Steentjes Pia, Krassovka Julia, Suschek Christoph V, Maus Uwe, Oezel Lisa
Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Biomedicines. 2025 Sep 10;13(9):2231. doi: 10.3390/biomedicines13092231.
: Abnormal differentiation of human skin fibroblasts into myofibroblasts contributes to fibrotic skin disorders such as hypertrophic scars, keloids, and Dupuytren's disease. This process is characterized by increased fibroblast proliferation, enhanced differentiation into myofibroblasts, and reduced programmed cell death (apoptosis). We previously demonstrated that blue light irradiation (λ = 453 nm) significantly and dose-dependently inhibits both spontaneous and TGF-β-induced fibroblast differentiation. : Because fibroblast differentiation depends on cellular energy metabolism, we investigated whether the inhibitory effect of blue light is linked to changes in the cells' energy balance. : We found that blue light reduced TGF-β-induced differentiation, as shown by decreased levels of α-SMA and EDA-fibronectin, key markers of myofibroblast formation. This effect was strongly associated with almost complete inhibition of mitochondrial respiration, reduced glycolysis, a lower NAD/NADH ratio, and decreased ATP production. ATP-dependent processes, including endocytosis and lysosomal activity, both essential parameters of fibroblast differentiation, were also strongly suppressed. Importantly, all these changes were fully reversible within 24 h after the last irradiation. : Mechanistically, we propose that blue light triggers photochemical reduction in flavins in proteins of the respiratory chain and possibly the Krebs cycle, which temporarily alters cellular energy metabolism. These findings suggest that non-toxic blue light therapy (80 J/cm) can effectively prevent factor-induced fibroblast differentiation and may serve as a standalone or supportive treatment to reduce fibrotic events such as scarring and keloid formation. Furthermore, our results indicate that targeting cellular energy metabolism, whether physically or pharmacologically, could be a promising strategy to prevent sclerotic skin disorders.
人类皮肤成纤维细胞异常分化为肌成纤维细胞会导致纤维化皮肤疾病，如增生性瘢痕、瘢痕疙瘩和掌腱膜挛缩症。这个过程的特征是成纤维细胞增殖增加、向肌成纤维细胞的分化增强以及程序性细胞死亡（凋亡）减少。我们之前证明蓝光照射（λ = 453 nm）能显著且剂量依赖性地抑制自发和TGF-β诱导的成纤维细胞分化。
因为成纤维细胞分化依赖于细胞能量代谢，我们研究了蓝光的抑制作用是否与细胞能量平衡的变化有关。
我们发现蓝光减少了TGF-β诱导的分化，α-SMA和EDA-纤连蛋白水平降低表明了这一点，α-SMA和EDA-纤连蛋白是肌成纤维细胞形成的关键标志物。这种作用与线粒体呼吸几乎完全被抑制、糖酵解减少、NAD/NADH比值降低以及ATP产生减少密切相关。依赖ATP的过程，包括内吞作用和溶酶体活性，这两者都是成纤维细胞分化的重要参数，也受到强烈抑制。重要的是，所有这些变化在最后一次照射后24小时内完全可逆。
从机制上讲，我们提出蓝光触发呼吸链和可能的三羧酸循环中蛋白质里黄素的光化学还原，这会暂时改变细胞能量代谢。这些发现表明无毒蓝光疗法（80 J/cm）可以有效预防因子诱导的成纤维细胞分化，并且可以作为一种独立或辅助治疗方法来减少诸如瘢痕形成和瘢痕疙瘩形成等纤维化事件。此外，我们的结果表明，无论是通过物理方式还是药物方式靶向细胞能量代谢，都可能是预防硬化性皮肤疾病的一种有前景的策略。
