a comprehensive understanding of the role of CsA in neurogenesis, thus suggesting a method for obtaining large numbers of neural progenitors from PSCs for possible transplantation.

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