Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nat Cell Biol. 2020 Oct;22(10):1197-1210. doi: 10.1038/s41556-020-0569-x. Epub 2020 Sep 28.
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.
肺泡上皮细胞再生对于治疗严重肺部疾病至关重要。该过程发生在 II 型肺泡上皮细胞（AT2 细胞）增殖并转分化为 I 型肺泡上皮细胞（AT1 细胞）时。我们利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。AT2 染色质可及性在损伤后发生显著变化，揭示了 STAT3 结合基序，这些基序紧邻调节重要再生途径的基因。单细胞转录组分析鉴定出脑源性神经营养因子（BDNF）是一种 STAT3 靶基因，其在再生 AT2 细胞的独特群体中具有新的可接近染色质。此外，BDNF 受体原肌球蛋白受体激酶 B（TrkB）在间充质肺泡龛细胞（MANCs）上富集。AT2 特异性 Stat3、Bdnf 或间充质特异性 TrkB 的缺失或阻断会损害修复，并减少龛细胞中 Fgf7 的表达。TrkB 激动剂可改善肺损伤后的体内预后。这些数据突出了 STAT3-BDNF-TrkB 轴在协调肺泡上皮细胞再生中的生物学和治疗重要性。
