Cell Reports Medicine最新文献

Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the ghrelin receptor, countering ghrelin's effects on cell signaling and feeding. However, despite an emerging interest in LEAP2's physiology and pharmacology, its endocrine regulation remains unclear. Here, we report that plasma LEAP2 levels decrease significantly upon glucagon infusions during somatostatin clamps in humans. This effect is preserved in patients with obesity and type 2 diabetes while diminished following a hypercaloric diet and a sedentary lifestyle for 2 weeks. Additionally, insulin receptor antagonism offsets the upregulation of LEAP2 during the postprandial state in mice. Finally, insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression, coinciding with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus. Collectively, our findings implicate insulin and glucagon in regulating LEAP2 and warrant further investigations into the exact mechanisms orchestrating this endocrine axis.

Transplantation of human myogenic progenitor cells (MPCs) is a promising therapeutic strategy for treating muscle-wasting diseases, e.g., Duchenne muscular dystrophy (DMD). To increase engraftment efficiency of donor stem cells, modulation of host muscles is required, significantly limiting their clinical translation. Here, we develop a clinically relevant transplantation strategy synergizing hydrogel-mediated delivery and engineered human MPCs generated from CRISPR-corrected DMD patient-derived pluripotent stem cells. We demonstrate that donor-derived human myofibers produce full-length dystrophin at 4 weeks and 5-6 months (long-term) after transplantation in the unmodulated muscles of the dystrophin-deficient mouse model of DMD. Remarkably, human myofibers are innervated by mouse motor neurons forming neuromuscular junctions and supported by vascularization after long-term engraftment in dystrophic mice. PAX7+ cells of human origin populate the satellite cell niche. There was no evidence of tumorigenesis in mice engrafted with hydrogel-encapsulated human MPCs. Our results provide a proof of concept in developing hydrogel-based cell therapy for muscle-wasting diseases.

Preclinical studies suggest synergistic effects between androgen receptor inhibitors and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. This phase 2 trial (NCT05223582) evaluates neoadjuvant fuzuloparib plus abiraterone in 35 treatment-naive men with localized high-risk prostate cancer. Patients receive six cycles of therapy followed by radical prostatectomy. Primary endpoints are pathological complete response (pCR) and minimal residual disease (MRD, ≤5 mm). The combined pCR/MRD rate is 46% (95% confidence interval [CI]: 29%-63%), with a 53% 2-year biochemical progression-free survival rate. Grade ≥3 adverse events occur in 23% of patients. Biallelic homologous recombination repair/BRCA2 alterations correlate with faster prostate-specific antigen decline. Post-treatment genomic analyses reveal reduced MYC amplification and proliferation markers, alongside activated epithelial-mesenchymal transition/activator protein 1 (AP-1) pathways. The trial meets its primary endpoint, demonstrating feasibility and preliminary efficacy, while exploratory biomarkers may guide future studies.

Conventional neoadjuvant chemotherapy provides limited benefit for patients with resectable non-small cell lung cancer (NSCLC). Recently, neoadjuvant chemoimmunotherapy (NCIT) has transformed the perioperative management of NSCLC by priming systemic anti-tumor immunity before surgery, yet it remains ineffective for at least 50% of patients. Through single-cell sequencing analysis of our NCIT cohort, we identify that antigen-presenting cancer-associated fibroblasts (apCAFs) can impede the efficacy of NCIT. Using a custom cancer-associated fibroblast biobank, we uncover that interferon (IFN)-γ stimulates apCAF expansion via the JAK1/2-STAT1-IFI6/27 pathway. Mechanistically, apCAFs significantly contribute to PD-L2 expression in the tumor microenvironment (TME), triggering the accumulation of FOXP1⁺regulatory T cells (Tregs) through the PD-L2-RGMB axis. Reprogramming apCAFs by inhibiting the IFN-γ pathway or blocking the PD-L2-RGMB axis substantially mitigates apCAFs-mediated FOXP1⁺Tregs' expansion. In summary, we reveal the role of apCAFs in compromising NCIT efficacy and propose applications for anti-PD-L2/RGMB regimens to synergize with anti-PD1 therapies by targeting apCAFs.

The microbiota-gut-brain axis has major implications for human health including gastrointestinal physiology, brain function, and behavior. The immune system represents a key pathway of communication along this axis with the microbiome implicated in neuroinflammation in health and disease. In this review, we discuss the mechanisms as to how the gut microbiota interacts with the brain, focusing on innate and adaptive immunity that are often disrupted in gut-brain axis disorders. We also consider the implications of these observations and how they can be advanced by interdisciplinary research. Leveraging an increased understanding of how these interactions regulate immunity has the potential to usher in a new era of precision neuropsychiatric clinical interventions for psychiatric, neurodevelopmental, and neurological disorders.

Autologous vascular grafts, the only clinically approved option for small-diameter (<6 mm) revascularizations, require invasive harvesting and have limited availability and variable quality. To address these challenges, we develop a 3-mm-diameter artery graft by using arterial endothelial cells (AECs) derived from pluripotent stem cells (PSCs). After establishing technologies for pure AEC generation and expanded polytetrafluoroethylene (ePTFE) graft coating, we engineer artery grafts by seeding the inner lumen of ePTFE vascular grafts with either major histocompatibility complex (MHC) mismatched unmodified-wild-type (MHC-WT) AECs or MHC class I/II double knockout (MHC-DKO) AECs. Their function is evaluated in a rhesus arterial interposition grafting model. MHC-WT grafts maintained 100% patency for 6 months, significantly better than naked and MHC-DKO grafts. Additionally, the endothelium of MHC-WT grafts is repopulated with host cells, supporting long-term patency. Collectively, our study demonstrates that PSC-derived MHC-WT artery grafts provide an unlimited homogenous resource for allogeneic arterial revascularization.

Lighting interventions can mitigate fatigue by promoting circadian rhythmicity. We test whether individualized, wearable-based lighting interventions delivered via a mobile app reduce cancer-related fatigue in a randomized controlled trial with 138 breast cancer, prostate cancer, and hematopoietic stem cell transplant patients. Participants are randomized to tailored lighting intervention or control. The primary endpoint is PROMIS fatigue 4a at trial end, with secondary endpoints including change in daily fatigue, sleep, anxiety, depression, physical function, and overall health. Fatigue T-scores at week 11 do not differ between groups but decrease significantly from week 1 to week 11 (3.07 points, p = 0.001) in the intervention group, with a significant final-week treatment effect (p = 0.014). Daily fatigue, anxiety, sleep disturbance, and physical function improve within intervention. Further studies are needed to see if these results generalize in broader cancer care. The trial is registered at ClinicalTrials.gov (trial registration number: NCT04827446).

Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe^-/- mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2's pivotal role in mediating hyperlipidemia's detrimental effects on myeloid cells and neurovascular units. Our findings suggest that TRPM2 is a promising therapeutic target for alleviating neurodegenerative diseases exacerbated by hyperlipidemia, such as ischemic stroke. These results also highlight TRPM2 expression in peripheral blood as a potential biomarker for predicting stroke outcomes in hyperlipidemic patients.

Accurate diagnosis of early Parkinson's disease requires platforms suitable for detecting minute amounts of neuronally derived biomarkers in the massive protein excess of easily accessible biofluids such as blood. Here, we describe an on-chip droplet-confined fluorescence reporting assay that identified α-synuclein on the membrane of L1CAM+ extracellular vesicles (EVs) immunocaptured from human serum and corroborate this finding by super-resolution direct stochastic optical reconstruction microscopy (dSTORM) microscopy. Using conditioned media from neuroblastoma cells expressing α-synuclein mutants or patient-derived induced pluripotent stem cell (iPSC) neurons with α-synuclein gene triplication, we found that association of α-synuclein with the L1CAM+ EV surface is increased under pathological conditions. Accordingly, this readout, as measured by the droplet-based assay, is an improved predictive biomarker in the prodromal phase (area under the receiver operating characteristic curve [AUC] = 0.93) or diagnostic biomarker in the clinical phase (AUC = 0.95) of Parkinson's disease. More broadly, our platform will simplify the assessment of EV membrane proteins and facilitate their application as diagnostic biomarkers across diverse clinical indications.

Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206⁺ macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.