Orchestrated response from heterogenous fibroblast subsets contributes to repair from surgery-induced stress after airway reconstruction

• DOI: 10.1172/jci.insight.186263
• Publication Date: 2025-01-21T17:00:35Z
• Authors: Jazmin Calyeca; Zakarie Hussein; Zheng Hong Tan; Lumei Liu; Sayali Dharmadhikari; Kimberly M. Shontz; Tatyana A. Vetter; Christopher K. Br...; Susan D. Reynolds; Tendy Chiang

Surgery of the tracheobronchial tree carries high morbidity, with over half complications occurring at anastomosis. Although fibroblasts are crucial in airway wound healing, underlying cellular and molecular mechanisms reconstruction remain unknown. We hypothesized that initiates a surgery-induced stress (SIS) response, altering fibroblast communication within tissues. Using single-cell RNAseq, we analyzed native reconstructed airways identified five subpopulations, each distinct spatial distributions across anastomotic, submucosal, perichondrial, paratracheal areas. During homeostasis, Adventitial Airway (Adventitial Fb Fb, respectively) maintained tissue structure created niches by regulating ECM turnover. Under SIS, Perichondrial (PC-Fb) exhibited chondroprogenitor-like gene signatures, Immune-recruiting (IR-Fb) facilitated cell infiltration. Cthrc1 activated (Cthrc1+ Fb), mainly derived from primarily contributed to fibrotic scar formation collagen production, mediated TGFβ. Furthermore, repeated SIS an imbalance states favoring emergence CTHRC1+ leading impaired fibroblasts-basal crosstalk. Collectively, these data identify PC, IR, Cthrc1+ as signaling hub, emerging mechanism initiating remodeling after that, if not controlled, may lead such stenosis or anastomotic breakdown.