BackgroundMucosal melanomas arise from melanocytes in mucosal tissues, and it’s usually detected at a late stage owing to its anatomic location. Advances in immunotherapies have proved to be promising therapeutic approaches for advanced mucosal melanoma patients, however, clinical studies have shown mucosal melanoma patients are less responsive to ICIs than cutaneous melanoma. Effective therapy is still lacking.ObjectiveTo investigate the efficacy and safety of SHR-1210 (an anti-programmed cell death-1 antibody) in combination with Apatinib (a vascular endothelial growth factor receptor 2 inhibitor) as late-line treatment in patients with advanced mucosal melanoma (Ethics approval number 2019184;ClinicalTrials.gov ID: NCT03986515).Patients and methodsPatients with confirmed metastatic mucosal melanoma according to AJCC 8.0. In this single-arm, single-center, phase II nonrandomized clinical trial, patients with advanced mucosal melanoma who have received several line treatments were enrolled between 2019.06 and 2022.12. The data cutoff date was June 11th, 2025. Patients received 200mg SHR-1210 intravenously every 3 weeks, and oral Apatinib 250 mg daily until unacceptable toxic effects or disease progression.ResultsA total of 13 patients were enrolled and received treatment. The disease control rate (DCR) reached 100% (SD = 13). The objective response rate (ORR) was 0%. The estimated median overall survival (OS) was 29.9 months (95% CI 15.26-44.54),. The estimated median progression-free survival (PFS) was 5.17 months (95% CI 3.27-10.27),. The most common grade 1–2 was hand and foot induration with desquamation and pain, and one case of grade 4 abnormal liver function and grade 3 hypertension. No treatment-related deaths occurred.ConclusionsThis suggests that this combination therapy model may be a promising disease control for mucosal melanomas. However, the sample size is relatively small and needs to be increased for further research.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT03986515, identifier NCT03986515.

ABSTRACT Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Inflammatory responses and lipid metabolism disorders are known to influence cancer development; however, their combined effects on HCC progression remain unclear. This study examined the associations between lipid profiles and inflammatory markers with HCC stage. Methods In this cross‐sectional study, data from 90 patients with HCC and available Barcelona Clinic Liver Cancer stage information were analyzed. Serum lipid profiles and inflammatory markers were measured, and derived indicators—including non–high‐density lipoprotein cholesterol (non–HDL‐C), the low‐density lipoprotein cholesterol (LDL‐C)‐to‐HDL‐C ratio, the total cholesterol (TC)‐to‐HDL‐C ratio, and the neutrophil‐to‐HDL‐C ratio (NHR)—were calculated. Correlation analysis and logistic regression were performed with adjustment for potential confounders. Interaction analysis was conducted to examine relationships among lipid–inflammatory profiles, with findings validated in an independent cohort of 200 patients with HCC. Results HDL‐C levels were significantly lower in patients with non‐advanced stage tumors (0.81 ± 0.27 vs. 1.15 ± 0.28, p < 0.01). HDL‐C showed a positive correlation with tumor stage (r = 0.544, p < 0.01), whereas non–HDL‐C, LDL‐to‐HDL ratio, TC‐to‐HDL ratio, and NHR demonstrated negative correlations (r = −0.269, −0.568, −0.382, and −0.432, respectively; all p < 0.05). In univariate logistic regression analysis, higher LDL‐to‐HDL ratio (odds ratio [OR] = 0.193, 95% confidence interval [CI]: 0.066–0.562) and higher TC‐to‐HDL ratio (OR = 0.378, 95% CI: 0.195–0.730) were significantly associated with non‐advanced stage, and these associations persisted after adjustment for NHR. Conclusions Lipid‐inflammatory profiles were associated with HCC staging in correlation and partially adjusted regression analyses and showed apparent discriminative performance in ROC analysis. However, no independent predictors were identified in the fully adjusted multivariable model. These findings should be considered exploratory and hypothesis‐generating, suggesting that lipid‐inflammatory profiles may reflect staging‐related metabolic and inflammatory alterations rather than serve as independent staging markers. Further validation in large prospective studies is required.

BACKGROUND & AIMS:Endothelial cell (EC) damage is an initiating event in acute cellular rejection after liver transplantation (LT). However, the origin and characteristics of post-transplant neonatal ECs remain controversial. We aimed to uncover the mechanisms underlying EC-T cell interactions after transplantation and to develop an EC-targeted strategy to alleviate transplant rejection. METHODS:Leveraging single-cell RNA sequencing from 13 human and 4 murine liver allografts, we mapped the functional atlas of ECs. Allogeneic orthotopic LT in CAG;R26-tdTomato and Cd34-CreERT2;R26-tdTomato mice confirmed the cellular origin of ECs. We used CellChat, multiplex immunohistochemistry, and in vitro co-culture models to investigate the mechanism of EC-T cell interactions. Using a platelet-based bio-delivery system, we achieved targeted delivery of a CXCL12 monoclonal antibody (αCXCL12). RESULTS:ECs in transplanted livers exhibited a dual origin, being derived from both donor and recipient cells. Recipient-derived ECs were characterized by high CD34 expression, high stemness, and pro-inflammatory characteristics. Using genetic lineage-tracing mice combined with an orthotopic LT model, we found that recipient CD34+ cell-derived ECs peaked at 2 weeks post-LT and declined by 4 weeks, consistent with the temporal pattern of rejection. We further identified that CD34+ ECs recruit and potentiate Th1 and cytotoxic CD8+ T cells via the CXCL12-CXCR4 axis and co-stimulatory molecules. In turn, cytotoxic CD8+ T cells induced pyroptosis of CD34+ cell-derived ECs through the Caspase1-GSDMD pathway. Platelets loaded with αCXCL12 specifically targeted ECs in the transplanted liver, reducing T-cell infiltration and mitigating rejection. CONCLUSIONS:We identified a population of recipient-derived CD34+ ECs that exacerbates acute rejection by activating T cells through the CXCL12-CXCR4 axis. We further developed a platelet-based delivery strategy that precisely targets EC-derived CXCL12 and effectively prevents acute cellular rejection. IMPACT AND IMPLICATIONS:We integrated single-cell transcriptomic data from human and murine liver allografts to delineate the dual cellular origins and functional atlas of endothelial cells. Using lineage-tracing mice in an allogeneic orthotopic liver transplantation model, we tracked the fate of CD34+ cells and demonstrated the contribution of recipient-derived CD34-lineage endothelial cells to liver allograft angiogenesis. These CD34-lineage endothelial cells recruited T cells through the CXCL12-CXCR4 axis and activated them via co-stimulatory molecules. Furthermore, a platelet-based biological delivery strategy targeting CXCL12 in CD34-lineage endothelial cells alleviated T cell-mediated rejection. This study provides an endothelial cell-centered perspective and proposes a potential novel immunosuppressive strategy for liver transplantation.

Oligogalacturonic acid demonstrated potent antibacterial efficacy against foodborne pathogens. To obtain oligogalacturonic acids with favorable antibacterial activity, this study established a controlled enzymatic hydrolysis process for citrus peel pectin based on the characterization of three commercial pectinases. Different fractions of the pectin hydrolysates were then obtained via ethanol fractional precipitation. Results showed that the supernatant from 90

Chronic stress is increasingly recognized as a driver of cancer metabolism, highlighting the need to elucidate the mechanism linking chronic stress to metabolic reprogramming. Here, we performed untargeted metabolomics on serum samples from esophageal squamous cell carcinoma (ESCC) patients and integrated the results with clinical and stress-related assessments, revealing pentose phosphate pathway (PPP) enrichment accompanied by elevated epinephrine levels in patients with stress-associated features. β2-adrenergic receptor (ADRB2) activated by chronic stress stabilized MYCBP by competitively displacing VHL, thereby enhancing MYC transcriptional activity and upregulating key PPP enzymes, including G6PD and TKT. Unexpectedly, stress-associated stimulation not only activated ADRB2 signaling but also increased ADRB2 protein abundance. Mechanistically, stress exposure enhanced RNMT-dependent N7-methylguanosine (m7G) cap modification of ADRB2 mRNA, thereby increasing its translational efficiency. Together, these findings define an RNMT-ADRB2-MYCBP-PPP axis that integrates epitranscriptomic regulation with adrenergic signaling to promote metabolic reprogramming and malignant progression in ESCC. The stress-associated RNA modification-metabolism circuitry comprises potential therapeutic targets to overcome stress-associated ESCC progression.

BACKGROUND:Fibrosis is one of the major causes of cardiac allograft malfunction and is mainly driven by fibroblasts. However, the role of recipient-derived cells in generating allograft fibroblasts and the underlying mechanisms remain to be explored. METHODS:We analyzed human heart allograft samples and used murine transplant models (C57BL/6J, Cd34 (cluster of differentiation 34)-CreERT2; R26-tdTomato, mRFP (cell membrane labeled with red fluorescence protein) mice, Rosa26-iDTR, Postn-CreERT2; R26-tdTomato, double-tdTomato, and immunodeficient mice with BALB/c donors). Human progenitor cells were cultivated from blood. Single-cell RNA sequencing, Western blotting, quantitative polymerase chain reaction, and immunohistochemistry, whole-mount staining with 3-dimensional reconstruction, and in vivo/in vitro experiments were applied to characterize allograft cellular composition and communication. RESULTS:Single-cell RNA sequencing was introduced to delineate the allograft cell atlas of patients and mice. Y chromosome analysis identified that recipient-derived cells contributed to allograft fibroblasts in both patients and murine models. Combining the genetic cell lineage tracing technique, we found that recipient-derived CD34+ cells could give rise to activated fibroblasts. Bone marrow transplantation and parabiosis models revealed that the recipient's circulating non-bone marrow Cd34+ cells could generate allograft fibroblasts. Human CD34+ cells could differentiate into fibroblasts both in vivo and in vitro. CD34+ fibroblast progenitors were recruited by CXCL12 (C-X-C motif chemokine ligand 12)-ACKR3 (atypical chemokine receptor 3) and MIF (macrophage migration inhibitory factor)-ACKR3 interactions and differentiated via the TGFβ (transforming growth factor beta)/GFPT2 (glutamine-fructose-6-phosphate transaminase 2)/SMAD2/4 (small mother against decapentaplegic 2/4) axis. Ablation of recipient Cd34+ cells reduced activated fibroblasts and alleviated allograft fibrosis. CONCLUSIONS:We identify circulating CD34+ cells as a novel source of fibroblast progenitors that contribute to cardiac allograft fibrosis, suggesting that targeting recipient CD34+ cells could be a novel therapeutic potential for treating cardiac fibrosis after heart transplantation.

[This corrects the article DOI: 10.3389/fmicb.2026.1891231.].

This study evaluated the anti-hypoxic activity of Biyang floral mushroom polyphenols (BFMPs) extracted using deep eutectic solvent (DES)-based ultrasound-assisted and ethanol methods. In vitro, BFMPs-DES (200 μg/mL) increased the viability of CoCl2-induced PC12 cells by 73.40

Early miscarriage, a common pregnancy complication predominantly occurring before 12 weeks, is conclusively linked to embryonic chromosomal abnormalities. Given the rising proportion of pregnancies at advanced maternal age, a contemporary re-examination of the relationships among early miscarriage, sex chromosomal anomalies, and maternal age is imperative to optimize clinical counseling strategies. This retrospective study analyzed cases from the Medical Genetics and Prenatal Diagnosis Center at the Third Affiliated Hospital of Zhengzhou University (July 2022–December 2024). Inclusion criteria required fetal samples with < 10

Hypoxia triggers excessive reactive oxygen species (ROS) accumulation, leading to oxidative stress and organ damage. While the natural product morin (MO) exhibits anti-hypoxic potential, its application is restricted by poor solubility and low bioavailability. To overcome these limitations, ROS-responsive nanoparticles (MO-PCD NPs) were constructed through conjugating dextran with 4-(hydroxymethyl)phenylboronic acid pinacol ester and encapsulating MO. The average particle size of MO-PCD NPs was 159.43 +/- 0.51 nm, with PDI of 0.07 +/- 0.01 and Zeta potential of -17.37 +/- 2.05 mV. They were uniformly distributed and could responsively release MO in the presence of H2O2. In PC12 cells subjected to CoCl2-simulated hypoxia, MO-PCD NPs significantly improved cell viability and helped preserve normal cell morphology compared to free MO. Hypoxia elevated intracellular ROS levels, treatment with MO-PCD NPs effectively suppressed ROS accumulation. Notably, hypoxic conditions accelerated nanoparticle uptake, confirming their ROS-responsive properties. In mice exposed to hypobaric hypoxia, MO-PCD NPs gavage significantly alleviated cerebral and pulmonary edema and improved cerebral energy metabolism. The nanoparticles also reduced cerebral ROS by nearly 35%, decreased MDA content by 16.58%, lowered H2O2 by 12.68%, and increased total antioxidant capacity by approximately 15%, indicating reinforced antioxidant defense system. Across these metrics, MO-PCD NPs surpassed an equivalent dose of free MO. These findings demonstrated MO-PCD NPs as effective ROS-responsive nanocarriers that enhanced the protective efficacy of MO against hypoxic injury, offering a new approach for applying functional food components more efficiently.

The methionine cycle plays critical roles in cell fate determination by shaping epigenetic landscape, yet its function in human erythropoiesis remains undefined. Here, we show that disruption of methionine metabolism by compromising the key enzyme adenosylhomocysteinase (AHCY) reshapes H3K4me3 landscape, causing erythroid cell fate reprogramming. AHCY deficiency severely impaired erythroid differentiation and expansion, leading to the generation of nonerythroid lineage hematopoietic cells, including stem/progenitor cells and immune cells, as evidenced by single-cell RNA-seq, and pseudo temporal analysis delineated a precise dedifferentiation trajectory, revealing erythroblasts transitioning back to MEPs and HSCs. Moreover, the human hematopoietic system could be reconstituted in the immunodeficient NCG-X mice by transplanting AHCY-deficient erythroblasts. Mechanistically, AHCY deficiency reduced global H3K4me3 levels and altered its genomic distribution, resulting in the upregulated expression of nonerythroid transcription factors and downregulated expression of erythrocyte lineage-specific transcription factors. Integrated single-cell analyses identified transitional states with diminished AHCY in the erythroblasts of a patient with acute myeloid leukemia (AML). Further flow cytometry confirmed the reduced H3K4me3 level in patient-derived erythroid cells. Erythroblasts isolated from patients with AML with reduced H3K4me3 exhibited a dedifferentiation potential into progenitor-like states. Our findings reveal a metabolic-epigenetic axis governing cell fate reprogramming in human erythropoiesis and provide insights into leukemia-associated anemia.

BackgroundHepatocellular carcinoma (HCC) is a highly heterogeneous malignancy, with variability in molecular features, clinical presentations, and treatment responses. Postoperative recurrence and disease-free survival (DFS) are important prognostic indicators for patient outcomes. The neutrophil-to-HDL ratio (NHR) is recognized as an inflammatory-lipid marker, however its age-dependent predictive value in HCC remains unclear and is not established in clinical practice. Therefore, we aimed to evaluate the prognostic significance of NHR in HCC patients undergoing surgical resection, with a focus on its age-dependent effects.MethodsWe retrospectively analyzed 121 HCC patients undergoing surgical resection and randomly divided them into training (n = 95) and validation (n = 26) cohorts. Multivariate logistic regression, Receiver operating characteristic (ROC) analysis, and nomogram construction were used to evaluate the prognostic significance of NHR, with age-stratified analyses conducted to explore its differential effects.ResultsIn the training cohort, both univariate and multivariate analysis identified NHR and age as statistically significant prognostic factors for HCC recurrence (P < 0.05). Age-stratified analysis further demonstrated that the prognostic value of NHR was significant in older patients (OR = 0.087, 95% CI: 0.009 - 0.835, P = 0.034), but not in younger patients. ROC analysis indicated good predictive performance for both NHR (AUC = 0.609) and age (AUC = 0.655). Similar trends were observed using the validation dataset.ConclusionsIn this cohort of 121 HCC patients, NHR showed a potential association with prognosis in older patients; However, these findings are preliminary due to limited sample size and lack of stratified analyses by disease stage and prior treatment. Future studies should validate these findings in larger, well-characterized cohorts and investigate underlying mechanisms.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with poor prognosis in advanced stage diseases. Although early diagnosis has the potential to improve patient outcomes, current diagnostic methods remain suboptimal, highlighting the need for accurate molecular biomarkers. We systematically reviewed 49 studies to evaluate the diagnostic performance of SHOX2 methylation, RASSF1A methylation, and their combined panel for lung cancer detection. The combined SHOX2/RASSF1A methylation panel demonstrated a pooled sensitivity of 77.8% (95% CI: 72.3%–82.5%) and specificity of 89.0% (95% CI: 86.6%–91.1%), with an HSROC area under the curve (AUC) of 0.916. SHOX2 methylation alone yielded a sensitivity of 69.4% and specificity of 91.7%, whereas RASSF1A methylation showed lower sensitivity (45.7%) but the highest specificity (93.8%). Pairwise comparisons demonstrated that the combined panel significantly improved sensitivity compared with either SHOX2 or RASSF1A alone while maintaining specificity comparable to SHOX2, although lower than that of RASSF1A. Subgroup analyses showed that assay method and pathological subtype contributed to differences in pooled sensitivity, whereas leave-one-out sensitivity analyses confirmed the robustness of the pooled estimates. In conclusion, the combined SHOX2/RASSF1A methylation panel provides a more balanced diagnostic performance than either biomarker alone and represents a promising adjunctive approach for lung cancer detection. Future studies should focus on standardizing detection methods, integrating these biomarkers with other diagnostic modalities, and evaluating their diagnostic performance in early-stage lung cancer to further enhance their clinical utility.

Neoadjuvant chemotherapy (NACT), a key strategy for various cancers, markedly improves patient prognosis and 5-year survival rates. However, numerous patients develop resistance to NACT and thus fail to benefit from it. Therefore, identifying reliable biomarkers to predict patient responsiveness to NACT remains a critical challenge. Here, we demonstrate that elevated expression of INCENP and CDCA8 contributes to poor NACT responsiveness across multiple cancers. Mechanistically, the 5'UTR (GGACT at position 113) of INCENP and the 3'UTR (GGACT at position 1041) of CDCA8 undergo m⁶A methylation and are recognized by YTHDF3, which facilitates their translation through interaction with eIF3A, ultimately driving poor response to NACT. Moreover, inhibition of INCENP and CDCA8 enhances NACT sensitivity by promoting multipolar spindle formation. Collectively, our findings establish that INCENP and CDCA8 serve as crucial biomarkers for predicting NACT responsiveness and as potential therapeutic targets for combination therapy with NACT to improve patient survival.

BackgroundThe tumor microenvironment (TME) of gastric adenocarcinoma is exceptionally heterogeneous, and epithelial-mesenchymal transition (EMT) is a central mechanism promoting local invasion and metastatic spread. Even so, how EMT-programmed cells are spatially arranged within tumor tissue, how they interact with neighboring immune populations, and which molecular nodes might be exploited therapeutically remain incompletely defined.MethodsWe built a large-scale, multi-layered analytical pipeline that combined single-cell transcriptomics (approximately 250,000 cells drawn from two independent patient cohorts), Visium-based spatial transcriptomics processed through Bayesian cell2location deconvolution, niche-level SpaTopic modeling, deep-learning histology analysis (ResNet50 feature extraction paired with CellProfiler-derived morphometrics), and ensemble survival modeling spanning over one hundred algorithmic combinations. Gaussian mixture modeling was used to define EMT-high cell states, the Scissor framework was applied to link fibroblast subsets to patient mortality, and a multi-tier filtering scheme was used to nominate druggable candidate genes. The top candidate, PVR/CD155, was interrogated experimentally by RT-qPCR, Western blotting, immunohistochemistry, and siRNA knockdown in AGS cells. We further evaluated PVR druggability by molecular docking, a 100-nanosecond molecular dynamics trajectory, and MM/GBSA binding-energy estimation using PP-121 as a candidate ligand.ResultsSub-clustering identified seven fibroblast subclusters: Fib_APOD, Fib_COL4A1, Fib_SLPI, Fib_COL1A1, Fib_CCL4, Fib_STMN1, and Fib_S100B. The SLPI-high subset preferentially localized to peritoneal metastases. Phenotype-guided Scissor mapping nominated a survival-associated fibroblast program enriched within COL4A1-expressing fibroblast states. PVR/CD155 was prioritized as an EMT-linked candidate gene; single-cell expression profiling showed that PVR was most frequently detected in endothelial, epithelial and fibroblast compartments, with low detection in lymphoid and plasma cells. PVR/CD155 was significantly upregulated in gastric cancer cell lines and tumor tissues. PVR/CD155 knockdown in AGS cells decreased proliferation, migration and invasion, supporting a tumor cell-intrinsic functional role rather than establishing PVR as a stromal immune biomarker. Molecular docking and dynamics simulations identified PP-121 as a candidate PVR-binding ligand for future biochemical validation.ConclusionThe proposed framework connects single-cell resolution with spatial and histological data, produces validated prognostic tools and nominates PVR/CD155 as a tumor cell-intrinsic EMT-associated target candidate for gastric cancer. Stromal or immune regulatory roles of PVR remain plausible but require direct compartment-specific and functional validation.

CD34 has long been defined as a canonical marker for endothelial progenitors as well as hematopoietic stem cells, implicating its role in vascular development and hematopoiesis. However, the precise developmental hierarchy and lineage potential of CD34+ cells remain controversial. In this study, we integrated inducible genetic lineage tracing techniques, proteomics and single-cell RNA-seq (scRNA-seq) analyses to elucidate the dynamic developmental trajectory of CD34+ cells during various embryonic periods in both humans and mice. Remarkably, our analyses indicated that the progeny of CD34+ cells marked distinct, spatiotemporally restricted progenitor waves with divergent fates, at which point cells adopted endothelial, hematopoietic and fibroblastic fates, respectively. During gastrulation (E6.5-E8.5), an initial wave of CD34+ progenitors predominantly orchestrates vasculogenesis via a Kdr-dependent mechanism. Subsequently, from E9.5 to E14.5, cell cycle activation serves as a molecular switch, facilitating the endothelial-to-hematopoietic transition (EHT) of CD34+ progenitors. Unexpectedly, we identify a wave of CD34+ progenitors in late embryogenesis that gives rise to fibroblasts, distinct from earlier endothelial or hematopoietic lineages. Furthermore, because umbilical cord blood is a valuable source of different circulating stem/progenitor cells, we distinguish circulating endothelial progenitors from fibroblast progenitors in human cord blood by unique molecular signatures, with GFPT2 specifically marking the fibroblast progenitors. Collectively, our study provides a high-resolution spatiotemporal atlas of CD34+ cells during embryogenesis, redefining the temporal shifts of CD34+ cells in cell states and offering a precise framework for manipulating CD34+ cells in regenerative medicine.

Background:Biliary atresia (BA) is a severe neonatal liver disorder that can progress to liver fibrosis and eventual failure. This bibliometric study evaluates global research on BA-related liver fibrosis from 2000 to 2024, highlighting emerging trends and key contributions. Methods:Data were retrieved from the Web of Science Core Collection, focusing on original articles and reviews. Bibliometric tools were employed to assess publication trends, citation impact, and research collaboration. Results:A total of 589 publications were identified from 2000 to 2024. Publication output showed relative stability from 2000 to 2014 (223 publications), followed by a marked increase to 296 publications during 2015-2022, with continued growth in 2023 (39 publications) and 2024 (31 publications) [χ 2(1) = 113.28, p < 0.001 for the 2000-2014 vs. 2015-2022 comparison]. The leading contributors were China, the USA, and Japan. Notable institutions included Chulalongkorn University, Fudan University, and University of Cincinnati. Author analysis identified a small group of prolific researchers with high publication counts and H-indices, such as Yong Poovorawan (40 publications, H-index 12) and Michael Davenport (24 publications, H-index 15), indicating substantial research impact. Core journals in the field included Pediatric Surgery International, Journal of Pediatric Surgery, and Journal of Pediatric Gastroenterology and Nutrition, all of which demonstrated high publication volumes and impact factors. Keyword co-occurrence analysis revealed research clusters around pathogenesis, management, molecular mechanisms, non-invasive biomarkers, and imaging techniques. Co-citation analysis highlighted early diagnosis, surgical outcomes, and pathogenesis as central research themes. Future trends suggest a growing focus on non-invasive diagnostics, molecular mechanisms, and international collaboration, with keywords such as "pathogenesis," "outcome," "elasticity imaging techniques," and "shear wave elastography" showing citation bursts. Conclusion:Research on BA-related liver fibrosis has significantly increased, with key contributions from leading countries, institutions, and authors. Core journals have been instrumental in shaping the research discourse. This study provides valuable insights into current research trends and future directions, emphasizing the importance of interdisciplinary collaboration in advancing the understanding and treatment of BA-related liver fibrosis.

Introduction: CD34 + progenitor cells are widely used for stem cell therapy for cardiovascular diseases, but the effectiveness of the treatment is variable. To understand the fundamental mechanism of CD34 + cell development, we aimed to investigate cell fates of CD34 + progenitors during the embryogenesis of mice and humans. Methods: Human embryos from PCW 6 to 12 were obtained from patients who had undergone induced or spontaneous abortions and samples were subjected to mass spectrometry. For the animal model, embryos were obtained among C57BL/6J, Cd34 -DreER T2 ; IR, CD34 -CreER T2 ; R26-tdTomato, Cdh5 -dre; IR; Cd34 -creER, Cd34 -CreER T2 ; R26-tdTomato; Kdr flox , Cd34 -CreER T2 ; R26-tdTomato; Pdgfra flox mice. Single-cell RNA sequence (scRNA-seq) was performed using the databases generated from our group and publicly data from NCBI Gene Expression (GEO) Omnibus (E6.5 to E18.5 cells). Additionally, whole-mount staining and three-dimensional reconstruction were used to depict different types of CD34 + progenitor distribution within transparent embryos. Results: The proteomics unveiled an assumed intricate orchestration in developing human embryos from patients who experienced induced or spontaneous abortions. Our study demonstrated that the high level of CD34-expressing cells uncovered the potential naïve pluripotency to differentiate during embryonic development. Moreover, deletion of Kdr in CD34-derived cells resulted in stalled vessel development in stages spanning E6.5 to E8.5, which is crucial to endothelium development. Also, the activation of the cell cycle machinery was identified as a driver of endothelial-to-hematopoietic transition (EHT) in Cd34 + Runx1 + Cd44 + cells from E9.5 to E11.5. Until late embryogenesis, CD34 + progenitors gave rise to fibroblasts. Finally, CD34 + cells contribute to the quiescent stem cell pool in the adult stage and enter the cell cycle when the body suffers damage. Conclusions: Our results conducted a comprehensive study on the spatial and temporal induction of CD34 + cells and their intricate functions in embryonic development. These findings enlightened us on paving the way to innovatively tackle the complex hurdles present in stem cell and regenerative medicine, particularly in stem cell therapy.

・Background: Malignant glioblastoma exhibits cellular senescence characterized by changing tumor microenvironment. Solute carrier family 6 member 6 (SLC6A6), a multichannel transmembrane protein, plays a crucial role in regulating cell proliferation, apoptosis, differentiation and cellular microenvironment. However, the molecular mechanism of SLC6A6 in the cellular senescence of glioblastoma remains unknown. Our study aimed to elucidate the regulatory role and molecular mechanisms of SLC6A6 in the proliferation and senescence of glioblastoma cells. ・Methods: Expression of SLC6A6 was examined in tumor samples from 50 patients with glioblastoma, and associations between SLC6A6 expression and survival outcome were evaluated using Kaplan–Meier survival and Cox regression analyses. To investigate the mechanism of SLC6A6, we used short hairpin RNA (shRNA) and overexpression vector to construct SLC6A6-knockdown and -overexpression glioblastoma cells, respectively. The role of SLC6A6 in glioblastoma was confirmed in vitro and in an orthotopic glioblastoma mouse model. ・Results: Patients with high expression of SLC6A6 had a worse prognosis. Downregulation of SLC6A6 protein inhibited malignant phenotypes of glioblastoma cells in vitro. In addition, SLC6A6 affected tumor senescence by directly binding to CSK with its N-terminal cytoplasmic domain, thereby enhancing AKT phosphorylation. Furthermore, SLC6A6 knockdown inhibited tumor growth and shortened survival in the glioblastoma xenograft mouse model. ・Conclusion: SLC6A6 can promote malignant progression and inhibit cellular senescence of glioblastoma cells by affecting the CSK/AKT/FoxO1 signaling pathway. SLC6A6 might be a valuable biomarker in the treatment of glioblastoma.