Litewka Jacek J, Jakubowska Monika A, Targosz-Korecka Marta, Wiercigroch Ewelina, Dybas Jakub, Cisak Natalia, Madeja Zbigniew, Ferdek Pawel E
Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Krakow, 30-387, Poland.
Doctoral School of Exact and Biological Sciences, Jagiellonian University, ul. Łojasiewicza 11, Kraków, 30-348, Poland.
Cell Commun Signal. 2025 Aug 4;23(1):363. doi: 10.1186/s12964-025-02354-1.
Pancreatic fibrosis is a key pathological feature of chronic pancreatitis and pancreatic cancer, driven by the persistent activation of pancreatic stellate cells. These cells, normally quiescent, undergo profound phenotypic changes in response to environmental cues, yet the interplay between mechanical forces and metabolic reprogramming during this transition remains poorly understood. As the stromal microenvironment actively communicates with epithelial and vascular compartments, understanding this mechano-metabolic signalling axis is critical for uncovering novel mechanisms of tissue remodelling.
To investigate the biomechanical and biochemical alterations during stellate cell activation, we employed atomic force microscopy and Raman spectroscopy to measure changes in cell stiffness, morphology, and molecular composition. These data were complemented by transcriptomic analyses to evaluate gene expression profiles related to lipid metabolism and autophagy. Quantitative statistical tests, including ANOVA and Kruskal-Wallis tests with appropriate post hoc corrections, were applied.
Activation of human pancreatic stellate cells led to progressive cytoskeletal remodelling, increased cellular stiffness, and a flattened morphology. Raman spectroscopy revealed an expansion of the cytoplasmic area, changes in nucleic acid signal, and significant increases in lipid content, particularly in unsaturated lipids and triacylglycerols. Gene expression analysis demonstrated upregulation of lipid elongation and desaturation pathways, along with enhanced autophagy, suggesting a coordinated metabolic adaptation. These changes support the myofibroblast-like phenotype and may influence intercellular signalling by altering extracellular matrix composition, mechanical tension, and the release of signalling molecules that affect the surrounding microenvironment.
Our findings reveal that pancreatic stellate cell activation involves a tightly coupled shift in mechanical and metabolic states, highlighting an integrated signalling process that may modulate stromal-vascular and stromal-epithelial communication. This mechano-metabolic axis represents a potential therapeutic target in fibrotic and neoplastic pancreatic diseases, where aberrant stromal signalling contributes to disease progression.
胰腺纤维化是慢性胰腺炎和胰腺癌的关键病理特征，由胰腺星状细胞的持续激活驱动。这些细胞通常处于静止状态，会根据环境信号发生深刻的表型变化，但在此转变过程中机械力与代谢重编程之间的相互作用仍知之甚少。由于基质微环境与上皮和血管腔室积极通信，了解这种机械代谢信号轴对于揭示组织重塑的新机制至关重要。
为了研究星状细胞激活过程中的生物力学和生化改变，我们采用原子力显微镜和拉曼光谱来测量细胞硬度、形态和分子组成的变化。这些数据通过转录组分析得到补充，以评估与脂质代谢和自噬相关的基因表达谱。应用了包括方差分析和Kruskal-Wallis检验以及适当的事后校正在内的定量统计测试。
人胰腺星状细胞的激活导致渐进性的细胞骨架重塑、细胞硬度增加和形态变平。拉曼光谱显示细胞质区域扩大、核酸信号变化以及脂质含量显著增加，特别是不饱和脂质和三酰甘油。基因表达分析表明脂质延长和去饱和途径上调，同时自噬增强，提示存在协调的代谢适应。这些变化支持肌成纤维细胞样表型，并可能通过改变细胞外基质组成、机械张力以及影响周围微环境的信号分子释放来影响细胞间信号传导。
我们的研究结果表明，胰腺星状细胞激活涉及机械和代谢状态的紧密耦合转变，突出了一个可能调节基质-血管和基质-上皮通信的整合信号过程。这种机械代谢轴代表了纤维化和肿瘤性胰腺疾病的潜在治疗靶点，其中异常的基质信号传导促进疾病进展。
