Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states

Terren K. Niethamer; Joseph D. Planer; Michael P. Morley; Apoorva Babu; Gan Zhao; Maria C. Basil; Edward Cantu; David B. Frank; Joshua M. Diamond; Ana N. Nottingham; Shanru Li; Arnav Sharma; Hannah Hallquist; Lillian I. Levin; Su Zhou; Andrew E. Vaughan; Edward E. Morrisey

doi:10.1016/j.stem.2024.12.002

Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states

Terren K. Niethamer
, Joseph D. Planer
, Michael P. Morley
, Apoorva Babu
, Gan Zhao
, Maria C. Basil
, Edward Cantu
, David B. Frank
, Joshua M. Diamond
, Ana N. Nottingham
, Shanru Li
, Arnav Sharma
, Hannah Hallquist
, Lillian I. Levin
, Su Zhou
, Andrew E. Vaughan
, Edward E. Morrisey

Surgery

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Functional regeneration of the lung's gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using single-cell transcriptomics combined with lineage tracing of proliferating progenitors, we examined mouse lung regeneration after influenza injury, demonstrating an asynchronously phased response across different cellular compartments. This longitudinal atlas of injury responses has produced a catalog of transient and persistent transcriptional alterations in cells as they transit across axes of differentiation. These cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares hallmarks with developing lung endothelium and endothelial aberrations found in degenerative human lung diseases. This dataset provides a foundational resource to understand the complexity of cellular and molecular responses to injury and correlations to responses found in human development and disease.

Original language	English
Pages (from-to)	302-321.e6
Journal	Cell Stem Cell
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2024.12.002
State	Published - Feb 6 2025

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Inc.

Funding

The authors thank Dr. E. John Wherry for providing the PR8/G33 mouse-adapted influenza virus strain. We acknowledge and thank the core facilities at Penn and the Center for Cancer Research (CCR) at NCI without whom we could not have completed this work. Flow cytometry data in this manuscript were generated in the Penn Cytomics and Cell Sorting Shared Resource Laboratory at the University of Pennsylvania (RRID: SCR_022376). This core facility is partially supported by the Abramson Cancer Center NCI (grant P30-016520). Confocal microscopy was performed in the Penn Cell and Developmental Biology Microscopy Core (RRID: SCR_022373) and the CCR Optical Microscopy and Analysis Laboratory. We thank the members of the Morrisey and Niethamer labs for their helpful suggestions and discussions over the course of this work. The study was supported by grants R01HL162683, R01HL168803, R01HL132999, R01HL152194, and R01HL164929 to E.E.M.; K99HL164960 to T.K.N.; and R01HL155821 to E.C. This work was also supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, and CCR (to T.K.N.).

Funders	Funder number
National Institutes of Health (NIH)
Council for Chemical Research
Center for Cancer Research
Abramson Cancer Center Translational Centers of Excellence	R01HL162683, R01HL168803, R01HL132999, R01HL155821, R01HL164929, P30-016520, SCR_022373, K99HL164960, R01HL152194
National Childhood Cancer Registry – National Cancer Institute	SCR_022376

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

alveolar
endothelial plasticity
influenza
injury
lineage tracing
lung
pulmonary endothelium
regeneration

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

Access to Document

10.1016/j.stem.2024.12.002

Cite this

Niethamer, T. K., Planer, J. D., Morley, M. P., Babu, A., Zhao, G., Basil, M. C., Cantu, E., Frank, D. B., Diamond, J. M., Nottingham, A. N., Li, S., Sharma, A., Hallquist, H., Levin, L. I., Zhou, S., Vaughan, A. E., & Morrisey, E. E. (2025). Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states. Cell Stem Cell, 32(2), 302-321.e6. https://doi.org/10.1016/j.stem.2024.12.002

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abstract = "Functional regeneration of the lung's gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using single-cell transcriptomics combined with lineage tracing of proliferating progenitors, we examined mouse lung regeneration after influenza injury, demonstrating an asynchronously phased response across different cellular compartments. This longitudinal atlas of injury responses has produced a catalog of transient and persistent transcriptional alterations in cells as they transit across axes of differentiation. These cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares hallmarks with developing lung endothelium and endothelial aberrations found in degenerative human lung diseases. This dataset provides a foundational resource to understand the complexity of cellular and molecular responses to injury and correlations to responses found in human development and disease.",

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Niethamer, TK, Planer, JD, Morley, MP, Babu, A, Zhao, G, Basil, MC, Cantu, E, Frank, DB, Diamond, JM, Nottingham, AN, Li, S, Sharma, A, Hallquist, H, Levin, LI, Zhou, S, Vaughan, AE & Morrisey, EE 2025, 'Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states', Cell Stem Cell, vol. 32, no. 2, pp. 302-321.e6. https://doi.org/10.1016/j.stem.2024.12.002

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AU - Zhao, Gan

AU - Basil, Maria C.

AU - Cantu, Edward

AU - Frank, David B.

AU - Diamond, Joshua M.

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AU - Li, Shanru

AU - Sharma, Arnav

AU - Hallquist, Hannah

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AU - Zhou, Su

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KW - endothelial plasticity

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Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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Cite this