PT  - JOURNAL ARTICLE
AU  - Ahmed A. Raslan
AU  - Tho X. Pham
AU  - Jisu Lee
AU  - Jeongmin Hong
AU  - Jillian Schmottlach
AU  - Kristina Nicolas
AU  - Taha Dinc
AU  - Andreea M. Bujor
AU  - Nunzia Caporarello
AU  - Aude Thiriot
AU  - Ulrich H. von Andrian
AU  - Steven K. Huang
AU  - Roberto F. Nicosia
AU  - Maria Trojanowska
AU  - Xaralabos Varelas
AU  - Giovanni Ligresti
TI  - Single Cell Transcriptomics of Fibrotic Lungs Unveils Aging-associated Alterations in Endothelial and Epithelial Cell Regeneration
AID  - 10.1101/2023.01.17.523179
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.01.17.523179
4099  - http://biorxiv.org/content/early/2023/01/20/2023.01.17.523179.short
4100  - http://biorxiv.org/content/early/2023/01/20/2023.01.17.523179.full
AB  - Lung regeneration deteriorates with aging leading to increased susceptibility to pathologic conditions, including fibrosis. Here, we investigated bleomycin-induced lung injury responses in young and aged mice at single-cell resolution to gain insights into the cellular and molecular contributions of aging to fibrosis. Analysis of 52,542 cells in young (8 weeks) and aged (72 weeks) mice identified 15 cellular clusters, many of which exhibited distinct injury responses that associated with age. We identified Pdgfra+ alveolar fibroblasts as a major source of collagen expression following bleomycin challenge, with those from aged lungs exhibiting a more persistent activation compared to young ones. We also observed age-associated transcriptional abnormalities affecting lung progenitor cells, including ATII pneumocytes and general capillary (gCap) endothelial cells (ECs). Transcriptional analysis combined with lineage tracing identified a sub-population of gCap ECs marked by the expression of Tropomyosin Receptor Kinase B (TrkB) that appeared in bleomycin-injured lungs and accumulated with aging. This newly emerged TrkB+ EC population expressed common gCap EC markers but also exhibited a distinct gene expression signature associated with aberrant YAP/TAZ signaling, mitochondrial dysfunction, and hypoxia. Finally, we defined ACKR1+ venous ECs that exclusively emerged in injured lungs of aged animals and were closely associated with areas of collagen deposition and inflammation. Immunostaining and FACS analysis of human IPF lungs demonstrated that ACKR1+ venous ECs were dominant cells within the fibrotic regions and accumulated in areas of myofibroblast aggregation. Together, these data provide high-resolution insights into the impact of aging on lung cell adaptability to injury responses.Competing Interest StatementThe authors have declared no competing interest.