Calyeca Jazmin, Hussein Zakarie, Tan Zheng Hong, Liu Lumei, Dharmadhikari Sayali, Shontz Kimberly M, Vetter Tatyana A, Breuer Christopher K, Reynolds Susan D, Chiang Tendy
Department of Otolaryngology and.
Center for Regenerative Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
JCI Insight. 2025 Jan 21;10(5):e186263. doi: 10.1172/jci.insight.186263.
Surgery of the tracheobronchial tree carries high morbidity, with over half of the complications occurring at the anastomosis. Although fibroblasts are crucial in airway wound healing, the underlying cellular and molecular mechanisms in airway reconstruction remain unknown. We hypothesized that airway reconstruction initiates a surgery-induced stress (SIS) response, altering fibroblast communication within airway tissues. Using single-cell RNA-Seq, we analyzed native and reconstructed airways and identified 5 fibroblast subpopulations, each with distinct spatial distributions across anastomotic, submucosal, perichondrial, and paratracheal areas. During homeostasis, adventitial and airway fibroblasts (Adventitial-Fb and Airway-Fb, respectively) maintained tissue structure and created cellular niches by regulating ECM turnover. Under SIS, perichondrial fibroblasts (PC-Fb) exhibited chondroprogenitor-like gene signatures, and immune-recruiting fibroblasts (IR-Fb) facilitated cell infiltration. Cthrc1-activated fibroblasts (Cthrc1+ Fb), mainly derived from Adventitial-Fb, primarily contributed to fibrotic scar formation and collagen production, mediated by TGF-β. Furthermore, repeated SIS created an imbalance in fibroblast states favoring emergence of CTHRC1+ Fb and leading to impaired fibroblasts-basal cell crosstalk. Collectively, these data identify PC, IR, and Cthrc1+ Fb as a signaling hub, with SIS emerging as a mechanism initiating airway remodeling after reconstruction that, if not controlled, may lead to complications such as stenosis or anastomotic breakdown.
气管支气管树手术具有较高的发病率，超过一半的并发症发生在吻合口处。尽管成纤维细胞在气道伤口愈合中至关重要，但气道重建中潜在的细胞和分子机制仍不清楚。我们假设气道重建会引发手术诱导应激（SIS）反应，改变气道组织内成纤维细胞的通讯。使用单细胞RNA测序，我们分析了天然气道和重建气道，确定了5个成纤维细胞亚群，每个亚群在吻合口、粘膜下层、软骨膜和气管旁区域具有不同的空间分布。在体内平衡期间，外膜和成纤维细胞（分别为外膜成纤维细胞和气道成纤维细胞）维持组织结构，并通过调节细胞外基质周转创造细胞龛。在SIS条件下，软骨膜成纤维细胞（PC-Fb）表现出软骨祖细胞样基因特征，免疫招募成纤维细胞（IR-Fb）促进细胞浸润。Cthrc1激活的成纤维细胞（Cthrc1+ Fb）主要来源于外膜成纤维细胞，主要由TGF-β介导，促成纤维化瘢痕形成和胶原蛋白产生。此外，反复的SIS导致成纤维细胞状态失衡，有利于CTHRC1+ Fb的出现，并导致成纤维细胞与基底细胞之间的串扰受损。总体而言，这些数据确定PC、IR和Cthrc1+ Fb为信号枢纽，SIS作为重建后启动气道重塑的一种机制出现，如果不受控制，可能会导致诸如狭窄或吻合口破裂等并发症。
