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Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown1. Hair follicles—mini-epithelial organs that grow hair—are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs)2. Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.Obesity in mice, caused by a high-fat diet, induces hair loss as a result of changes in the differentiation of hair follicle stem cells. [ABSTRACT FROM AUTHOR]

Stem cells underlie tissue homeostasis, but their dynamics during ageing—and the relevance of these dynamics to organ ageing—remain unknown. Here we report that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the resulting differential expression of COL17A1 in individual stem cells generates a driving force for cell competition. In vivo clonal analysis in mice and in vitro 3D modelling show that clones that express high levels of COL17A1, which divide symmetrically, outcompete and eliminate adjacent stressed clones that express low levels of COL17A1, which divide asymmetrically. Stem cells with higher potential or quality are thus selected for homeostasis, but their eventual loss of COL17A1 limits their competition, thereby causing ageing. The resultant hemidesmosome fragility and stem cell delamination deplete adjacent melanocytes and fibroblasts to promote skin ageing. Conversely, the forced maintenance of COL17A1 rescues skin organ ageing, thereby indicating potential angles for anti-ageing therapeutic intervention. COL17A1-driven stem cell competition and symmetric cell divisions initially govern skin homeostasis, but the same mechanisms result in skin ageing later in life. [ABSTRACT FROM AUTHOR]

Many studies have reported the roles played by regulated proteolysis in synaptic plasticity and memory, but the role of autophagy in neurons remains unclear. In mammalian cells, autophagy functions in the clearance of long-lived proteins and organelles and in adaptation to starvation. In neurons, although autophagy-related proteins (ATGs) are highly expressed, autophagic activity markers, autophagosome (AP) number, and light chain protein 3-II (LC3-II) are low compared with other cell types. In contrast, conditional knock-out of ATG5 or ATG7 inmousebrain causes neurodegeneration and behavioral deficits. Therefore, this study aimed to test whether autophagy is especially regulated in neurons to adapt to brain functions. In cultured rat hippocampal neurons, we found that KCl depolarization transiently increased LC3-II and AP number, which was partially inhibited with APV, an NMDA receptor (NMDAR) inhibitor. Brief low-dose NMDA, a model of chemical long-term depression (chem-LTD), increased LC3-II with a time course coincident with Akt and mammalian target of rapamycin (mTOR) dephosphorylation and degradation of GluR1, an AMPA receptor (AMPAR) subunit. Downstream of NMDAR, the protein phosphatase 1 inhibitor okadaic acid, PTEN inhibitor bpV(HOpic), autophagy inhibitor wortmannin, and short hairpin RNA-mediated knockdown of ATG7 blocked chem-LTD-induced autophagy and partially recovered GluR1 levels. After chem-LTD, GFP-LC3 puncta increased in spines and in dendrites when AP-lysosome fusion was blocked. These results indicate that neuronal stimulation induces NMDAR-dependent autophagy through PI3K-Akt-mTOR pathway inhibition, which may function in AMPAR degradation, thus suggesting autophagy as a contributor to NMDAR-dependent synaptic plasticity and brain functions. [ABSTRACT FROM AUTHOR]

The objective of the study was to investigate the potential of mono- l-aspartyl chlorine e6 (NPe6), a water-soluble photosensitizer derived from chlorophyll, for use in photodynamic diagnosis (PDD) of malignant brain tumor. A C6 glioma cell line was transplanted in the SD rat brain to create a brain tumor model. Five days after transplantation, NPe6 was administrated via the tail vein at concentrations ranging from 1.25 to 10 mg/kg; then the skull was opened in the rat brain, the site of tumor transplant was irradiated with a diode laser beam at 664 nm, and the time-course intensity and distribution of emerging fluorescence were observed. Furthermore, the correlation between fluorescence distribution and histopathological findings was investigated in the removed brain. Fluorescence was observed in the site of brain tumor transplant from 5 min after injection, and stable fluorescence was recognized at the site until 4 h after administration. No differences were noted in fluorescence intensity at NPe6 doses of 2.5 mg/kg or more; therefore, it was possible to estimate the optimal dose range. Fluorescence distribution had a clear correlation with tumor cell density, and it was possible to capture the margin of tumor cell invasion with fluorescence. The photosensitizer NPe6 is capable of assessing tumor cell density in malignant glioma tissue in terms of differences in fluorescence intensity. The usefulness of PDD using 5-aminoleveulinic acid during surgery for malignant glioma has been recognized in recent years. The results of the present study suggested the potential of NPe6 as a promising photosensitizer for use in PDD for accurate grasp of the extent of removal during the course of malignant glioma surgery. [ABSTRACT FROM AUTHOR]

To engineer a stem cell genome, we developed a technology for targeted elimination of chromosomes from mouse embryonic stem (ES)–somatic hybrid cells. Here we demonstrate the use of a universal chromosome elimination cassette (CEC) for elimination of a single embryonic stem cell (ESC)-derived chromosome 11 or 12, and also both copies of chromosome 6, which harbor pluripotency-associated genes including Nanog. We attribute hybrid-cell pluripotency to the expression of Nanog from the reprogrammed somatic-cell nuclei. [ABSTRACT FROM AUTHOR]

Beclin 1 is a key regulator of autophagy and endocytosis. However, its autophagy-independent functions remain poorly understood. Here, we report that Beclin 1 regulates recycling endosome and is required for skin development in vivo. We first established keratinocyte-specific Beclin 1-knockout mice and found that these mutant mice died owing to severe impairment of epidermal barrier. Beclin 1 plays a role in autophagy and the endocytic pathway in cooperation with Atg14 and UVRAG, respectively, and keratinocyte-specific Atg14-knockout mice do not show any abnormal phenotypes, suggesting that Beclin 1 has a role in skin development via the endocytic pathway. Furthermore, we found that Beclin 1 deficiency causes mislocalization of integrins via a defect of recycling endosome, abnormal cell detachment of basal cells and their immature differentiation, and abnormal skin development. These results provide the first genetic evidence showing the roles of Beclin 1 in recycling endosome and skin development. Saori Noguchi et al. demonstrate the role of Beclin 1 for recycling endosome during skin development, using keratinocyte-specific Beclin 1-knockout mice. This study suggests that a key autophagy player Beclin 1 is also important for skin formation by ensuring a proper localization of integrins. [ABSTRACT FROM AUTHOR]

Calnexin (CANX) and calreticulin (CALR) chaperones mediate nascent glycoprotein folding in the endoplasmic reticulum. Here we report that these chaperones have distinct roles in male and female fertility. Canx null mice are growth retarded but fertile. Calr null mice die during embryonic development, rendering indeterminate any effect on reproduction. Therefore, we conditionally ablated Calr in male and female germ cells using Stra8 (mcKO) and Zp3 (fcKO) promoter-driven Cre recombinase, respectively. Calr mcKO male mice were fertile, but fcKO female mice were sterile despite normal mating behavior. Strikingly, we found that Calr fcKO female mice had impaired folliculogenesis and decreased ovulatory rates due to defective proliferation of cuboidal granulosa cells. Oocyte-derived, TGF-beta family proteins play a major role in follicular development and molecular analysis revealed that the normal processing of GDF9 and BMP15 was defective in Calr fcKO oocytes. These findings highlight the importance of CALR in female reproduction and demonstrate that compromised CALR function leads to ovarian insufficiency and female infertility. [ABSTRACT FROM AUTHOR]