The dynamically evolving cell states and ecosystem from benign nevi to melanomaLi, Zhang, Zhao
et alClin Cancer Res (2025)
Abstract: Approximately 30% of non-chronically sun-damaged melanomas originate from nevi, yet the dynamic changes and crucial mechanisms driving the transition from benign nevi to melanoma remain elusive.Here, we performed single-cell transcriptome sequencing on multiple paired tissue sites from 5 patients diagnosed with melanoma arising in congenital melanocytic nevi (CMN), identifying four distinct states of melanocyte subpopulations during the progression from nevi to melanoma, characterized by dynamic changes in their functions and regulatory pathways.In the nevi state, interferon regulatory factor 1 (IRF1) was specifically upregulated in melanocytes, fibroblasts, and endothelial cells (ECs), potentially activating immune surveillance in the microenvironment. Conversely, the critical inhibitory checkpoint HLA-E for NK cells exhibited high expression in a cluster of malignant melanocytes and fibroblasts enriched in melanoma. This interaction with ligands expressed in NK cells could potentially serve as a key factor leading to immune evasion. In malignant melanoma samples, we detected high expression of Midkine (MDK) in melanocytes. It is a pivotal factor that facilitates melanoma invasion and malignant transformation, potentially through interaction with ECs to stimulate angiogenesis. The targets identified in our study are crucial factors in detecting the malignant transformation of nevi. Ultimately, we developed a malignant progression model capable of predicting patient prognosis and malignant progression status using bulk RNA sequencing (RNA-seq) data.Our study provides a high-resolution atlas of the malignant transformation of melanoma from nevi and highlights potential targets for further investigation.
Midkine, a novel MCP-1 activator mediated PM2.5-aggravated experimental pulmonary fibrosisCheng, He, Jia
et alEnviron Int (2025) 197, 109354
Abstract: Exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality among patients with idiopathic pulmonary fibrosis (IPF). Pathological alterations in IPF typically originate in the subpleural regions of the lungs. However, it was unclear how PM2.5 affected subpleural pulmonary fibrosis. In this study, atmospheric PM2.5 and carbon blacks were utilized as representative particulate matter to investigate these effects. Mouse models and cell models were made to investigate macrophage chemotaxis changes under PM2.5 exposure in vivo and in vitro. The findings indicated that PM2.5 promoted macrophage aggregation in the subpleural region of lung and aggravated bleomycin-induced pulmonary fibrosis in mice. At the same time, we uncovered for the first time that PM2.5 exposure led to an upregulation of midkine, which subsequently enhanced the production of monocyte chemotactic protein-1 (MCP-1) through the cell surface receptor Syndecan 4 (SDC4) in pleural mesothelial cells (PMCs), thereby, inducing macrophage aggregation in subpleural region of lung. Furthermore, our results indicated that PM2.5 and bleomycin facilitated macrophage M1 polarization and the production of profibrotic inflammatory factors, culminating in fibrotic alterations in PMCs, lung fibroblasts, and alveolar epithelial cells. Finally, we demonstrated that inhibition of midkine ameliorated lung function and mitigated pulmonary fibrosis in vivo. In conclusion, our findings elucidated that midkine acted as a novel MCP-1 activator, mediating PM2.5-aggravated experimental pulmonary fibrosis, and suggested that the midkine/SDC4/MCP-1 signal should be a new therapeutic target for the treatment of PM2.5-related IPF.Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Midkine Serum Levels in Inflammatory and Non-Inflammatory Dilated CardiomyopathyGrabmaier, Ferraro, Lehnert
et alBiomedicines (2025) 13 (2)
Abstract: Objectives: This retrospective study examines midkine, an inflammatory cytokine, as a potential serological biomarker to distinguish dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Identifying such a biomarker is crucial for effective treatment of these two entities. Methods: The study included 54 patients with heart failure, reduced left ventricular systolic function, and suspected cardiac inflammation. Endomyocardial biopsies were obtained from all 54 patients to differentiate between DCM and DCMi. Blood sera were collected from these patients the same day the endomyocardial biopsy was performed and compared with those of 13 age-matched healthy individuals for different measurements such as midkine and NT-proBNP. Patients were followed up to a median of 194 days after the baseline visit. Results: Endomyocardial biopsies from patients with DCMi were associated with more infiltrating immune cells such as CD68+ macrophages and CD3+ T cells and a more frequent presence of a viral genome than those from patients with DCM. Both groups showed similar improvements in LV function and dimensions over time. MK serum levels were significantly higher in DCM/ DCMi patients than in healthy individuals but did not differ significantly between DCM and DCMi. MK levels did not significantly correlate with NYHA class, NT-proBNP, LVEDD, or LVEF, except for a weak correlation with LVEF at follow-up. Conclusions: Midkine serum levels were significantly higher in patients with a DCM phenotype and severely reduced systolic function. However, these levels could not distinguish between DCM and DCMi and showed no correlation with baseline or follow-up parameters. Therefore, midkine cannot be used as a biomarker to distinguish between DCM and DCMi.
Midkine-a interacts with Ptprz1b to regulate neural plate convergence and midline formation in the developing zebrafish hindbrainLe, Rajasekhar, Loo
et alDev Biol (2025) 521, 52-74
Abstract: A midline in the developing central nervous system allows symmetric distribution of neural progenitors that later establish functional, bilaterally symmetric neural circuits. In the zebrafish hindbrain, a midline forms early during neurulation as a result of coordinated cell convergence and midline-crossing cell divisions (C-divisions). These processes are controlled by the Wnt/planar cell polarity (PCP) pathway that positions progenitors close to a presumptive midline to perform C-divisions. Other upstream cues that control the extent of neural plate convergence, however, remain unclear. Midkine (Mdk) and pleiotrophin (Ptn) are structurally related heparin-binding growth factors that are dynamically expressed in the developing hindbrain. We show that two zebrafish Mdks, Mdka and Mdkb, as well as Ptn interact with distinct affinities in vivo with the protein tyrosine phosphatase receptor Ptprz1b. Zebrafish mdka and ptprz1b mutants exhibit impaired neural plate convergence along with misplaced C-divisions, defective cell polarity and transiently duplicated midlines. These defects are absent in mdka; mdkb double mutants suggesting antagonistic roles of Mdka and Mdkb to coordinate convergence and C-divisions. Overexpression of Drosophila Prickle, a key component of the Wnt/PCP pathway, rescued the midline duplications in mdka and ptprz1b mutants that exhibited significantly reduced levels of prickle pk1b, pk2a, and pk2b expression. Ptprz1b overexpression, on the other hand, up-regulated pk2a transcription. Our findings therefore suggest roles for Mdka, Mdkb and Ptprz1b in coordinating neural plate convergence, neural progenitor positioning and midline formation by controlling the levels of prickle expression.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
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