Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal cells.
Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal cells.
复制标题
人肺泡2上皮跨分化分解为化生型KRT5（+）基底细胞。
DOI：
10.1038/s41556-021-00809-4
复制
发表时间：
2022-01
影响因子：
21.3
通讯作者：
Peng T
中科院分区：
文献类型：
--
作者：
Kathiriya JJ;Wang C;Zhou M;Brumwell A;Cassandras M;Le Saux CJ;Cohen M;Alysandratos KD;Wang B;Wolters P;Matthay M;Kotton DN;Chapman HA;Peng T
肺泡2型细胞（AEC 2）的丢失和肺泡中基底细胞的异位出现是严重肺损伤（如特发性肺纤维化（IPF））的特征。在这里，我们证明了人肺泡2型细胞（hAEC 2），不像小鼠AEC 2，转分化成基底细胞在体外和体内肺间充质纤维化信号的反应。类器官共培养物中正常hAEC 2和间充质细胞的单细胞分析揭示了先前在IPF中描述的病理性成纤维细胞和碱性细胞的出现。类器官中的TGFβ1和抗BMP信号传导促进转分化。hAEC 2衍生的类器官和IPF上皮的轨迹和组织学分析表明，hAEC 2通过肺泡-基底中间体（ABI）转分化为基底细胞，这些中间体在病理性CTHRC 1高/TGF β 1高成纤维细胞附近积累。我们的研究表明，在严重的人类肺损伤中，肺泡化生基底细胞的hAEC 2-损失和扩张通过由异常间充质驱动的hAEC 2-基底细胞谱系轨迹因果相关。
Loss of alveolar type 2 cells (AEC2s) and ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signaling in the lung mesenchyme in vitro and in vivo. Single cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basloid cells previously described in IPF. TGFβ1 and anti-BMP signaling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates (ABIs) that accumulate in proximity to pathologic CTHRC1high/TGFB1high fibroblasts. Our study indicates that hAEC2-loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through a hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.
登录
查看更多内容
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
64.5
作者：
Kumar PA;Hu Y;Yamamoto Y;Hoe NB;Wei TS;Mu D;Sun Y;Joo LS;Dagher R;Zielonka EM;Wang de Y;Lim B;Chow VT;Crum CP;Xian W;McKeon F
通讯作者：
McKeon F
影响因子：
82.9
作者：
Liang J;Zhang Y;Xie T;Liu N;Chen H;Geng Y;Kurkciyan A;Mena JM;Stripp BR;Jiang D;Noble PW
通讯作者：
Noble PW
影响因子：
23.9
作者：
Katsura H;Sontake V;Tata A;Kobayashi Y;Edwards CE;Heaton BE;Konkimalla A;Asakura T;Mikami Y;Fritch EJ;Lee PJ;Heaton NS;Boucher RC;Randell SH;Baric RS;Tata PR
通讯作者：
Tata PR
影响因子：
23.9
作者：
Jacob A;Morley M;Hawkins F;McCauley KB;Jean JC;Heins H;Na CL;Weaver TE;Vedaie M;Hurley K;Hinds A;Russo SJ;Kook S;Zacharias W;Ochs M;Traber K;Quinton LJ;Crane A;Davis BR;White FV;Wambach J;Whitsett JA;Cole FS;Morrisey EE;Guttentag SH;Beers MF;Kotton DN
通讯作者：
Kotton DN