Early human lung immune cell development and its role in epithelial cell fate

Barnes, Josephine L.; Yoshida, Masahiro; He, Peng; Worlock, Kaylee B.; Lindeboom, Rik G.H.; Suo, Chenqu; Pett, J. Patrick; Wilbrey-Clark, Anna; Dann, Emma; Mamanova, Lira; Richardson, Laura; Polanski, Krzysztof; Pennycuick, Adam; Allen-Hyttinen, Jessica; Herczeg, Iván T.; Arzili, Romina; Hynds, Robert E.; Teixeira, Vitor H.; Haniffa, Muzlifah; Lim, Kyungtae; Sun, Dawei; Rawlins, Emma L.; Oliver, Amanda J.; Lyons, Paul A.; Marioni, John C.; Ruhrberg, Christiana; Tuong, Zewen Kelvin; Clatworthy, Menna R.; Reading, James L.; Janes, Sam M.; Teichmann, Sarah A.; Meyer, Kerstin B.; Nikolić, Marko Z.

doi:10.1126/sciimmunol.adf9988

Cited by 17 publications

(6 citation statements)

References 82 publications

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“…Our data also revealed that while the fraction of proliferating macrophages decreased during the investigated period, the fraction of proliferating B cells increased and B cells contained the highest fraction of proliferating cells. This aligns with previous reports stating that although B cells are rare, they express proliferation markers 11,35 .…”

Section: Discussionsupporting

confidence: 93%

“…In recent years, single-cell transcriptomics studies have identified close to 60 different cell types in the adult human lung 3,4 . Despite limited availability of human embryonic tissues, recent initiatives like the Human Developmental Cell Atlas (HDCA) 5 , have facilitated single-cell or spatial transcriptomic characterization of over 80 different cell types and states in the developing human lung 6–11 . These studies have shed light on the dynamic processes involved in lung development and have provided important insights into the spatial organization of cells in the early-developing human lung.…”

Section: Introductionmentioning

confidence: 99%

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High-parametric protein maps reveal the spatial organization in early-developing human lung

Sariyar,

Sountoulidis,

Hansen

et al. 2024

Preprint

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The respiratory system, encompassing the lungs, trachea, and vasculature, is essential for terrestrial life. Although recent research has illuminated aspects of lung development, such as cell lineage origins and their molecular drivers, much of our knowledge is still based on animal models, or is deduced from transcriptome analyses. In this study, conducted within the Human Developmental Cell Atlas (HDCA) initiative, we describe the spatiotemporal organization of lung during the first trimester of human gestation in situ and at protein level. We used high-parametric tissue imaging on human lung samples, aged 6 to 13 post-conception weeks, using a 30-plex antibody panel. Our approach yielded over 2 million individual lung cells across five developmental timepoints, with an in-depth analysis of nearly 1 million cells. We present a spatially resolved cell type composition of the developing human lung, with a particular emphasis on their proliferative states, spatial arrangement traits, and their temporal evolution throughout lung development. We also offer new insights into the emerging patterns of immune cells during lung development. To the best of our knowledge, this study is the most extensive protein-level examination of the developing human lung. The generated dataset is a valuable resource for further research into the developmental roots of human respiratory health and disease.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

High-parametric protein maps reveal the spatial organization in early-developing human lung

Sariyar,

Sountoulidis,

Hansen

et al. 2024

Preprint

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“…Recently, a role for IL1b in the development of lung epithelial cells has been described 89 . Our work expands the emerging concept that local immune cell niches are essential for the development of different epithelial organs.…”

Section: Discussionmentioning

confidence: 99%

Development in context: interferon response networks regulate human fetal thymic epithelial cell differentiation

Mohammed

Slepicka

Solomon

et al. 2022

Preprint

Self Cite

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The thymus is the primary lymphoid organ that instructs adaptive T cell immunity and central tolerance. Within the thymus, the thymic epithelium comprises a diverse and highly specialized set of cells that promote T cell maturation, proliferation, and selection of a diverse and self-tolerant T cell receptor repertoire. As such, the function of the thymic epithelium is central to the integrity of the immune system in health and disease and regenerating thymic function holds great therapeutic promise. However, the gene regulatory networks that drive thymic epithelial cell ontogeny and maintenance during human embryonic development remain incompletely understood. Elucidating the complex interplay between cell intrinsic and environmental signals that contribute to thymic morphogenesis is essential to derive thymic epithelial cells from pluripotent stem cells to reconstitute thymic function for therapeutic purposes. To deduce the signals instructing the development and specialization of the human thymic epithelial stroma, we have used a dual single cell transcriptomic approach: A, To dissect lineage bifurcations on the trajectory towards thymic fate, we have compared transcriptional signatures of epithelial cells from human fetal thymus to epithelial cells derived from the other major anterior foregut-derived organs, i.e., bronchus, lung, and esophagus as well as the parathyroid. B, To define the proliferative dynamics that give rise to developmental hierarchies within specialized thymic epithelial compartments, we have compared human thymus samples sequentially during embryonic, fetal, and early postnatal stages of organogenesis. Distinct gene regulatory patterns delineate cortical, and medullary thymic epithelial cells, conducting airway basal cells, respiratory bud-tip progenitor cells and esophageal basal cells. Specifically, the transcription factors SOX2 and TP63, that promote basal epithelial cell fate when co-expressed and drive branching morphogenesis when cycled in a coordinated fashion, show a uniquely divergent TP63highSOX2low expression pattern in the thymic epithelium. In addition, the thymic epithelium shows distinctive interferon and NFkb-driven signature which is not present in other epithelial cells. Within the thymic epithelial compartments, a cycling progenitor pool gives rise to three distinct developmental trajectories. A dichotomy between PI3Kinase and TGFb signaling between cTECs and mTECs was observed. Our studies map gene regulatory signatures during thymic epithelial cell ontogeny with the intent to advance directed differentiation approaches for translational applications.

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“…In humans, SOX2 and SOX9 have been identified as progenitor markers, and their maintenance requires EGF, FGF, and WNT signaling, as well as the inhibition of BMP and TGF-β [ 98 ]. The interaction between epithelium and immune cells was also shown to play an important role in lung development using fetal lung organoids [ 99 ]. In immunohistochemistry of fetal lungs, immune cells were found surrounding lung progenitor cells.…”

Section: Interactions Of Epithelial and Immune Cells In The Lung Barriermentioning

confidence: 99%

Physiological and immunological barriers in the lung

Kageyama,

Ito,

Tanaka

et al. 2024

Semin Immunopathol

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The lungs serve as the primary organ for respiration, facilitating the vital exchange of gases with the bloodstream. Given their perpetual exposure to external particulates and pathogens, they possess intricate protective barriers. Cellular adhesion in the lungs is robustly maintained through tight junctions, adherens junctions, and desmosomes. Furthermore, the pulmonary system features a mucociliary clearance mechanism that synthesizes mucus and transports it to the outside. This mucus is enriched with chemical barriers like antimicrobial proteins and immunoglobulin A (IgA). Additionally, a complex immunological network comprising epithelial cells, neural cells, and immune cells plays a pivotal role in pulmonary defense. A comprehensive understanding of these protective systems offers valuable insights into potential pathologies and their therapeutic interventions.

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Early human lung immune cell development and its role in epithelial cell fate

Cited by 17 publications

References 82 publications

High-parametric protein maps reveal the spatial organization in early-developing human lung

High-parametric protein maps reveal the spatial organization in early-developing human lung

Development in context: interferon response networks regulate human fetal thymic epithelial cell differentiation

Physiological and immunological barriers in the lung

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