Latest ArticlesHuman or humanized immune system (HIS) animal models have emerged as indispensable tools for studying human biology and disease in vivo. By engrafting human hematopoietic and hematopoietic stem cells (HSC) into immunodeficient hosts, these models have enabled the development of a functional HIS, allowing the study of immune responses, disease mechanisms, and therapeutic interventions in a physiologically relevant setting. HIS models have broad applications across cancer research, infectious disease, regenerative medicine, and immunotherapy development. This review provides a comprehensive overview of the current landscape of HIS model generation, including HSC-based approaches, host strain selection, and recent advances involving genetically engineered mouse models expressing human cytokines and human leukocyte antigen molecules. We evaluated the strengths and limitations of these models, including issues with incomplete immune reconstitution and species-specific incompatibilities. We also discuss their increasing role in preclinical drug development and explore emerging innovations such as multitissue humanization and genome-editing strategies. As HIS models continue to evolve, they provide strong opportunities to bridge basic research and clinical translation.
Idiopathic membranous nephropathy (IMN) is one of the main causes of adult nephrotic syndrome. A subset of untreated or inadequately treated patients eventually progress to end-stage renal disease (ESRD), posing a significant clinical challenge. Although the discovery of novel podocyte target antigens has deepened our understanding of IMN pathogenesis, the precise molecular mechanisms remain incompletely elucidated, and effective targeted therapies are still lacking. Animal models play an irreplaceable role in uncovering IMN pathogenesis and developing effective therapies. In recent years, with a deeper understanding of IMN, researchers have successfully established various animal models, including Heymann nephritis (HN), cationic bovine serum albumin (C-BSA), Aminopeptidase A (APA), thrombospondin type 1 domain-containing 7A (THSD7A)-related, and phospholipase A2 receptor (PLA2R)-related IMN models. These models have substantially advanced the simulation of pathological human IMN features. Notably, the development of human PLA2R1-related animal models marks a landmark breakthrough in this field, as these models are the first to recapitulate the immunopathological processes driven by a key human autoantigen in experimental animals. However, current animal models have their own limitations and still cannot fully replicate the complex pathological process of human IMN. This review summarizes recent progress in animal IMN models, analyzes their methods, pathological features, strengths, and limitations, and discusses future directions. Future model development should integrate advanced multi-omics and artificial intelligence (AI) to achieve greater accessibility and precision, enabling the construction of multidimensional models encompassing genetics, environment, and immunity, thereby enabling a leap from "disease simulation" to "personalized treatment".
U6 biogenesis 1 (USB1) gene mutations cause poikiloderma with neutropenia (PN), which is clinically characterized by skin hyperpigmentation, nail dysplasia, neutropenia, and an elevated risk of cancer. USB1 functions as an RNA exonuclease involved in RNA maturation and stability regulation, although its precise mechanism of action in the hematopoietic system remains unclear.
We established a myeloid cell-specific USB1 knockout mouse model (USB1fl/fl-Lyz2-cre) using CRISPR/Cas9. Using a combination of research methods, including Western blot, flow cytometry, messenger RNA (mRNA) sequencing, micro-RNA (miRNA) sequencing, and quantitative polymerase chain reaction (qPCR), we investigated the effects of USB1 deficiency on neutrophil development and differentiation, along with the underlying signaling molecular mechanisms.
Experimental results indicated that USB1 deficiency in mouse myeloid cells not only leads to dysregulation of miRNA expression but also interferes with the developmental, differentiation, and maturation processes of neutrophils by affecting key genes, such as IL1a, Selp, and Kilt. This impact can be traced back to the stages of myeloid progenitor cells.
USB1 influences neutrophil maturation and myeloid progenitor cell differentiation by regulating the expression of specific miRNAs and mRNAs. This provides novel in vivo experimental evidence for understanding the pathogenesis of PN in patients.
Ulcerative colitis (UC) is a typical inflammatory bowel disease requiring long-term management. Although fecal calprotectin (FC) is widely employed for assessing disease activity, it is still considered insufficient as a standalone tool. New biomarkers are needed to better predict risk and comprehensively reflect biological pathways. This study aimed to identify potential fecal biomarkers to monitor disease activity in UC.
C57BL/6J mice were exposed to dextran sulfate sodium (DSS) treatment for 7 days. Feces were collected and subjected to proteomic analysis and enzyme-linked immunosorbent assay (ELISA). Mouse colon tissues were subjected to histopathological and immunofluorescence analyses. The correlations between the selected fecal proteins and disease severity were evaluated and compared with FC.
Proteomic analysis revealed increases in fecal complement component 3 (C3) and fibronectin (FN) in the DSS group. Next, we measured fecal C3 and FN levels in mice using ELISA. Significant elevation in C3 and FN levels was observed as early as day 1 after DSS treatment, preceding the increase in FC. Both fecal C3 and FN demonstrated significant correlations with disease activity, with C3 exhibiting a stronger correlation than FC. Using immunofluorescence, we observed distinct C3 and FN expressions in both the colonic tissues and the intestinal lumen.
These findings demonstrate that fecal C3 and FN are promising candidate biomarkers for monitoring UC disease activity, and their utility requires further validation in other colitis models and human cohorts.
Psoriasis is an immune-driven dermatosis marked by keratinocyte hyperproliferation. GS-9620, a TLR7 agonist, previously mitigated EV71-triggered inflammation in mice; here we probe its anti-psoriatic potential and mechanisms.
IMQ-induced psoriasis-like mice were treated with GS-9620 or MTX; severity was tracked by PASI and histology. Skin/spleen cytokines (IL-1β, IL-6, IL-18, HMGB1, TNF-α) were quantified via ELISA; immune subsets were quantified by flow cytometry. Autophagy proteins (ATG5/12/16 L1) and NLRP3 were assessed by IHC/Western blot. In vitro, M5-stimulated primary keratinocytes were treated with GS-9620 ± autophagy modulators, followed by cytokine and protein analyses.
GS-9620 markedly reduced erythema, scaling and epidermal thickness, lowered skin and systemic cytokines, and decreased splenic CD3+/CD4+IL-17A+ cells. It restored ATG5/12/16 L1 expression while suppressing NLRP3 both in lesions and in M5-stimulated keratinocytes, leading to diminished IL-1β, IL-6, IL-18, HMGB1 and TNF-α release.
GS-9620 alleviates psoriasis by enhancing autophagy and dampening NLRP3-mediated inflammation, offering a promising therapeutic avenue.
Rodentibacter pneumotropicus and Rodentibacter heylii are important exclusion pathogens in specific pathogen-free (SPF) laboratory animals. However, routine detection methods such as traditional bacterial culture remain labor-intensive and time-consuming. The loop-mediated isothermal amplification-lateral flow dipstick (LAMP-LFD) assay provides a self-contained format for nucleic acid testing that combines speed, sensitivity, and specificity while minimizing aerosol contamination, making it well-suited for point-of-need applications.
This study aimed to develop a streamlined, on-site detection platform capable of rapidly identifying both pathogens with high analytical accuracy, operational simplicity, and suitability for routine laboratory surveillance.
A LAMP-LFD system was established for the detection of the two pathogens using primers designed against the conserved 16S-23S rRNA ITS region. The assay's specificity, sensitivity, repeatability, and limit of detection (LoD) were evaluated.
The assay achieved detection limits of 1 × 10−4 ng/μL for R. pneumotropicus and 1 × 10−5 ng/μL for R. heylii, demonstrating significantly higher sensitivity than PCR. No cross-reactivity was observed with 15 non-target bacteria. Among 28 infected samples, the method detected 19 positives, compared with 21 by multiplex PCR and 23 by qPCR. In 842 laboratory animal samples, culture-based, qPCR, and LAMP-LFD detected 2, 41, and 37 positive samples, respectively. The LoDs were 102 and 101 CFU/mL in fecal samples and 101 and 100 CFU/mL in throat swab samples for R. pneumotropicus and R. heylii, respectively.
This method provides an approach for monitoring the health status of laboratory mice by enabling the detection of these two target pathogens.
The Nuclear Factor of Activated T Cells (NFAT) family comprises closely related transcription factors. Numerous biological processes including angiogenesis, invasion, migration, proliferation, and cell survival are regulated by the NFAT family. NFATs are overexpressed and have increased transcriptional activity in a variety of human solid tumors and hematological cancers. Beyond tumor cell-intrinsic roles, NFAT has also emerged as an important regulator of the tumor microenvironment (TME), where it can influence immune cell behavior and contribute to mechanisms of immune evasion. The discovery of the multifaceted functions of NFATs has driven the need to further unveil their role in cancer and provide new insights into other potential roles. This review provides a comprehensive narrative synthesis of current molecular and clinical studies, with particular emphasis on how NFAT shapes tumor immune interactions and modulates the TME. By integrating findings across different cancer types, we highlight how NFAT may contribute to both tumor progression and immune regulation. The review concludes by highlighting significant knowledge gaps and recommending future paths for translational and therapeutic research to leverage NFAT signaling as a potential target in precision cancer therapy.
Given the need to translate basic research into human therapies, the development and refinement of clinically relevant animal models for bronchiectasis are critically important. To date, there are no well-established animal models for bronchiectasis. Thus, our aim was to develop a novel animal model that accurately recapitulates bronchiectasis-like pathologies.
To address this question, clinical strains of chronic Pseudomonas aeruginosa (CPA) were embedded in agar beads in vitro; then CPA-loaded agar beads and papain were repeatedly instilled intratracheally in female C57BL/6 J mice. Experimental assessments included micro-computed tomography (micro-CT) imaging, histological analysis, immune cell infiltration, cytokines, and lung function parameter measurements to evaluate structural damage, immune responses, and lung function impairments in the mouse model.
In this mouse model, we observed that lung micro-CT imaging revealed significant bronchiectasis, with visible airways in the periphery, cylindrical airway expansion, and an airway-to-artery ratio > 1. Histopathology highlighted immune cell infiltration around the trachea, including lymphocytes, neutrophils, and monocytes, along with Periodic acid-Schiff staining-positive hypermucinous secretion. Compared to controls, the bronchiectasis group exhibited elevated pro-inflammatory cytokines in bronchoalveolar lavage fluid and worse lung function.
Our study presented a novel mouse model that better replicated the bronchiectasis-like phenotype than the CPA airway infection model, showing the advantages of the "CPA-loaded agar beads and papain"-driven approach in optimizing the disease models. The model mimicked the progression of bronchiectasis closely and could be used for studies on disease pathogenesis as well as the evaluation of novel therapies in the near future.
Calpainopathy is a rare genetic myopathy without causal treatment available. Recent advances have produced promising treatment strategies, including genetic treatment and immunomodulation, that are currently being tested pre-clinically in murine models. Traditional behavioral assays frequently fail to detect early motor deficits in corresponding mouse models. Thus, this study investigated whether more sophisticated measures, such as quantitative magnetic resonance imaging (qMRI) and automated motor assessments can reveal early pathological changes in a mouse model of calpainopathy, particularly in the subclinical stages. In this study, Calpain 3-deficient mice (Capn3-deficient) and wild-type controls underwent a standardized qMRI protocol on a 7T scanner at 5 and 15 months of age. Fat fraction (FF), water T2 relaxation time (wT2), and diffusion metrics were analyzed across selected hindlimb muscles. Additionally, voluntary motor activity was monitored using an intelligent phenotyping housing system. Motor activity assays revealed minimal and inconsistent genotype effects. Sex significantly affected qMRI measures, altering fat distribution and wT2 at 5 and 15 months. At 5 months, no significant differences were detected between genotypes. At 15 months, Capn3-deficient mice exhibited elevated wT2 in the soleus and gastrocnemius muscles, correlating with endomysial immune cell infiltration. Diffusion parameters and FF remained unchanged. Taken together, the results show that muscle qMRI, particularly T2 mapping, can sensitively detect subclinical muscle changes in aging Capn3-deficient mice, pointing towards inflammatory processes. Pronounced sex differences and measurement variability underscore the need for larger, sex-balanced cohorts. Extending follow-up beyond 15 months will likely increase sensitivity for later-stage pathology.
Oxidative stress plays a pivotal role in the pathogenesis of heart failure and is closely linked to myocardial remodeling, which includes myocardial hypertrophy and fibrosis. Chrysin (CHR) has multiple medicinal effects such as antioxidant, anti-inflammatory, and anti-apoptosis. This research seeks to investigate whether CHR can protect against pressure overload-induced myocardial remodeling and to explore the underlying mechanism.
Transverse aortic constriction (TAC) surgery was conducted to establish a model of cardiac hypertrophy on male C57BL/6J mice. A model of cardiomyocyte hypertrophy in H9C2 cells induced by angiotensin II (Ang II) was also established.
The results showed that CHR significantly improved survival and cardiac function, reduced myocardial hypertrophy and fibrosis, inhibited the expression of inflammatory mediators TNF-α and IL-1β, suppressed cell apoptosis rate, downregulated the levels of Bcl-2 Associated X protein (BAX) and Cleaved-Caspase-3, and upregulated B-cell lymphoma/leukemia 2 (BCL-2) expression in TAC surgical mice or AngⅡ-treated H9C2 cells. CHR could also upregulate the levels of antioxidant enzymes SOD1 and HO-1 by mediating the nuclear translocation and expression of NRF2 to counteract oxidative stress response. The further mechanism investigation utilizing bioinformatics analysis and western blot revealed that the disease of heart failure is associated with the phosphatidylinositol-3-kinase (PI3K)/serine/threonine-protein kinase B (AKT) signaling pathway.
Collectively, our findings demonstrated that CHR might exert the improvement effects on pressure overload-induced myocardial remodeling with hypertrophy and fibrosis through regulating the PI3K/AKT/NRF2 pathway-mediated oxidative stress response to alleviate myocardial cell inflammation and apoptosis, suggesting that CHR may be a promising therapeutic agent for cardiac diseases induced by pressure overload.
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