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A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung.

ABSTRACT: The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

SUBMITTER: Sountoulidis A

PROVIDER: S-EPMC9928586 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung.

Sountoulidis Alexandros A Marco Salas Sergio S Braun Emelie E Avenel Christophe C Bergenstråhle Joseph J Theelke Jonas J Vicari Marco M Czarnewski Paulo P Liontos Andreas A Abalo Xesus X Andrusivová Žaneta Ž Mirzazadeh Reza R Asp Michaela M Li Xiaofei X Hu Lijuan L Sariyar Sanem S Martinez Casals Anna A Ayoglu Burcu B Firsova Alexandra A Michaëlsson Jakob J Lundberg Emma E Wählby Carolina C Sundström Erik E Linnarsson Sten S Lundeberg Joakim J Nilsson Mats M Samakovlis Christos C

Nature cell biology 20230116 2

The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, ope ...[more]

PMID: 36646791

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Project description:The establishment of neural circuits involves both the precise positioning of cells within brain regions and projection of axons to specific target cells. In the cerebellum (Cb), the medial-lateral (M-L) and anterior-posterior (A-P) position of each Purkinje cell (PC) and the topography of its axon can be defined with respect to two coordinate systems within the Cb; one based on the pattern of lobules and the other on PC gene expression in parasagittal clusters in the embryo (e.g. Pcp2) and stripes in the adult (e.g. ZebrinII). The relationship between the embryonic clusters of molecularly defined PCs and particular adult PC stripes is not clear. Using a mouse genetic inducible fate mapping (GIFM) approach and a Pcp2-CreER-IRES-hAP transgene, we marked three bilateral clusters of PC clusters with myristolated green fluorescent protein (mGfp) on approximately embryonic day (E) 15 and followed their fate into adulthood. We found that these three clusters contributed specifically to ZebrinII-expressing PCs, including nine of the adult stripes. This result suggests that embryonic PCs maintain a particular molecular identity, and that each embryonic cluster can contribute PCs to more than one adult M-L stripe. Each PC projects a primary axon to one of the deep cerebellar nuclei (DCN) or the vestibular nuclei in the brainstem in an organized fashion that relates to the position of the PCs along the M-L axis. We characterized when PC axons from the three M-L clusters acquire topographic projections. Using a combination of GIFM to mark the PC clusters with mGfp and staining for human placental alkaline phosphatase (hAP) in Pcp2-CreER-IRES-hAP transgenic embryos we found that axons from each embryonic PC cluster intermingled with neurons within particular DCN or projected out of the Cb toward the vestibular nuclei by E14.5. These studies show that PC molecular patterning, efferent circuitry, and DCN nucleogenesis occur simultaneously, suggesting a link between these processes.

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A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung.

Publications

A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung.

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