Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

• Published in: Cell reports (Cambridge) Vol. 42; no. 5; p. 112451
• Main Authors: Cardenas-Diaz, Fabian L., Liberti, Derek C., Leach, John P., Babu, Apoorva, Barasch, Jonathan, Shen, Tian, Diaz-Miranda, Maria A., Zhou, Su, Ying, Yun, Callaway, Danielle A., Morley, Michael P., Morrisey, Edward E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.05.2023; Elsevier
• Subjects: alveolar type 2 cell; Animals; Cell Differentiation; CP: Stem cell research; Gene Expression Regulation; hyperoxia; inflammatory signaling; influenza; Lung - metabolism; lung injury; lung regeneration; Mice; Pulmonary Alveoli; single-cell transcriptomics; Tfcp2l1; Transcription Factors - metabolism; influenza; single-cell transcriptomics; CP: Stem cell research; lung injury; hyperoxia; inflammatory signaling; Tfcp2l1; alveolar type 2 cell; lung regeneration
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112451

Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single-cell transcriptomics, software-guided segmentation of tissue damage, and in vivo mouse lineage tracing, we identified the grainyhead transcription factor cellular promoter 2-like 1 (Tfcp2l1) as a regulator of this regenerative process. Tfcp2l1 loss in adult AT2 cells inhibits self-renewal and enhances AT2-AT1 differentiation during tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute injury phase. Tfcp2l1 temporally regulates AT2 self-renewal and differentiation in alveolar regions undergoing active regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics across the AT2-AT1 differentiation and restricts the inflammatory program in murine AT2 cells. Organoid modeling shows that Tfcp2l1 regulation of interleukin-1 (IL-1) receptor expression controlled these cell fate dynamics. These findings highlight the critical role Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation during alveolar regeneration. [Display omitted] •Tfcp2l1 maintains temporal and spatial AT2 self-renewal during lung regeneration•Tfcp2l1 regulates AT2-AT1 cell differentiation in regional zones of active regeneration•Tfcp2l1 dampens the early response to the inflammatory milieu through control of Il1r1 Cardenas-Diaz et al. use single-cell transcriptomics, software-guided segmentation of tissue damage, and mouse lineage tracing to interrogate the role of Tfcp2l1 in alveolar type 2 cells during lung regeneration. Tfcp2l1 regulates cell fate dynamics across AT2-AT1 differentiation and restricts the inflammatory program in murine AT2 cells.