Cell Adhesion Molecule Research Articles

Background: The goal of tissue regeneration is to restore structure and function. In adult regenerative wound healing, dermal fibroblasts exhibit multipotency and can be reprogrammed into lineages such as hair follicle cells and adipocytes, etc. Neural cell adhesion molecule 1 (NCAM1), a membrane-bound adhesion protein expressed in dermal fibroblasts, plays a key role in cell-cell and cell-matrix interactions and has been implicated in fate transitions during tissue remodeling. NCAM1 is absent in normal endothelium but is aberrantly expressed in tumor-derived endothelial cells, where it promotes capillary morphogenesis. These observations suggest that NCAM1+ fibroblasts may represent a progenitor-like state more capable of endothelial conversion than NCAM1- cells. While angiogenesis is the main vascularization process in adult wounds, vasculogenesis from progenitors like fibroblasts may also contribute. Fibroblast-to-endothelial reprogramming has been demonstrated in vitro using defined reprogramming factors, but its in vivo evidence remains to be investigated. We hypothesized that NCAM1+ dermal fibroblasts give rise to a subset of regenerated endothelial cells. Aims: (1) Characterize vasculature formation during regenerative wound healing (2) Identify progenitor populations and reprogramming cues, including transcription factors and adhesion molecules Method: Using a wound-induced hair neogenesis (WIHN) mouse model, we performed scRNA sequencing and RNA velocity analyses on post-wounding day 14. Wholemount immunostaining assessed vascular morphology and cell identity. NCAM1-CreERT2×ROSA26 reporter mice for lineage tracing. Results: The regenerated wound bed showed two contrasting vasculature patterns: disrupted, discontinuous vessels in the regenerating wound center and organized vasculature in the wound margin. scRNA-seq and velocity analyses indicated PECAM1+ cells may originate from NCAM1+ fibroblast-like cells that also expressed fibroblast-to-endothelial cells reprogramming factors such as FOXO1, TAL1 and SOX17. Wholemount staining revealed individual cells and a fraction of endothelial cells co-expressing PECAM1, PDGFRα, and NCAM1 in the capillary-like vasculature in wound dermis. Conclusion: Our findings support vasculogenesis during regenerative wound healing, with NCAM1+ fibroblasts contributing to endothelial cell populations. These results provide new insights into fibroblast-endothelial plasticity and vascular regeneration in adult tissue regeneration.

Background: Atrial fibrosis induces atrial fibrillation (AF) and increases the risk of stroke. In our previous study, we demonstrated that tumor endothelial marker 1 (TEM1/CD248), a transmembrane protein only expressed in mesenchymal cells during embryonic development, is re-expressed in atrial cardiac fibroblasts (CFs) of AF patients (pts) and TEM1 modulates CF cellular behaviors. We further explored the role of TEM1 in atrial inflammation, a key driver of atrial fibrosis. Methods and Results: Data are presented as mean ± standard error. Left atrial (LA) appendages were collected from 30 AF pts (mean age 64.0±1.6 yrs; 76.7% male) undergoing cardiac surgery. Western blot analysis and real-time quantitative polymerase chain reaction (RT-qPCR) were used to assess expression levels of TEM1 and pro-inflammatory mediators in the LA tissues. Pearson correlation analyses of western blot revealed significantly positive correlations between TEM1 expression with interleukin (IL)-6 (r=0.53), IL-1β (r=0.52), intercellular adhesion molecule 1 (ICAM1) (r=0.54), and vascular cell adhesion molecule 1 (VCAM1) (r=0.69, all p<0.01). Multivariate regression analysis confirmed these associations were independent of age, sex, hypertension, diabetes, and dyslipidemia. RT-qPCR also shows positive correlations of relative TEM1 expression level with IL-1β (r=0.99), tumor necrosis factor (TNF)-α (r=0.99), ICAM1 (r=0.76), VCAM1 (r=0.69) and the macrophage marker CD68 (r=0.68, all p<0.001). Immunohistochemical staining with F4/80 demonstrated increased macrophage infiltration in the LA tissues of AF pts compared to normal control (US Biomax). Osmotic mini-pumps delivering angiotensin II (Ang II, 1000 ng/kg/min for 4 wks) were implanted in mice to induce atrial fibrosis. Ang II significantly increased atrial macrophage infiltration in wild-type (WT) mice (n=3), which was markedly attenuated in TEM1-deficient transgenic mice (n=3) (F4/80-positive/total area [%]: 0.07±0.01 [WT+saline] vs. 1.62±0.19 [WT+Ang II] vs. 0.53 ± 0.03 [TEM1-deficient+Ang II], p<0.001). Sirius Red staining showed significantly reduced atrial fibrosis in TEM1-deficient mice compared to WT mice after Ang II infusion. Conclusions: TEM1 expression in atrial CFs promotes atrial inflammation and contributes to atrial fibrosis.

Receptor activator of nuclear factor kappa B ligand (RANKL) is an essential cytokine that induces osteoclastic differentiation by monocyte-macrophage lineage precursors. Here, we showed that in addition to its conventional action, RANKL controls vascular permeability in the bone marrow, where it facilitates the mobilization of hematopoietic monocytic cells, including osteoclast precursors, and resultantly regulates bone metabolism. RANK, a cognate receptor for RANKL, is abundantly expressed in sinusoidal endothelial cells and controls vascular permeability by regulating the expression patterns of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. High RANKL expression was detected in perivascular C-X-C motif chemokine ligand 12-abundant reticular (CAR) stromal cells. Specific deletion of RANKL expression in CAR cells abrogated the vascular leakage, suggesting that perivascular RANKL is responsible for controlling permeability. In summary, our study revealed a role for RANK/RANKL signaling as a gatekeeper of bone marrow sinusoids in vivo.

ABSTRACT This study explores the development and characterization of iron oxide nanoclusters (NCs) functionalized with vascular cell adhesion molecule 1 (VCAM‐1) for targeted magnetic resonance imaging (MRI) of early atherosclerotic lesions. The NCs were synthesized via a high‐temperature polyol method and functionalized using 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide/N‐hydroxysuccinimide (EDC/NHS) chemistry to enable conjugation with VCAM‐1 antibodies. Dynamic light scattering and transmission electron microscopy TEM confirmed controlled growth of NCs with a size ranging from 40 nm, in the parent to 110 nm post‐functionalization, maintaining though colloidal stability in aqueous media. Cytotoxicity assays using mesenchymal stem cells (MSCs) demonstrated high biocompatibility. Confocal and electron microscopy confirmed specific binding of VCAM‐1‐NCs to VCAM‐1‐overexpressing MSCs under inflammatory conditions, with internalization through the endolysosomal pathway. The functionalized NCs remained bound under shear stress in an orbital flow model, mimicking early atherosclerotic conditions. MRI phantom analysis demonstrated preserved contrast capability despite increased T 2 * relaxation times following antibody conjugation. These findings highlight the potential of VCAM‐1‐NCs as noninvasive imaging agents for early‐stage atherosclerosis and vascular inflammation. Although this study is limited by the lack of in vivo validation and therapeutic evaluation, it provides a strong foundation for future translational research.

Successful cutaneous wound healing requires reepithelialization by keratinocytes using a coordinated migratory process called keratinocyte collective cell migration (KCCM). Environmental stresses such as wounding induce the integrated stress response (ISR) initiated by protein kinases that phosphorylate the α subunit of eIF2 and mitigate translational control to alleviate stress damage. We previously reported that the ISR protein kinase GCN2 (EIF2AK4) facilitates KCCM via sustained phosphorylation of eIF2α and coordinated production of reactive oxygen species and amino acid transport. In this study, we show that a second ISR protein kinase, PERK (EIF2AK3), also contributes to KCCM. PERK promotes KCCM by protein-protein interactions requiring the cytoplasmic portion of PERK but independent of its catalytic functions. To discern these PERK interactions, we used BioID proximity labeling, immunoprecipitation analyses, and immunofluorescence microscopy to show that PERK interacts with multiple cell adhesion and cytoskeletal complexes important for KCCM. PERK engages with the hemidesmosome proteins ITGA6, ITGB4, COLXVII, and the desmosome proteins JUP, DSG2, and DSG3. Loss of PERK disrupts expression and localization of these cell adhesion proteins, which alters keratinocyte morphology and increases cell-substrate and intercellular adhesions. Our results define an underappreciated scaffolding function for PERK involving cell adhesions that are critical for KCCM.

Inflammation markers associated with symptoms and neighborhood deprivation in black adults with heart failure.

Cell adhesion molecule ITGB2 promotes CAR-T cell therapy in B-cell malignancies.

Colorectal cancer (CRC) is a common gastrointestinal tumor with a high incidence worldwide. L1 cell adhesion molecule (L1CAM) is highly expressed in CRC tissues and can promote tumor growth and metastasis. Autophagy regulates oncogenesis and tumor progression through context-dependent mechanisms and is regulated by multiple signaling pathways, including the p38 MAPK signaling pathway. However, the relationship between L1CAM and autophagy is not known yet. In this study, we are trying to dissect the role of L1CAM-autophagy interaction in the development and progression of CRC and its underlying mechanism. Stable L1CAM knockdown was achieved in SW480 and HT29 cells via lentiviral transduction of specific shRNAs. Autophagic flux was detected using western blotting and Tandem mRFP-GFP-LC3 assay. The protein levels were measured via western blotting. Cell proliferation was tested via CCK-8 proliferation assay and Edu staining. Apoptosis was evaluated using flow cytometry. We found that upon L1CAM knockdown, the phosphorylation of p38 was enhanced, and autophagy was weakened. When p38 phosphorylation was inhibited, the inhibitory effect of L1CAM knockdown on autophagy was restored. And L1CAM can promote cell proliferation and inhibit cell apoptosis. Taken together, these findings indicate that L1CAM promotes autophagy by inhibiting the phosphorylation of p38, and that it also promotes cell proliferation and inhibits cell apoptosis in colon cancer cells. L1CAM might be as a new target in CRC therapy.

Hyperglycemia accelerated the metastasis of triple-negative breast cancer via promoting TNFα/Gli-1 axis in endothelial cells.

Structural Interactions of Ankyrin B with NrCAM and β2 Spectrin.

Csk-dependent and independent control of Src family kinases directs neuronal migration in the developing cerebral cortex.

Gene transfection techniques have potential therapeutic value in reducing the inflammatory response in atherosclerosis. Atherosclerosis is a chronic inflammatory disease. Its pathological process involves multiple types of cells and signaling pathways. In recent years, researchers have used gene transfection techniques to introduce specific genes into vascular or immune cells in order to inhibit inflammatory responses, stabilize plaques, and slow down the process of atherosclerosis. Research progress has shown that gene transfection can exert anti-inflammatory effects through various mechanisms. IL-10 transfection suppresses atherosclerosis by activating the STAT3 pathway, reducing TNF-α and IL-6 expression in macrophages. Conversely, eNOS transfection enhances nitric oxide bioavailability, inhibiting endothelial cell adhesion molecule expression (e.g., VCAM-1) and monocyte recruitment. Other studies have regulated the expression of inflammation-related genes by transfecting miRNA (tiny RNA), thus inhibiting the inflammatory response of atherosclerosis. Despite preclinical efficacy, clinical translation is hindered by suboptimal vector tropism (e.g., viral vectors exhibit off-target hepatotoxicity) and immune-mediated clearance of non-viral vectors (e.g., liposomes trigger complement activation). Long-term risks of insertional mutagenesis (retroviral vectors) and epigenetic silencing of transgenes further limit durability. This paper discusses the role and mechanism of gene transfection in reducing the inflammatory response in atherosclerosis.

Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, presents with multiple variants. This study aimed to identify potential biomarkers and therapeutic candidates for PTC through computational analyses and molecular docking. Gene expression data related to PTC were obtained from the TCGA-THCA and GEO datasets (GSE35570 and GSE33630) to identify differentially expressed genes (DEGs). Functional enrichment analysis was performed on the DEGs, followed by construction of a protein-protein interaction (PPI) network. Hub genes were identified using recursive feature elimination (RFE) and LASSO regression analyses. A nomogram incorporating these hub genes was developed, and its diagnostic performance was evaluated using receiver operating characteristic (ROC) curves. Furthermore, the relationship between hub genes and immune cell infiltration was investigated. Potential drug candidates targeting the hub genes were predicted and validated through molecular docking. Common DEGs across the three datasets were enriched in pathways such as ECM-receptor interaction, proteoglycans in cancer, and cell adhesion molecules. Significantly enriched GO terms included 'binding,' 'receptor activity,' 'integral component of membrane,' 'cytoplasm,' 'cell adhesion,' and 'immune response.' A PPI network was constructed by intersecting the common DEGs with PTC-related targets. Machine learning algorithms identified three hub genes: SRY-box transcription factor 4 (SOX4), cyclin D1 (CCND1), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1). These hub genes exhibited differential expression in PTC and were used to construct a reliable diagnostic model. Furthermore, molecular docking revealed stable binding between CCND1 and Tipifarnib, suggesting potential therapeutic relevance. While previous studies have applied bioinformatics and molecular docking in PTC research, this study uniquely integrates both approaches to identify the hub gene CCND1 and its potential targeting drug, Tipifarnib, as promising molecular markers and therapeutic candidates for PTC. The hub gene CCND1 and its targeting drug candidate Tipifarnib may contribute to PTC treatment.

Communication between the vascular endothelium and peripheral leukocytes is an important process controlling inflammatory responses in the brain. Increased plasma levels of CTSD (cathepsin D) have been associated with vascular events, but whether circulating CTSD may affect the functional status of the endothelium remains unknown. To resolve this issue, two groups of transgenic hCTSDhi mice with high levels of circulating CTSD were subjected to traumatic and ischemic injury, respectively. Then, single-cell RNA sequencing was performed to characterize gene expression changes in the brains of hCTSDhi mice. Additionally, transgenic CTSDMono knockout mice with reduced plasma CTSD levels were generated to investigate whether CTSD downregulation confers protection against ischemic injury and traumatic brain injury-induced brain damage. We found the hCTSDhi mice showed increased brain neutrophil infiltration in response to the brain injury. Severe motor deficit and delayed behavioral recovery were observed in hCTSDhi mice after brain traumatic and ischemic injury. Mechanistically, the circulating CTSD was characterized as the nonenzymatic prototype CTSD, pro-CTSD. We further found the circulating nonenzymatic pro-CTSD was able to activate brain endothelium by upregulating VCAM-1 (vascular cell adhesion molecule 1) expression, which is necessary for the transmigration of neutrophils into the brain. Furthermore, genetic reduction of CTSD effectively attenuated the ischemic injury-induced neutrophil infiltration and motor deficits. Taken together, these results demonstrate that circulating prototype CTSD exacerbates the injury-induced brain damage by upregulating brain endothelial VCAM-1 and promoting neutrophil transmigration into the brain.

L1 cell adhesion molecule (L1CAM, CD171) is a transmembrane glycoprotein important for nervous system development. Conversely, L1CAM is overexpressed in many human solid tumors with poor prognosis. Nonclinical safety evaluation and pharmacokinetics (PK) of Ab612, a human anti-L1CAM monoclonal antibody (mAb), were conducted to support a first-in-human (FIH) clinical trial for the treatment of L1CAM overexpressing tumors. A tissue cross-reactivity (TCR) assessment showed that Ab612 exhibited staining in various tissues from mouse, rat, canine, cynomolgus monkey, and human, including those associated with peripheral nerves, myenteric plexus, spinal nerve roots, and certain cell types, such as mononuclear cells (lymphocytes), cardiac Purkinje fibers, and epithelial cell in the lung and kidney. These findings were consistent with the reported expression of the L1CAM by these cell types. Dose range-finding (DRF) studies were conducted in rats and cynomolgus monkeys at doses up to 500 and 400 mg/kg, respectively, by intravenous (IV) administration once weekly for 2 weeks. Results showed no treatment-related adverse findings, and the maximum tolerated dose (MTD) was the highest dose tested. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to MTD, by IV administration once weekly for 4 weeks with a 28-day recovery period. Results showed no treatment-related adverse findings, and the no-observed-adverse-effect-level (NOAEL) was the highest dose tested. Single dose PK studies in rats and cynomolgus monkeys with doses of 5–100 and 5–50 mg/kg, respectively, confirmed the PK in the expected range for mAbs. These preclinical data indicate no safety concerns and provide adequate safety margins for the planned dose levels in the FIH trial.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-025-04142-9.

Clinical trials have shown favorable effects of exercise on frailty, supporting physical activity (PA) as a treatment and prevention strategy. Proteomics studies suggest that PA alters levels of many proteins, some of which may function as molecules in the biological processes underlying frailty. However, these studies have focused on structured exercise programs or cross-sectional PA-protein associations. Therefore, the effects of long-term PA on frailty-associated proteins remain unknown. Among 14,898 middle-aged adults, we emulated a target trial that assigned individuals to either (i) achieve and maintain the recommended PA level (≥ 150min/week of moderate-to-vigorous physical activity [MVPA]) through 6 (± 0.3) years of follow-up or (ii) follow a "natural course" strategy, where all individuals engage in various amounts of habitual MVPA. We estimated the effects of long-term adherence to recommended MVPA versus the natural course strategy on 45 previously identified frailty-associated proteins at the end of the follow-up using inverse probability of weighting (IPW) and iterative conditional expectations (ICE). We found that long-term adherence to recommended MVPA improved the population levels of many frailty-associated proteins (ranged from 0.04 to 0.11 standard deviation); the greatest benefits were seen in proteins involved in the nervous system (e.g., voltage-dependent calcium channel subunit alpha-2/delta-3 [CACNA2D3], contactin-1 [CNTN1], neural cell adhesion molecule 1 [NCAM1], and transmembrane protein 132D [TMEM132D]) and inflammation (e.g., high-temperature requirement serine protease A1 [HTRA1] and C-reactive protein [CRP]). Our findings suggest improved nervous system and reduced inflammation as the biological basis of long-term engagement in adequate PA as an intervention strategy for frailty.

Background Polydatin, a natural component of Polygonum cuspidatum, exhibits potent anti-metabolic properties. The treatment with Poly (10 µm/L) effectively reversed the high glucose (HG)-induced reduction in acetylcholine (ACh)-elicited vasodilation in the aortas of Sprague-Dawley rats. Methods Male Sprague-Dawley rats were used to evaluate the effects of polydatin on endothelial function under HG conditions. Endothelium-dependent relaxation (EDR) was assessed in isolated thoracic aortic rings using ACh, with or without L-NAME or tempol. Human umbilical vein endothelial cells (HUVECs) were also treated under normal glucose (NG), HG, or HG + polydatin conditions. Gene expression (NLRP3, VCAM-1, GAPDH) was measured by RT-PCR, while protein levels of eNOS, iNOS, NLRP3, VCAM-1, and GAPDH were analyzed by western blotting. Results HG significantly impaired ACh-induced EDR in rat aortic rings, while polydatin (10 µmol/L) restored vascular responsiveness. Mechanistically, polydatin upregulated eNOS and suppressed iNOS expression, and its vasoprotective effects were partially inhibited by L-NAME, indicating nitric oxide (NO) pathway involvement. In both aortic tissues and HUVECs, HG markedly increased NLRP3 and VCAM-1 expression, which was effectively reversed by polydatin, indicating its anti-inflammatory action. Conclusion Polydatin counteracts hyperglycemia-induced endothelial dysfunction by enhancing eNOS-dependent NO signaling to restore vasodilatory capacity, while inhibiting NLRP3 inflammasome activation and downstream VCAM-1 expression to attenuate vascular inflammation. These dual mechanisms position polydatin as a therapeutic agent for preserving vascular function in diabeticconditions.

AimsThe plasma protein soluble vascular cell adhesion molecule 1 (sVCAM-1) has been suggested as a biomarker for atrial fibrillation (AF). This study aimed to evaluate sVCAM-1 as a marker of AF and heart failure (HF) risk in the UK Biobank, incorporating genetic risk.Methods and resultsParticipants were included from 2006 to 2010. End of follow-up was 2023. Outcomes were incident AF and HF. Hazard ratios (HRs) per standard deviation increase in sVCAM-1 were assessed using Cox proportional hazard regression models. In sub-analyses, the cohort was stratified by tertiles of polygenic risk score (PRS) of AF and sVCAM-1. Associations between sVCAM-1 and cardiac magnetic resonance imaging measures were assessed in a sub-cohort. Among 48 495 included individuals, 54.6% were women. Median age at enrollment was 58 (50–63) years. During follow-up, 3484 were diagnosed with AF and 1937 with clinically diagnosed HF. Increasing sVCAM-1 levels were associated with rates of AF [HR: 1.72, 95% confidence interval (CI): 1.54–1.91] and HF (HR: 2.04, 95% CI: 1.78–2.34). In the highest sVCAM-1 tertile, 10-year cumulative incidence for AF and HF were 6.44% (95% CI: 6.05–6.82) and 3.01% (95% CI: 2.74–3.29), respectively. Stratified by tertiles of AF PRS and sVCAM-1 levels, a dose–response-like relationship emerged. In the imaging sub-cohort (n = 933), higher sVCAM-1 levels were associated with a reduced LAEF (β: −2.51, 95% CI: −4.33 to −0.70).ConclusionHigher sVCAM-1 levels were associated with AF and HF and lower LAEF. Integration of an AF PRS with sVCAM-1 levels identified a dose–response-like relationship with risk of AF.

The treatment of morphine addiction remains a significant clinical challenge, and the development of novel pharmacotherapies for opioid use disorder (OUD) is imperative. Agmatine, an endogenous neuromodulator, has promising antiaddictive potential, although its precise mechanisms remain incompletely characterized. In this study, a single morphine-induced behavioral sensitization model was established in mice, and immunofluorescence staining, transmission electron microscopy (TEM), RNA sequencing and network pharmacology were used to explore the mechanism of the anti-morphine addiction effects of agmatine. We found that agmatine improved morphine-induced behavioral sensitization without affecting spontaneous activity in mice and improved the changes in synapses in the NAc induced by morphine exposure. Network pharmacological analysis revealed that the key targets associated with agmatine-morphine dependence included TNF-α, IL-6 and IL-1β. Morphine exposure can lead to increased expression of these inflammatory factors, which are closely related with the M1 microglia. Agmatine administration significantly reduced morphine-induced neuroinflammation and activation of microglia. RNA sequencing revealed that the hub genes included TEK receptor tyrosine kinase (TEK), cadherin 5 (CDH5), platelet and endothelial cell adhesion molecule 1 (PECAM1) and so on, which are closely related to endothelial adhesion and angiogenesis. Morphine exposure can downregulate the expression of VE-cadherin, Pecam1, claudin-5, occludin and ZO-1, disrupt the integrity of the BBB and increase its permeability, whereas agmatine can protect the BBB. Agmatine reversed morphine induced BBB leakage and reduced NAc infiltration of peripheral cytokines. This study revealed that agmatine mitigates morphine-induced behavioral sensitization through anti-inflammatory and BBB protection in the NAc and thus provides mechanistic evidence for the development of therapeutic agents for OUD.

ABSTRACTImmune cells in early atherosclerotic lesions promote inflammation and acute coronary syndrome (ACS), but the precise link between inflammation and ACS progression is still unclear. In this study, we analysed mRNA and miRNA expression profiles of ACS from GEO, identifying 98 mRNAs and 627 miRNAs by differentially expressed analysis. GSEA revealed abnormal activation of immune‐ and inflammation‐related pathways, such as T cell receptor signalling pathway and cell adhesion molecules cams. The biomarkers ARG1, HECW2, and PFKFB3 were identified through WGCNA, LASSO, and SVM‐RFE. Diagnostic performance and miRNA–mRNA interaction network were performed using ROC curves and Cytoscape. CIBERSORT analysis revealed that the levels of CD4 memory resting T cells were downregulated, whereas monocytes and neutrophils were upregulated. ARG1, HECW2 and PFKFB3 showed close relationships with specific immune cell types. These findings offer new avenues for ACS treatments and identify ARG1, HECW2 and PFKFB3 as potential biomarkers.