Scientists create the first 3D nanoscale maps of human airway epithelium, revealing the hidden architecture of lung defence cells

Figure 1. FIB-SEM 3D reconstruction of the human airway multiciliated epithelium

The study, published in Cell Reports, combines advanced volume electron microscopy with super-resolution light microscopy to reconstruct individual airway cells in three dimensions at nanometre resolution. The work provides an unprecedented view of how the internal structures of human cells are organised as airway cells mature and acquire specialised functions. 

"Our understanding of cells has traditionally relied on looking at thin 2D slices or individual molecular components," said Dr Vito Mennella, Reader in Nanoscale Biology at Queen Mary University of London and senior author of the study. "By reconstructing complete cells in three dimensions, we can now see how the different parts of a cell are arranged and connected, providing a much more complete and time resolved picture of how human tissues are made and function." 

The nanoscale maps have the potential to provide a better understanding of respiratory diseases. Many lung diseases, such as asthma, chronic bronchitis, and chronic obstructive pulmonary disease, involve changes or damage to airway cells. By comparing diseased cells with these healthy reference maps, researchers could pinpoint exactly what changes occur, revealing early warning signs and mechanisms of disease and providing new treatment targets.  

A new way to see human cells 

The airway epithelium, the thin layer of cells that line the inside surface of the respiratory tract, forms the first line of defense against the external environment, continuously protecting the lungs from inhaled particles, pathogens, and pollutants. To perform this role, airway cells undergo a highly organised process of differentiation, developing specialised structures including motile cilia - the microscopic, hair-like structures that extend from the surface of certain cells - which help clear material from the respiratory tract. 

Until now, it has not been possible to follow this process, capturing the complete three-dimensional organisation of the cell and its internal components. The researchers combined large-scale three-dimensional volume electron microscopy with AI based segmentation, super-resolution microscopy, and CRISPR Cas9 KO approaches allowing them to connect information across different biological scales—from entire cells and organelles down to the function of specific molecular structures. 

This multimodal approach revealed unexpected complexity and plasticity in the architecture of airway cells and uncovered previously unrecognised relationships and physical contacts between cellular structures involved in building and maintaining the machinery required for airway defence. 

A publicly available resource for the scientific community 

A key outcome of the study is the creation of an openly accessible digital resource generated in collaboration with the enhanced FIB-SEM imaging shared resource at HHMI Janelia. The resulting nanoscale datasets will be made available to researchers worldwide through the CellMap initiative, supporting broader exploration and reuse by the scientific community. The datasets will also be linked with the LungMAP and the EMBL-EBI Cell Ontology efforts, allowing these nanoscale maps to be integrated with existing molecular and cellular reference resources. 

"These are not simply images—they are detailed digital representations of human cells that can be explored, analysed and reused by scientists around the world," said Dr Mennella. "By making these resources openly available, we hope to accelerate discoveries in lung biology, respiratory disease and the development of new computational approaches for studying human cells." 

Implications for human health 

Understanding how healthy airway cells are assembled provides an essential reference point for investigating diseases where these structures become disrupted, including asthma, chronic obstructive pulmonary disease (COPD), and inherited disorders affecting cilia function. “Our lab is currently involved in a major nanopathology effort aimed at understanding how chronic respiratory diseases change the single cell biology of the airway to identify new therapeutic targets.” said Dr Vito Mennella. 

The study also demonstrates how advances in imaging, computational biology and artificial intelligence are transforming biomedical research. Large-scale cellular maps such as these could provide the foundation for future AI-driven approaches to understand human biology and predict how cells respond to disease or treatment. 

By contributing detailed nanoscale reconstructions of human airway cells, this work represents a step towards a future where researchers can navigate the complexity of human tissues with the same precision that modern maps allow us to explore the world around us. 

Volume Electron Microscopy 

Volume electron microscopy (volume EM) enables scientists to create high-resolution 3D images of cells and tissues at a scale that was previously impossible. It is one of the most promising technologies to watch because it overcomes the limitations of traditional electron microscopy, providing unprecedented insights into diseases such as cancer and enabling ambitious projects like mapping the brain in extraordinary detail. 

Notes:

3D Nanoscale Reconstruction of Human Airway 2 Multiciliogenesis Reveals Cellular Architecture Remodeling and Cilia to Mitochondria Link Through Rootlets published in Cell Reports can be accessed here:   

https://www.sciencedirect.com/science/article/pii/S2211124726007928?via%3Dihub   

DOI: 10.1083/jcb.202602140 

Figure 1. FIB-SEM 3D reconstruction of the human airway multiciliated epithelium 

(A) Workflow for FIB-SEM 3D reconstruction of the human airway epithelium. 

(B) 3D volume segmentation of the human nasal airway epithelium containing early differentiating and differentiated multiciliated cells (MCCs, right), and airway basal stem progenitor cell (left). 

(C) Examples of organelles identification on 2D SEM micrographs using segmentation masks. 

(D) 3D volume segmentations of an early differentiating and MCC apical regions shown in side view. 

(E) Top: high-magnification inset from (D) showing 3D reconstruction of a centriole rosette. Arrowheads indicate rosette with associated vesicle, growing axoneme (Ax), basal bodies (BB), and fibro-granular material (FGM; perimeter in gold highlights electron-dense region). Bottom: corresponding 2D SEM image overlaid with segmentation contours. Empty arrowheads indicate rosette, BB, and FGM. 

(F) Top: high-magnification inset from (D) of MCC volume. Arrowheads indicate fully formed Ax, rootlets (ROOT), BB, and aligned basal feet (BF). Bottom: corresponding 2D EM image overlaid with segmentation contours. Empty arrowheads indicate Ax, BB, mitochondria, and rootlets. rootlet segmentation contours are traced from the basal body proximal region toward the cytoplasmic interior across the full volume. 

(G) Organelle breakdown of the 3D FIB-SEM reconstruction from (B).