A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary Disease.
A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary Disease.
复制标题
人类远端气道的独特细胞组织及其在慢性阻塞性肺疾病中的混乱。
DOI：
10.1164/rccm.202207-1384oc
复制
发表时间：
2023
影响因子：
24.7
通讯作者：
Ran
中科院分区：
文献类型：
--
作者：
Rustam,Samir;Hu,Yang;Mahjour,SeyedBabak;Rendeiro,AndreF;Ravichandran,Hiranmayi;Urso,Andreacarola;D'Ovidio,Frank;Martinez,FernandoJ;Altorki,NasserK;Richmond,Bradley;Polosukhin,Vasiliy;Kropski,JonathanA;Blackwell,TimothyS;Ran
原理：远端传导气道（包括终末前和终末细支气管（pre-TB/TB））的重塑和丧失是慢性阻塞性肺疾病（COPD）进行性气流受限的基础。这些结构变化的细胞基础仍然unknown. Objective. To确定COPD中前TB/TB在单细胞分辨率下的生物学变化，并确定其细胞起源.Methods：我们建立了一种新的远端气道解剖方法，并对111，412个分离自12名健康肺供体和5名COPD患者前TB的不同气道区域的细胞进行单细胞转录组学分析。对来自24名健康肺供体和11名COPD受试者的前TB/TB进行成像CyTOF和免疫荧光分析，以在组织水平上表征细胞表型。区域特异性分化的基底细胞分离近端和远端airways.Measurements和主要结果：细胞异质性的图集沿着近端-远端轴的人肺组装和识别区域特异性细胞状态，includingSCGB 3A 2 +SFTPB+终端气道富集分泌细胞（TASC）独特的远端气道。TASC在COPD pre-TB/TB中丢失，这是由于区域特异性内皮毛细血管细胞的丢失、通常在近端气道中富集的CD 8 +T细胞频率增加以及IFN-γ信号传导增强。位于前TB/TB中的基底细胞被鉴定为TASC的细胞来源。IFN-γ抑制了这些祖细胞的TASC再生。结论：改变了前TB/TB的独特细胞组织的维持，包括这些细支气管中区域特异性上皮分化的丧失，代表了COPD远端气道重塑的细胞表现和可能的细胞基础。
Rationale:Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown.Objectives:To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin.Methods:We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air–liquid interface model.Measurements and Main Results:The atlas of cellular heterogeneity along the proximal–distal axis of the human lung was assembled and identified region-specific cellular states, includingSCGB3A2+SFTPB+terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8+T cells normally enriched in proximal airways, and augmented IFN-γ signaling. Basal cells residing in pre-TBs/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-γ.Conclusions:Altered maintenance of the unique cellular organization of pre-TBs/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD.