Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Abbvie Inc, North Chicago, IL, USA.
Nat Commun. 2020 Apr 21;11(1):1920. doi: 10.1038/s41467-020-15647-5.
Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.
产生胶原蛋白的细胞维持着肺部的复杂结构，并导致肺纤维化中的病理性瘢痕形成。在这里，我们进行了单细胞 RNA 测序，以鉴定正常和纤维化肺中的所有产生胶原蛋白的细胞。我们描述了在不同的小鼠肺隔室中具有不同解剖定位的多个胶原蛋白产生亚群。一个亚群，其特征在于 Cthrc1（胶原蛋白三螺旋重复序列包含 1）的表达，在纤维化肺中出现，并表达最高水平的胶原蛋白。对包括特发性肺纤维化和硬皮病患者在内的人类肺部的单细胞 RNA 测序显示出类似的异质性，并且 CTHRC1 表达的成纤维细胞仅存在于纤维化肺中。免疫染色和原位杂交显示这些细胞集中在纤维母细胞灶内。我们纯化了产生胶原蛋白的亚群，并在体外和过继转移实验中发现了 Cthrc1 表达成纤维细胞的疾病相关表型。我们的胶原蛋白产生细胞图谱为研究这些独特群体在稳态和病理性纤维化中的作用提供了路线图。
