Zooming In on COPD: A Single-Cell Atlas of the Diseased Lung

People diagnosed with chronic obstructive pulmonary disease (COPD) often experience markedly different symptoms, disease trajectories, and responses to treatment. To better understand this variability, a new study from researchers at Yale School of Medicine (YSM), published in Nature Genetics, used single-cell sequencing technology alongside complementary spatial transcriptomic and proteomic analyses to examine lung tissue from people with COPD in unprecedented detail.

The study offers a new way to understand the long-recognized heterogeneity of COPD, reframing it not as a single disorder with variable severity, but as an evolving cellular ecosystem shaped by coordinated interactions among distinct cell states, says the study’s senior author, Maor Sauler, MD, associate professor adjunct in the Section of Pulmonary, Critical Care and Sleep Medicine at YSM.

Importantly, these microenvironments varied in their abundance across patients and were linked to differences in disease severity and symptom burden, helping explain why COPD can look so different from one person to the next.

It is the largest study of COPD, involving 141 individuals and 1.5 million cells, according to Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine and section chief of Yale-PCCSM, one of the study's authors.

“As one of the investigators who helped create the NHLBI-funded Lung Tissue Resource Consortium, I find it remarkable that tissue collected more than 15 years ago has yielded such transformative insights,” Kaminski says.

Kaminski adds that as Yale-PCCSM section chief and one of Sauler’s mentors, he had the privilege of watching Sauler begin his research training through Yale-PCCSM’s NIH-funded T32 program and grow into a “superb” independent investigator who secured his own federal funding for this project.

“Both are powerful examples of the value NIH investment brings to our society and to our patients—because these discoveries will ultimately impact patient care,” Kaminski says.

The researchers say the study’s scale was key to revealing these cellular patterns. “What sets this study apart is the use of a large, well-phenotyped human cohort across disease stages combined with integrated multi-omic analyses,” says Yuening Zhang, PhD, a postdoctoral associate in Sauler’s lab. “Collectively, this provides us with an unprecedented resolution of the diseased lung, enabling us to discover new disease microenvironments and therapeutic targets.”

Zhang served as co–first author of the study alongside YSM researchers Huanhuan Wei, PhD, and Jessica Nouws, PhD. The study was a collaborative effort, involving many others from YSM and across multiple institutions, who worked together on data generation, analysis, and interpretation.

Sauler hopes the team’s findings could ultimately help guide more targeted treatments for patients.

“Right now, our understanding of COPD subtypes is largely based on imaging or symptoms,” he says. “Here, we’re seeing clear evidence of distinct underlying biologies. Stratifying patients based on these differences could allow for more precise treatment, where one patient responds to one therapy and another to something else.”

Sauler also hopes the study encourages a broader shift in how COPD is viewed.

“COPD is often unfairly framed as a disease people brought on themselves,” he says. “In reality, there’s a substantial genetic component, and many environmental exposures, not just smoking, contribute to risk. Even as smoking rates decline, COPD continues to rise, underscoring the need to treat it as the complex, biologically driven disease it is.”

Pulmonary, Critical Care and Sleep Medicine is one of 10 sections in the Yale Department of Internal Medicine. To learn more about Yale-PCCSM, visit PCCSM's website, or follow them on Facebook and X/Twitter.