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It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs. Ablation of hypothalamic stem/progenitor cells in mice leads to ageing-related decreases in physiological parameters and lifespan, and the speed of ageing is partially controlled by these cells through the release of exosomal miRNAs. Hypothalamus controls the speed of ageing Dongsheng Cai and colleagues previously showed that the hypothalamus has a critical role in systemic ageing. Here they observe a substantial loss of hypothalamic stem cells in middle-aged mice. They show in several mouse models that ablation of these cells results in ageing-like physiological changes and a shortened lifespan. Conversely, ageing could be slowed and lifespan extended by transplantation of healthy hypothalamic stem cells into middle aged mice. Hypothalamic stem cells secrete exosomal miRNAs, contributing to a pool of circulating miRNAs in the cerebrospinal fluid that declines with age. These secreted exosomes contribute, at least in part, to a deceleration of ageing. The authors conclude that the speed of ageing is partially controlled by hypothalamic stem cells and their exosomal miRNAs in the cerebrospinal fluid.

To investigate the effect of pyrroloquinoline quinone (PQQ) on skin aging in the Bmi-1 KO mice and its underlying mechanisms, we administered a normal diet to both Wild type mice (WT) and Bmi-1 KO mice, while supplementing the diet of Bmi-1 KO mice with PQQ (PQQ+Bmi-1 KO). Subsequently, we compared the thickness of the skin epidermis, dermis, pilosebaceous unit and collagen ratio using HE staining and Masson’s trichrome. Additionally, immunohistochemical staining, Western blotting and electron microscopy were applied across all three groups. The results revealed that Bmi-1 KO mice exhibited premature aging phenotypes compared to the WT group; however, PQQ administration effectively delayed premature aging in Bmi-1 KO mice. Furthermore, reduced epidermal thickness, dermal thickness, pilosebaceous units count as well as collagen ratio were observed in Bmi-1 KO mice. Moreover, the PCNA positive cell percentage also decreased in Bmi-1 KO mice. Conversely, treatment with PQQ significantly increased epidermal thickness, dermal thickness, pilosebaceous unit count, collagen ratio and PCNA positive cell percentage when compared to Bmi-1 KO mice. In order to further investigate the anti-aging mechanism of PQQ, experiments have revealed that PQQ effectively suppressed the expression of cell cycle proteins p16, p19, and p53 in Bmi-1 KO mice. In addition, autophagy-related experiments demonstrated that compared to the WT group, Bmi-1 KO mice exhibited an increased number of autophagosomes along with decreased expression of Beclin-1 and LC3Ⅱ/LC3Ⅰratio, and increased expression of p62. However, supplementation with PQQ resulted in a reduction in the number of autophagosomes while increasing the expression of Beclin-1 and LC3Ⅱ/LC3Ⅰratio and decreasing the expression of p62. This study provides evidence that downregulation of Bmi-1 promotes skin aging, whereas PQQ delays skin aging in Bmi-1 KO mice by promoting cell proliferation, inhibiting the expression of p16, p19 and p53 and enhancing autophagy levels.

The Polycomb repressive complex 1 (PRC1) is found to have important gene-dosage-dependent and sex-specific roles in primordial germ cell (PGC) development, including the maintenance of high levels of Oct4 and Nanog and ensuring the proper timing of meiosis through the suppression of retinoic acid signalling in female PGCs. PRC1 role in germ cell development Polycomb group proteins are involved in the transcriptional repression of developmental regulators in embryonic stem cells, where they maintain pluripotency and cell identity during subsequent development. Antoine Peters and colleagues have studied the function of the Polycomb repressive complex 1 (PRC1) in the development of mouse primordial germ cells (PGCs). They observed multiple sex-specific roles of PRC1 in development. PRC1 is required for the maintenance of high levels of expression of the transcription factors Oct4 and Nanog. And by suppressing retinoic acid signalling provided by the somatic compartment of the female genital ridge, PRC1 also ensures proper timing of meiotic induction. In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment 1 . In mouse female PGCs, expression of stimulated by retinoic acid gene 8 ( Stra8 ) and meiosis are induced in response to retinoic acid provided from the mesonephroi 2 , 3 , 4 , 5 . Given the widespread role of retinoic acid signalling during development 6 , 7 , the molecular mechanisms that enable PGCs to express Stra8 and enter meiosis in a timely manner are unknown 2 , 8 . Here we identify gene-dosage-dependent roles in PGC development for Ring1 and Rnf2 , two central components of the Polycomb repressive complex 1 (PRC1) 9 , 10 . Both paralogues are essential for PGC development between days 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs to maintain high levels of Oct4 (also known as Pou5f1 ) and Nanog expression 11 , and to prevent premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of retinoic acid signalling partially suppresses precocious Oct4 downregulation and Stra8 activation in Rnf2 -deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic retinoic acid signalling.

XX and XY fetal gonads are initially bipotential, poised between the ovary and testis fate. Multiple lines of evidence suggest that commitment to testis fate requires the repression of genes associated with ovary fate. It was previously shown that loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans. While it had been proposed that CBX2 is an activator of the testis-determining gene Sry, we investigated the alternative possibility that CBX2 has a direct role as a repressor of the antagonistic ovary-promoting pathway. To investigate this possibility, we developed a quantitative genome-wide profile of the repressive histone mark H3K27me3 and its active counterpart H3K4me3 in isolated XY and XX gonadal supporting cells before and after sex determination. We show that testis and ovary sex-determining (SD) genes are bivalent before sex determination, providing insight into how the bipotential state of the gonad is established at the epigenetic level. After sex determination, many SD genes of the alternate pathway remain bivalent, possibly contributing to the ability of these cells to transdifferentiate even in adults. The finding that many genes in the Wnt signaling pathway were targeted for H3K27me3-mediated repression in Sertoli cells led us to test whether deletion of Wnt4 could rescue testis development in Cbx2 mutants. We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice. Furthermore, we show that CBX2 directly binds the downstream Wnt signaler Lef1, an ovary-promoting gene that remains bivalent in Sertoli cells. Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development.

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.

The transcriptional repressor Bmi‐1 is involved in cell‐cycle regulation and cell senescence, the deficiency of which has been shown to cause oxidative stress. This study investigated whether Bmi‐1 deficiency plays a role in promoting disc degeneration and the effect of treatment with antioxidant N‐acetylcysteine (NAC) on intervertebral disc degeneration. Bmi‐1−/− mice were treated with the antioxidant NAC, supplied in drinking water (Bmi‐1−/−+NAC). For in vitro experiments, mouse intervertebral discs were cultured under low oxygen tension and serum‐limiting conditions in the presence of tumour necrosis factor α and interleukin 1β in order to mimic degenerative insult. Disc metabolism parameters in these in vitro and in vivo studies were evaluated by histopathological, immunohistochemical and molecular methods. Bmi‐1−/− mice showed lower collagen Ⅱ and aggrecan levels and higher collagen Ⅹ levels than wild‐type and Bmi‐1−/−+NAC mice. Bmi‐1−/− mice showed significantly lower superoxide dismutase (SOD)‐1, SOD‐2, glutathione peroxidase (GPX)‐1 and GPX‐3 levels than their wild‐type littermates and Bmi‐1−/−+ NAC mice. Relative to Bmi‐1−/− mice, the control and Bmi‐1−/−+NAC mice showed significantly lower p16, p21, and p53 levels. These results demonstrate that Bmi‐1 plays an important role in attenuating intervertebral disc degeneration in mice by inhibiting oxidative stress and cell apoptosis.

To determine whether transplanted amniotic membrane mesenchymal stem cells (AMSCs) ameliorated the premature senescent phenotype of Bmi-1-deficient mice, postnatal 2-day-old Bmi-1(-/-) mice were injected intraperitoneally with the second-passage AMSCs from amniotic membranes of β-galactosidase (β-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old β-gal(+) AMSC-transplanted or 6-week-old DiI(+) AMSC-transplanted Bmi-1(-/-) mice were compared with vehicle-transplanted Bmi-1(-/-) and WT mice. Vehicle-transplanted Bmi-1(-/-) mice displayed growth retardation and premature aging with decreased cell proliferation and increased cell apoptosis; a decreased ratio and dysmaturity of lymphocytic series; premature osteoporosis with reduced osteogenesis and increased adipogenesis; redox imbalance and DNA damage in multiple organs. Transplanted AMSCs carried Bmi-1 migrated into multiple organs, proliferated and differentiated into multiple tissue cells, promoted growth and delayed senescence in Bmi-1(-/-) transplant recipients. The dysmaturity of lymphocytic series were ameliorated, premature osteoporosis were rescued by promoting osteogenesis and inhibiting adipogenesis, the oxidative stress and DNA damage in multiple organs were inhibited by the AMSC transplantation in Bmi-1(-/-) mice. These findings indicate that AMSC transplantation ameliorated the premature senescent phenotype of Bmi-1-deficient mice and could be a novel therapy to delay aging and prevent aging-associated degenerative diseases.

The mature mammalian organ of Corti does not regenerate spontaneously after injury, mainly due to the absence of cell proliferation and the depletion of otic progenitors with age. The polycomb gene B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) promotes proliferation and cell cycle progression in several stem cell populations. The cell cycle inhibitor p16ink4a has been previously identified as a downstream target of Bmi1. In this study, we show that Bmi1 is expressed in the developing inner ear. In the organ of Corti, Bmi1 expression is temporally regulated during embryonic and postnatal development. In contrast, p16ink4a expression is not detectable during the same period. Bmi1-deficient mice were used to investigate the role of Bmi1 in cochlear development and otosphere generation. In the absence of Bmi1, the postnatal organ of Corti displayed normal morphology at least until the end of the first postnatal week, suggesting that Bmi1 is not required for the embryonic or early postnatal development of the organ of Corti. However, Bmi1 loss resulted in the reduced sphere-forming capacity of the organ of Corti, accompanied by the decreased cell proliferation of otic progenitors in otosphere cultures. This reduced proliferative capacity was associated with the upregulation of p16ink4a in vitro. Viral vector-mediated overexpression of p16ink4a in wildtype otosphere cultures significantly reduced the number of generated otospheres in vitro. The findings strongly suggest a role for Bmi1 as a promoter of cell proliferation in otic progenitor cells, potentially through the repression of p16ink4a.

The epigenetic regulator BMI1 is upregulated progressively in a wide variety of human tumors including colorectal cancer. In this study, we assessed the requirement for Bmi1 in intestinal tumorigenesis using an autochthonous mouse model in which Apc was conditionally ablated in the intestinal epithelium. Germline mutation of Bmi1 significantly reduced both the number and size of small intestinal adenomas arising in this model, and it acted in a dose-dependent manner. Moreover, in contrast to wild-type controls, Bmi1 −/− mice showed no increase in median tumor size, and a dramatic decrease in tumor number, between 3 and 4 months of age. Thus, Bmi1 is required for both progression and maintenance of small intestinal adenomas. Importantly, Bmi1 deficiency did not disrupt oncogenic events arising from Apc inactivation. Instead, the Arf tumor suppressor, a known target of Bmi1 epigenetic silencing, was upregulated in Bmi1 mutant tumors. This was accompanied by significant upregulation of p53, which was confirmed by sequencing to be wild-type, and also elevated apoptosis within the smallest Bmi1 −/− adenomas. By crossing Arf into this cancer model, we showed that Arf is required for the induction of both p53 and apoptosis, and it is a key determinant of the ability of Bmi1 deficiency to suppress intestinal tumorigenesis. Finally, a conditional Bmi1 mutant strain was generated and used to determine the consequences of deleting Bmi1 specifically within the intestinal epithelium. Strikingly, intestinal-specific Bmi1 deletion suppressed small intestinal adenomas in a manner that was indistinguishable from germline Bmi1 deletion. Thus, we conclude that Bmi1 deficiency impairs the progression and maintenance of small intestinal tumors in a cell autonomous and highly Arf -dependent manner.

Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we reported the expression of Bmi1 in mouse cochlea and investigated the role of Bmi1 in hair cell survival. Bmi1 expressed in hair cells and supporting cells in mouse cochlea. Bmi1 −/− mice displayed severe hearing loss and patched outer hair cell loss from postnatal day 22. Ototoxic drug-induced hair cells loss dramatically increased in Bmi1 −/− mice compared with that in wild-type controls both in vivo and in vitro , indicating Bmi1 −/− hair cells were significantly more sensitive to ototoxic drug-induced damage. Cleaved caspase-3 and TUNEL staining demonstrated that apoptosis was involved in the increased hair cell loss of Bmi1 −/− mice. Aminophenyl fluorescein and MitoSOX Red staining showed the level of free radicals and mitochondrial ROS increased in Bmi1 −/− hair cells due to the aggravated disequilibrium of antioxidant–prooxidant balance. Furthermore, the antioxidant N -acetylcysteine rescued Bmi1 −/− hair cells from neomycin injury both in vitro and in vivo , suggesting that ROS accumulation was mainly responsible for the increased aminoglycosides sensitivity in Bmi1 −/− hair cells. Our findings demonstrate that Bmi1 has an important role in hair cell survival by controlling redox balance and ROS level, thus suggesting that Bmi1 may work as a new therapeutic target for the prevention of hair cell death.