组织特征映射抗纤维化因子在小鼠和人的肺，这一成果由斯坦福大学医学院Michael T. Longaker小组经过不懈努力而取得。2025年3月19日，国际知名学术期刊《自然》发表了这一成果。

无主题肺在博来霉素损伤后遵循纤维形成到消退的固定序列，研究小组推断，分析损伤后的组织学分期可以揭示促纤维化与抗纤维化的特征，对人类纤维化具有功能价值。

在这里，课题组人员量化了与多组数据集成的时空分辨矩阵变换。首先，课题组研究人员绘制了矩阵像差与分辨率的逐步轨迹，这是由一组高维组织纤维特征得出的，这表明了组织结构从均匀到无序的可逆转变。沿着这些轨迹的单细胞测序确定了在各自的损伤后阶段暂时富集的“ecm分泌”（表达csmd1）和“促分解”（表达cd248）成纤维细胞。基于视觉的空间分析进一步表明，成纤维细胞亚型的基质结构和空间转录邻近区存在差异，从而确定了不同的纤维化和非纤维化生物分子环境。关键是，促溶解成纤维细胞的灌注有助于改善体内纤维化。

此外，成纤维细胞邻近相关因子SERPINE2和PI16在体外对人肺纤维化有功能调节。特发性肺纤维化在蛋白水平上的空间表型还揭示了人类疾病中类似的成纤维细胞亚型和邻域。总的来说，这些发现建立了促纤维化因子和抗纤维化因子的图谱，这些因子是肺基质结构的基础，并暗示成纤维细胞相关的生物学特征在调节纤维化进展与消退。

据介绍，纤维化是指健康组织被富含胶原的基质所取代，几乎在所有器官损伤后都会发生。

附：英文原文

Title: Histological signatures map anti-fibrotic factors in mouse and human lungs

Author: Guo, Jason L., Griffin, Michelle, Yoon, Jung-Ki, Lopez, David M., Zhu, Yili, Lu, John M., Mikos, Georgios, Parker, Jennifer B. L., Mascharak, Shamik, Brenac, Camille, Guardino, Nicholas J., Abbas, Darren B., Li, Dayan J., Valencia, Caleb, Liang, Norah E., Januszyk, Michael, Chang, Howard Y., Wan, Derrick C., Desai, Tushar J., Longaker, Michael T.

Issue&Volume: 2025-03-19

Abstract: Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ1,2. Mouse lungs follow a stereotyped sequence of fibrogenesis-to-resolution after bleomycin injury3, and we reasoned that profiling post-injury histological stages could uncover pro-fibrotic versus anti-fibrotic features with functional value for human fibrosis. Here we quantified spatiotemporally resolved matrix transformations for integration with multi-omic data. First, we charted stepwise trajectories of matrix aberration versus resolution, derived from a high-dimensional set of histological fibre features, that denoted a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally enriched ‘ECM-secreting’ (Csmd1-expressing) and ‘pro-resolving’ (Cd248-expressing) fibroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial–transcriptional neighbourhoods by fibroblast subtype, identifying distinct fibrotic versus non-fibrotic biomolecular milieu. Critically, pro-resolving fibroblast instillation helped to ameliorate fibrosis in vivo. Furthermore, the fibroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis at protein level additionally uncovered analogous fibroblast subtypes and neighbourhoods in human disease. Collectively, these findings establish an atlas of pro- and anti-fibrotic factors that underlie lung matrix architecture and implicate fibroblast-associated biological features in modulating fibrotic progression versus resolution.

DOI: 10.1038/s41586-025-08727-3

Source: https://www.nature.com/articles/s41586-025-08727-3