From Single-Cell Maps to Trial-Ready COPD Endotypes

A recent review surveys how single-cell transcriptomic, metabolomic, and proteomic tools are being used to study COPD progression, alongside calls for cohorts and early-disease biomarkers to support translation into clinical trials. Single-cell and spatial profiling are positioned with microbiome and cohort biomarker observations as inputs for endotype building, moving from cell-state maps to candidate endotypes and then to biomarker-informed trial concepts. The authors also describe translating emerging findings into trial-relevant constructs—what might be thought of as trial-ready COPD endotypes—that connect tissue biology to how studies enroll participants and measure outcomes.

Epithelial regeneration is presented as one of the review’s most specific single-cell themes, focusing on progenitor and transitional programs that may be altered in COPD. The authors highlight terminal and respiratory bronchiolar secretory populations described as terminal and respiratory bronchiolar secretory cells (TRB-SCs), including respiratory airway secretory (RAS) cells and terminal airway–enriched secretory cells (TASCs), as facultative progenitors with markers such as SCGB3A2 and SFTPB and the capacity to generate AT2 cells after injury. They also describe a transitional AT2-to-AT1 differentiation intermediate, framed as a discrete state along alveolar repair trajectories.

Within this narrative, epithelial-state signatures are described as clues to airway and alveolar repair programs (for example, TRB-SCs marked by SCGB3A2 and SFTPB that can differentiate into AT2 cells after injury).

Immune and spatial layers are presented as a parallel set of endotype inputs that add context on where inflammatory and structural processes co-occur. The review synthesizes single-cell studies describing macrophage diversity, including recruited monocyte-derived states linked to chronic inflammatory programs, and it notes reported expansions of cytotoxic CD8+ T cell subsets in COPD lungs. Spatial approaches are summarized as offering niche-level resolution in terminal airways, with immune cell accumulation and localized immune–structural interactions described around small-airway pathology and alveolar attachments. The authors also emphasize integrating scRNA-seq and spatial approaches, including spatial metabolomics, with GWAS and cohort datasets to map susceptibility signals onto specific cell types and microenvironments.

Cohort observations extend the endotype discussion from tissue atlases to more trial-feasible assays, emphasizing soluble or accessible measures discussed in relation to early disease constructs and progression. The authors summarize SPIROMICS findings that elevated sputum MUC5AC (in contrast to MUC5B) is described as a biomarker for pre-COPD, alongside reports that lower circulating club cell secretory protein (CC16) and lower soluble receptor for advanced glycation end products (sRAGE) have been linked to progression and outcomes in COPDGene analyses. Polygenic risk scores are also discussed as identifying individuals more likely to show early airflow limitation even without spirometrically defined COPD. In the authors’ framing, these cohort-level signals can complement cell-type or cell-state markers when assembling composite endotype signatures.

Trial design concepts in the review emphasize COVID-era flexibility, including testing multiple agents and using a mix of surrogate and definitive readouts. The authors provide examples in which inflammation-high endotypes are paired with exacerbation frequency and inflammatory readouts, while emphysema or regenerative-failure endotypes are discussed alongside imaging-based measures or lung-function trajectories; biomarker change is also mentioned as a candidate co-primary or secondary measure. To support operationalization, the review highlights cohort-level harmonization, describing COPD-iNET as a platform to integrate basic, translational, and clinical data for meta-analyses. These elements are presented as part of making biomarker-informed endotypes usable in trials.

Key Takeaways:

• The authors describe altered epithelial progenitor and transitional programs (including TRB-SC/RAS/TASC populations and transitional AT2/AT1 states) as molecular features linked to impaired regeneration in COPD.
• The review summarizes cohort biomarkers and genetics—including sputum MUC5AC, circulating CC16, soluble RAGE, and polygenic risk scores—as measures discussed in relation to pre-COPD, early airflow limitation, or progression.
• The review proposes linking endotype mechanisms to endpoint classes and describes harmonization and staged validation steps (SOPs, reproducibility, multicenter replication, and clinical association/predictive utility) as operational components for trial use.