Human distal lung maps and lineage hierarchies reveal a bipotent progenitor.

Abstract

Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.

Department

Description

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Citation

Published Version (Please cite this version)

10.1038/s41586-022-04541-3

Publication Info

Kadur Lakshminarasimha Murthy, Preetish, Vishwaraj Sontake, Aleksandra Tata, Yoshihiko Kobayashi, Lauren Macadlo, Kenichi Okuda, Ansley S Conchola, Satoko Nakano, et al. (2022). Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature, 604(7904). pp. 111–119. 10.1038/s41586-022-04541-3 Retrieved from https://hdl.handle.net/10161/30081.

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Scholars@Duke

Tata

Aleksandra Tata

Assistant Research Professor of Cell Biology
Gregory

Simon Gray Gregory

Professor in Neurosurgery

Dr. Gregory is a tenured Professor and Director of the Brain Tumor Omics Program (BTOP) in the Duke Department of Neurosurgery, the Vice Chair of Research in the Department of Neurology, and Director of the Molecular Genomics Core at the Duke Molecular Physiology Institute. 

As a neurogenomicist, Dr. Gregory applies the experience gained from leading the sequencing of chromosome 1 for the Human Genome Project to elucidating the mechanisms underlying multi-factorial diseases using genetic, genomic, and epigenetic approaches. Dr. Gregory’s primary areas of research involve understanding the molecular processes associated with disease development and progression in brain tumors and Alzheimer’s disease, novel drug induced white matter injury repair in multiple sclerosis, and social and behavioral response to oxytocin treatment animal models of autism. 

He is broadly regarded across Duke as a leader in the development of novel single cell and spatial molecular technologies towards understanding the pathogenic mechanisms of disease development. Dr. Gregory is also the Section Chair of Genomics and Epigenetics at the DMPI and Director of the Duke Center of Autoimmunity and MS in the Department of Neurology.

Tata

Purushothama Rao Tata

Associate Professor of Cell Biology

Lung regeneration
Lung stem cells
Cell plasticity
Organoid models
Lung Fibrosis
Single Cell Biology


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