鉴于纤维化疾病和癌症的治疗靶点的识别仍面临挑战，本研究旨在研究TGF-β1和TGF-β3对各种类型的成纤维细胞（包括正常/皮肤、癌相关和瘢痕来源的成纤维细胞）的成肌成纤维细胞分化和细胞外基质沉积的影响。通过比较表型和信号通路激活，我们观察到不同成纤维细胞群体中研究标志物的极端异质性，甚至在同一组织中分离的细胞中也存在异质性。具体而言，成肌成纤维细胞的存在和细胞外基质的沉积取决于成纤维细胞的起源和接受的处理类型（TGF-β1 vs. TGF-β3）。同时，我们检测到在所有研究的成纤维细胞中有传统信号通路（pSMAD2/3）的激活，尽管程度不同。TGF-β1和TGF-β3的处理导致传统和多种非传统通路（包括AKT，ERK和ROCK）的激活。在研究的细胞中，癌相关成纤维细胞对TGF-β1/3处理的反应最为异质。总体而言，与TGF-β3相比，TGF-β1表现出更强的信号通路激活，而TGF-β3对瘢痕和肥厚瘢痕来源的成纤维细胞显示出抑制作用，预示着其在瘢痕治疗中的临床潜力。总之，我们的研究对理解TGF-β信号在成纤维细胞生物学、纤维化疾病和癌症中的作用具有重要意义。未来的研究应该集中于揭示成纤维细胞对TGF-β异构体的不同反应背后的机制，考虑到不同成纤维细胞的异质性。©2023. 作者。

Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-β1 and TGF-β3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-β1 vs. TGF-β3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-β1 and TGF-β3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-β1/3 treatments. In general, TGF-β1 demonstrated a more potent activation of signaling pathways compared to TGF-β3, whereas TGF-β3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-β signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-β isomers considering inherent fibroblast heterogeneity.© 2023. The Author(s).