摘要: During early embryonic development, particularly in the transition from totipotency to pluripotency, energy metabolism is closely linked to cell fate. However, the essential regulators of energy metabolism in this transition remain unclear. In this study, we reveal that Tcl1 influences energy metabolic characteristics and regulates the totipotency-pluripotency transition. Our findings demonstrate that the absence of Tcl1 triggers the upregulation of totipotency genes and reduces H3K4me3 modifications at glycolysis enzyme promoters, thereby suppressing glycolytic processes. Furthermore, we found that a reduction in AKT, a downstream target of Tcl1, is associated with activation of the 2C gene and consequent shifts in energy metabolism. Specifically, AKT inhibition leads to succinate accumulation, further highlighting the role of succinate in the cell fate transition. Our findings underscore the central role of Tcl1-AKT-succinate axis in regulating totipotency and pluripotency through coordinated energy metabolic pathways.

摘要: Adult ovarian tissues or biopsies isolated from patients prior to chemotherapy or irradiation can reconstitute ovarian functions when transplanted either in the abdomen or subcutaneously. Subcutaneously transplantation avoids invasive surgery and potential risks associated with internal procedures. We investigated whether functional ovaries could develop subcutaneously from early E12.5 fetal gonads without entering meiosis in mouse model. Unexpectedly, the subcutaneously transplanted fetal gonads failed to undergo folliculogenesis in the recipient mice. The transplanted gonads experienced meiotic deficiency and exhibited significant defects in DNA repair and recombination, increased apoptosis levels. Meiotic defects in the subcutaneous grafts were partly attributable to variations in temperature and oxygen concentration. However, completion of meiotic prophase I was effectively achieved through in vitro culture of the gonads at 37°C. Subsequently, the in vitro cultured E12.5 gonads, following subcutaneous transplantation, became competent in folliculogenesis, restoring endocrine functions. This finding may have implications for rejuvenating ovarioids from fetal gonad-like cells using pluripotent stem cell technologies, as well as for enhancing endocrine recovery and health span.

摘要: Rosacea, as a progressive and chronic inflammatory skin disease, lacks safe and effective treatment options. Our previous study reported metabolic disturbance in rosacea patients, containing abnormal lipid metabolism. Building on this, we characterized significant alterations in fatty acid metabolism among rosacea patients, with a notable increase in linoleic acid (LNA) levels. We further demonstrated that LNA prevents rosacea-like dermatitis in LL37-induced rosacea-like mouse model. Our evidence indicated that LNA hyperactivates PPARγ signaling in the epidermis, a phenomenon observed in both rosacea patients and mouse model. Inhibiting PPARγ rescued the effect of LNA in LL37-induced mice. Additionally, our in vivo and in vitro evidence strongly supported the presence of mitochondrial damage in the keratinocytes of rosacea. LNA stimulated PPARγ to reduce the reactive oxygen species production, increasing the generation of ATP and recovering mitochondrial membrane potential. Finally, through a prospective cohort study utilizing UK Biobank data and linkage disequilibrium score regression (LDSC) regression analysis, we further confirmed LNA levels are negatively related to the risk of rosacea, highlighting LNA as a promising therapeutic strategy for rosacea treatment.

摘要: Cellular senescence is a key contributor to aging and aging-related diseases, but its metabolic profiles are not well understood. Here, we performed a systematic analysis of the metabolic features of four types of cellular senescence (replication, irradiation, reactive oxygen species [ROS], and oncogene) in 12 cell lines using genome-wide metabolic modeling and meta-analysis. We discovered that replicative and ROS-induced senescence share a common metabolic signature, marked by decreased lipid metabolism and downregulated mevalonate pathway, while irradiation and oncogene-induced senescence exhibit more heterogeneity and divergence. Our genome-wide knockout simulations showed that enhancing the mevalonate pathway, by administrating mevalonate for instance, could reverse the metabolic alterations associated with senescence and human tissue aging, suggesting a potential anti-aging or lifespan-extending effect. Indeed, the experiment in Caenorhabditis elegans showed that administrating mevalonate significantly increased the lifespan. Our study provides a new insight into the metabolic landscape of cell senescence and identifies potential targets for anti-aging interventions.

摘要: Gut organoids are 3D cellular structures derived from adult or pluripotent stem cells, capable of closely replicating the physiological properties of the gut. These organoids serve as powerful tools for studying gut development and modeling the pathogenesis of intestinal diseases. This review provides an in-depth exploration of technological advancements and applications of gut organoids, with a focus on their construction methods. Additionally, the potential applications of gut organoids in disease modeling, microenvironmental simulation, and personalized medicine are summarized. This review aims to offer perspectives and directions for understanding the mechanisms of intestinal health and disease as well as for developing innovative therapeutic strategies.

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摘要: Cell-based immunotherapy, recognized as living drugs, is revolutionizing clinical treatment to advanced cancer and shaping the landscape of biomedical research for complex diseases. The differentiation of human pluripotent stem cells (PSCs) emerges as a novel platform with the potential to generate an unlimited supply of therapeutic immune cells, especially when coupled with gene modification techniques. PSC-based immunotherapy is expected to meet the vast clinical demand for living drugs. Here, we examine recent preclinical and clinical advances in PSC-based immunotherapy, focusing on PSC gene modification strategies and differentiation methods for producing therapeutic immune cells. We also discuss opportunities in this field and challenges in cell quality and safety and stresses the need for further research and transparency to unlock the full potential of PSC immunotherapies.

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摘要: Systemic lupus erythematosus (SLE) is characterized by the overproduction of autoantibodies, and B cells are considered to be the primary cells involved in the development of SLE. Studies have shown that DNA damage responses play a role in B cell activity in SLE. However, the exact role of DNA damage-induced transcript 3 (DDIT3) in humoral immune response and SLE pathogenesis remains unknown. We observed increased expression of DDIT3 in B cells of SLE patients and this expression was positively correlated with disease activity. In DDIT3-knockout mice, we observed disturbances in B cell development and differentiation, inhibition of B cell activation, and BCR signaling. In addition, DDIT3 deficiency leads to a reduction in T-cell-dependent humoral immune responses. Mechanistically, we found that DDIT3 promotes the transcription and expression of Itgad, which enhances PI3K signaling and B cell activation. Finally, we found that DDIT3 deficiency attenuated lupus autoimmunity and reduced germinal center responses. In conclusion, our study reveals for the first time the role of DDIT3 in adaptive immune responses, especially in B cell homeostasis, B cell activation, BCR signaling, and B cell function. These findings provide a new potential target for therapeutic intervention in SLE.