The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals ...program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.
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•Microbiota-induced type I IFN programs antitumorigenic mononuclear phagocytes (MPs)•Monocytes in the TME produce type I IFN in response to microbial STING agonists•High-fiber diet induces type I IFN, remodels MPs in the TME, and improves ICB efficacy•Microbiota from ICB responders induces IFN-I and shapes the MP landscape in the TME
The gut microbiota tunes the pro/anti-tumorigenic balance of the tumor microenvironment via a STING-type I IFN-dependent mechanism. Feeding a high-fiber diet or transferring the fecal microbiota from immune checkpoint blockade (ICB) responder melanoma individuals triggers this pathway and programs intratumoral mononuclear phagocytes to promote anticancer immunity and ICB efficacy.
The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ ...localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to ...exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
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•β-aminoisobutyric acid (BAIBA) is secreted from PGC-1α-expressing myocytes•BAIBA activates the thermogenic program in white adipocytes via PPARα•Circulating BAIBA levels in mice and humans are increased with exercise•BAIBA is inversely correlated with cardiometabolic risk factors in humans
Roberts et al. use metabolic profiling to identify β-aminoisobutyric acid (BAIBA) as a PGC-1α-responsive small molecule myokine that induces β-oxidation in hepatocytes and the browning of white adipose tissue. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors.
Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT ...remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT.
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•Cold exposure selectively induces FGF21 expression in thermogenic adipose tissues•Autocrine actions of FGF21 are obligatory for type 2 immune activation and beiging•FGF21 induces CCL11 production in adipocytes to promote recruitment of eosinophils•The FGF21-CCL11 axis couples nervous and immune systems to induce beiging in scWAT
Zhe Huang et al. show that cold activates type 2 immune responses and beiging in subcutaneous WAT through an FGF21-CCL11 axis which drives eosinophil recruitment, M2 macrophage accumulation and proliferation and commitment of beige adipocyte precursors. These findings explain how the immune system communicates with sympathetic nerves to control adaptive thermogenesis.
Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control ...glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.
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•GSCs can become drug-tolerant and persister-like following RTK inhibitor exposure•Persister GSCs exhibit NSC-like programs and are sustained by Notch signaling•Notch-high, slow-cycling GSCs are found in primary GBM tumors•Persister GSCs reorganize their repressive chromatin and are dependent on KDM6
Liau et al. find that glioblastoma stem cells (GSCs) reversibly transition to a slow-cycling, persister-like state following RTK inhibitor treatment. The persister state is marked by redistribution of repressive chromatin, upregulation of neurodevelopmental programs, and dependency on KDM6. Thus, cancer cells may hijack chromatin reorganization for proliferation, adaptation, and tolerance.
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely ...understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn’s disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
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•Defective cAMP response underlies mucosal immune defects in pediatric colitis or IBD•Platelets are activated at colonic mucosae in pediatric colitis or IBD•Dipyridamole promoted mucosal healing in nine children with colitis in a pilot study•Candidate risk genes are differentially enriched in mucosal cellular subsets
Single-cell and risk gene analysis of children with undifferentiated colitis, Crohn’s disease, and ulcerative colitis identifies common underlying mechanisms of pathogenesis and reveals the potential therapeutic benefit of modulating cAMP signaling via the drug dipyridamole.
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In order to improve the osseointegration and long-term survival of dental implants, it is urgent to develop a multifunctional titanium surface which would simultaneously have ...osteogeneic, angiogeneic and antibacterial properties. In this study, a potential dental implant material-dual Zn/Mg ion co-implanted titanium (Zn/Mg-PIII) was developed via plasma immersion ion implantation (PIII). The Zn/Mg-PIII surfaces were found to promote initial adhesion and spreading of rat bone marrow mesenchymal stem cells (rBMSCs) via the upregulation of the gene expression of integrin α1 and integrin β1. More importantly, it was revealed that Zn/Mg-PIII could increase Zn2+ and Mg2+ concentrations in rBMSCs by promoting the influx of Zn2+ and Mg2+ and inhibiting the outflow of Zn2+, and then could enhance the transcription of Runx2 and the expression of ALP and OCN. Meanwhile, Mg2+ ions from Zn/Mg-PIII increased Mg2+ influx by upregulating the expression of MagT1 transporter in human umbilical vein endothelial cells (HUVECs), and then stimulated the transcription of VEGF and KDR via activation of hypoxia inducing factor (HIF)-1α, thus inducing angiogenesis. In addition to this, it was discovered that zinc in Zn/Mg-PIII had certain inhibitory effects on oral anaerobic bacteria (Pg, Fn and Sm). Finally, the Zn/Mg-PIII implants were implanted in rabbit femurs for 4 and 12weeks with Zn-PIII, Mg-PIII and pure titanium as controls. Micro-CT evaluation, sequential fluorescent labeling, histological analysis and push-out test consistently demonstrated that Zn/Mg-PIII implants exhibit superior capacities for enhancing bone formation, angiogenesis and osseointegration, while consequently increasing the bonding strength at bone-implant interfaces. All these results suggest that due to the multiple functions co-produced by zinc and magnesium, rapid osseointegration and sustained biomechanical stability are enhanced by the novel Zn/Mg-PIII implants, which have the potential application in dental implantation in the future.
In order to enhance the rapid osseointegration and long-term survival of dental implants, various works on titanium surface modification have been carried out. However, only improving osteogenic activity of implants is not enough, because angiogenesis and bacteria inhibition are also very important for dental implants. In the present study, a novel dental implant material-dual Zn/Mg ion co-implanted titanium (Zn/Mg-PIII) was developed, which was found to have superior osteoinductivity, pro-angiogenic effects and inhibitory effects against oral anaerobes. Furthermore, synergistic effects of Zn/Mg ions on osteogenic differentiation of rBMSCs and the possible mechanism were discovered. In addition, rapid osseointegration and sustained biomechanical stability are greatly enhanced by Zn/Mg-PIII implants, which may have the potential application in dental implantation in the future. We believe this paper may be of particular interest to the readers.
Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β-cell death. ...In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline. AAT suppressed blood-mediated coagulation pathways by diminishing tissue factor production, reducing plasma thrombin-antithrombin complex levels and fibrinogen deposition on islet grafts, which correlated with less graft damage and apoptosis. AAT-treated mice showed reduced serum tumor necrosis factor-α levels, decreased lymphocytic infiltration, and decreased nuclear factor (NF)-κB activation compared with controls. The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-terminal kinase (JNK) phosphorylation. Blocking JNK activation failed to further reduce cytokine-induced apoptosis in β-cells. Taken together, AAT significantly improves islet graft survival after intraportal islet transplantation by mitigation of coagulation in IBMIR and suppression of cytokine-induced JNK and NF-κB activation. AAT-based therapy has the potential to improve graft survival in human islet transplantation and other cellular therapies on the horizon.
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem ...cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
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•Tau and P-tau accumulation and autophagy disruption in tau-V337M organoids•Accelerated synaptic maturation and loss of glutamatergic cortical-layer neurons•Altered ELAVL4 expression, dysregulated splicing, accelerated synaptic maturation•Rescue of susceptibility to glutamatergic toxicity by PIKFYVE inhibitor apilimod
Characterization of iPSC-derived cerebral organoids with the tau-V337M mutation, which causes frontotemporal dementia, reveals changes preceding neuron death as potential targets for therapeutic intervention, as demonstrated by rescue of susceptibility to glutamatergic toxicity by the PIKFYVE inhibitor apilimod.
Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in ...order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT
) and 5-HT
serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT
, but surprisingly not the 5-HT
, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT
receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.
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