Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3–BDNF–TrkB axis in orchestrating alveolar epithelial regeneration.

肺泡上皮再生对于从破坏性肺部疾病中恢复至关重要。这个过程发生在 II 型肺泡肺细胞（AT2 细胞）增殖并转分化为 I 型肺泡肺细胞（AT1 细胞）时。我们使用急性肺损伤后染色质可及性和基因表达的全基因组分析来阐明修复机制。损伤后 AT2 染色质可及性发生显着变化，以揭示与调节重要再生途径的基因相邻的 STAT3 结合基序。单细胞转录组分析鉴定出脑源性神经营养因子（Bdnf) 作为一个 STAT3 靶基因，在一个独特的再生 AT2 细胞群中具有新近可获得的染色质。此外，BDNF 受体原肌球蛋白受体激酶 B (TrkB) 在间充质肺泡生态位细胞 (MANCs) 上富集。AT2 特异性Stat3、Bdnf或间充质特异性TrkB的丢失或阻断会损害修复并降低生态位细胞的Fgf7表达。TrkB 激动剂改善了肺损伤后的体内结果。这些数据突出了 STAT3–BDNF–TrkB 轴在协调肺泡上皮再生中的生物学和治疗重要性。