TENASCIN-Dependent Mesenchymal-Epithelial Interactions Associated with Interstitial Microenvironment Remodeling in Cattle-Yak Lung: Insights from Single-Nucleus Transcriptomics.

Cattle-yak, a hybrid of cattle and yak, exhibits improved milk yield, accelerated growth, and strong physiological adaptation to high-altitude environments, conferring substantial commercial value. However, the transcriptomic basis of hypoxia adaptation in cattle-yak remains poorly characterized at the single-nucleus level. More than 20,000 cells were profiled, and subpopulations representing the major lung cell types in yak and cattle-yak were identified. A higher proportion of mesenchymal cells were observed in cattle-yak compared with yak. Tnc ligands expressed by alveolar fibroblasts, alveolar lipofibroblasts, and ductal myofibroblasts interact with the epithelial Itgav + Itgb6 and Itgav + Itgb3 receptors through the TENASCIN signaling pathway, thereby potentially contributing to lung morphogenesis in cattle-yak. These findings suggest that cattle-yaks have an enhanced capacity for lung interstitial remodeling, which may underlie their hybrid advantage in adapting to high-altitude hypoxia while maintaining growth and production performance. In addition, genes associated with lung mesenchymal cell remodeling and differences in lung tissue were identified. This study first delineated the molecular characteristics of lung cell types in cattle-yak and addressed the gap in comparative single-nucleus analyses between yak and cattle-yak lung tissues. Collectively, these results advance the understanding of high-altitude adaptation in highland cattle breeds and provide valuable insights into animal husbandry in such environments.