Sox2 is well known for its functions in embryonic stem (ES) cell pluripotency, maintenance, and self-renewal, and it is an essential factor in generating inducible pluripotent stem (iPS) cells. It also plays an important role in development and adult tissue homeostasis of different tissues, especially the central nervous system. Increasing evidence has shown that aging is a stemness-related process in which Sox2 is also implicated as a key player, especially in the neural system. These distinct roles that Sox2 plays involve delicate regulatory networks consisting of other master transcription factors, microRNAs and signaling pathways. Additionally, the expression level of Sox2 can also be modulated transcriptionally, translationally or post-translationally. Here we will mainly review the roles of Sox2 in stem cell related development, homeostasis maintenance, aging processes, and the underlying molecular mechanisms involved.

Lung fibrosis is characterized by vascular leakage and myofibroblast recruitment, and both phenomena are mediated by lysophosphatidic acid (LPA) via its type‐1 receptor (LPA1). Following lung damage, the accumulated myofibroblasts activate and secrete excessive extracellular matrix (ECM), and form fibrotic foci. Studies have shown that bone marrow‐derived cells are an important source of myofibroblasts in the fibrotic organ. However, the type of cells in the bone marrow contributing predominantly to the myofibroblasts and the involvement of LPA‐LPA1 signalling in this is yet unclear. Using a bleomycin‐induced mouse lung‐fibrosis model with an enhanced green fluorescent protein (EGFP) transgenic mouse bone marrow replacement, we first demonstrated that bone marrow derived‐mesenchymal stem cells (BMSCs) migrated markedly to the bleomycin‐injured lung. The migrated BMSC contributed significantly to α‐smooth muscle actin (α‐SMA)‐positive myofibroblasts. By transplantation of GFP‐labelled human BMSC (hBMSC) or EGFP transgenic mouse BMSC (mBMSC), we further showed that BMSC might be involved in lung fibrosis in severe combined immune deficiency (SCID)/Beige mice induced by bleomycin. In addition, using quantitative‐RT‐PCR, western blot, Sircol collagen assay and migration assay, we determined the underlying mechanism was LPA‐induced BMSC differentiation into myofibroblast and the secretion of ECM via LPA1. By employing a novel LPA1 antagonist, Antalpa1, we then showed that Antalpa1 could attenuate lung fibrosis by inhibiting both BMSC differentiation into myofibroblast and the secretion of ECM. Collectively, the above findings not only further validate LPA1 as a drug target in the treatment of pulmonary fibrosis but also elucidate a novel pathway in which BMSCs contribute to the pathologic process.

The transcription factor Sox2 [SRY (sex-determining region Y)-box 2] is essential for the regulation of self-renewal and homoeostasis of NSCs (neural stem cells) during brain development. However, the downstream targets of Sox2 and its underlying molecular mechanism are largely unknown. In the present study, we found that Sox2 directly up-regulates the expression of survivin, which inhibits the mitochondria-dependent apoptotic pathway in NSCs. Although overexpression of Sox2 elevates survivin expression, knockdown of Sox2 results in a decrease in survivin expression, thereby initiating the mitochondria-dependent apoptosis related to caspase 9 activation. Furthermore, cell apoptosis owing to knockdown of Sox2 can be rescued by ectopically expressing survivin in NSCs as well as in the mouse brain, as demonstrated by an in utero-injection approach. In short, we have found a novel Sox2/survivin pathway that regulates NSC survival and homoeostasis, thus revealing a new mechanism of brain development, neurological degeneration and such aging-related disorders.

Chimeric antigen receptor T cell immunotherapy is a promising therapeutic strategy for treating tumors, demonstrating its efficiency in eliminating several hematological malignancies in recent years. However, a major obstacle associated with current chimeric antigen receptor T cell immunotherapy is that the limited replicative lifespan of chimeric antigen receptor T cells prohibits the long-term persistence and expansion of these cells in vivo, potentially hindering the long-term therapeutic effects of chimeric antigen receptor T cell immunotherapy. Here we showed that the transient delivery of modified mRNA encoding telomerase reverse transcriptase to human chimeric antigen receptor T cells targeting the CD19 antigen (CD19 chimeric antigen receptor T cells) would transiently elevate the telomerase activity in these cells, leading to increased proliferation and delayed replicative senescence without risk of insertion mutagenesis or immortalization. Importantly, compared to conventional CD19 chimeric antigen receptor T cells, after the transient delivery of telomerase reverse transcriptase mRNA, these CD19 chimeric antigen receptor T cells showed improved persistence and proliferation in mouse xenograft tumor models of human B-cell malignancies. Furthermore, the transfer of CD19 chimeric antigen receptor T cells after the transient delivery of telomerase reverse transcriptase mRNA enhanced long-term antitumor effects in mouse xenograft tumor models compared with conventional CD19 chimeric antigen receptor T cell transfer. The results of the present study provide an effective and safe method to improve the therapeutic potential of chimeric antigen receptor T cells, which might be beneficial for treating other types of cancer, particularly solid tumors.

Heterozygous paired box6 (Pax6) mutations lead to abnormal glucose metabolism in mice older than 6 months as well as in human beings. Our previous study found that Pax6 deficiency caused down-expression of prohormone convertase 1/3 (Pcsk1), resulting in defective proinsulin processing. As a protein cleaving enzyme, in addition to its expression, the activity of PC1/3 is closely related to its function. We therefore hypothesize that Pax6 mutation alters the activity of PC1/3, which affects proinsulin processing. Using quantitative RT-PCR, western blot and enzyme assay, we found that PC1/3 C-terminal cleavage and its activity were compromised in Pax6 R266Stop mutant mice, and the expression of Pcsk1n, a potent inhibitor of PC1/3, was elevated by Pax6 deficiency in the mutant mice and MIN6 cells. We confirmed the effect of proSAAS, the protein encoded by Pcsk1n, on PC1/3 C-terminal cleavage and its activity by Pcsk1n RNAi in MIN6 cells. Furthermore, by luciferase-reporter analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assay, we revealed that Pax6 bound to Pcsk1n promoter and directly down-regulated its expression. Finally, by co-transfecting Pax6 siRNA with Pcsk1n siRNA, we showed that Pax6 knock-down inhibited proinsulin processing and that this effect could be rescued by proSAAS down-regulation. These findings confirm that Pax6 regulates proinsulin processing partially through proSAAS-mediated PC1/3 processing and activity. Collectively, the above experiments demonstrate that Pax6 can directly down-regulate Pcsk1n expression, which negatively affects PC1/3 C-terminal cleavage and activity and subsequently participates in proinsulin processing. We identified proSAAS as a novel down-regulated target of Pax6 in the regulation of glucose metabolism. This study also provides a complete molecular mechanism for the Pax6 deficiency-caused diabetes.