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.
Highlights d Knockdown of mitochondrial ETC subunit COX7a cooperates with Notch signaling d Mitochondrial ETC knockdown induces a transcriptional response through ATF4 d The ATF4 adaptation induces a Warburg-like phenotype and cellular pH changes d These changes fuel Notch driven proliferation toward an oncogenic phenotype
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 first comprehensive topographic atlas of early human lung development. We report 83 cell states, several spatially-resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated scRNA-Seq and spatial transcriptomics into a web-based, open platform for interactive exploration. To illustrate the utility of our approach we show distinct states of secretory and neuroendocrine cells, largely overlapping with the programs activated either during lung fibrosis or small cell lung cancer progression. We define the origin of uncharacterized 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.
1 Vertebrate organs are arranged in a stereotypic, species-specific position along the animal body 2 plan. Substantial morphological variation exists between related species, especially so in the vastly 3 diversified teleost clade. It is still unclear how tissues, organs and systems can accommodate such 4 diverse scaffolds. Here, we use the sequential formation of neuromasts in the posterior lateral line 5 (pLL) system of medaka fish to address tissue-interactions defining a pattern. We show that the 6 pLL pattern is established independently of its neuronal wiring, and demonstrate that the neuromast 7 precursors that constitute the pLL behave as autonomous units during pattern construction. We 8 uncover the necessity of epithelial integrity for correct pLL patterning by disrupting keratin 15 (krt15) 9 and creating epithelial lesions that lead to novel neuromast positioning. By using krt15/wt chimeras, 10 we determined that the new pLL pattern depends exclusively on the mutant epithelium, which 11 instructs wt neuromast to locate ectopically. Inducing epithelial lesions by 2-photon laser ablation 12 during pLL morphogenesis phenocopies krt15 genetic mutants and reveals that epithelial integrity 13 defines the final position of the embryonic pLL neuromasts. Our results show that a fine-balance 14 between primordium intrinsic properties and instructive interactions with the surrounding tissues is 15 necessary to achieve proper organ morphogenesis and patterning. We speculate that this logic 16 likely facilitates the accommodation of sensory modules to changing and diverse body plans.
The mitochondrial electron transport chain (ETC) enables many important metabolic reactions, like ATP generation and redox balance. While the vital importance of mitochondrial function is obvious, the cellular response to defects in mitochondria and in particular the modulation of signalling pathway outputs is not understood. Using the Drosophila eye as model, we show that the combination of Notch signalling and a mild attenuation of the ETC via knock-down of COX7a causes massive cellular overproliferation. The tumour like growth is caused by a transcriptional response through the eIF2α-kinase PERK and ATF4, a stress-induced transcription factor, which activates the expression of many metabolic enzymes, nutrient transporters and mitochondrial chaperones. We find this stress adaptation to be beneficial for progenitor cell fitness upon ETC attenuation. Activation of the ATF4 mediated stress response renders cells sensitive to proliferation induced by the growth-promoting Notch or Ras signalling pathways, leading to severe tissue over-growth. In sum, our results suggest ETC function is monitored by the PERK-ATF4 pathway, a cellular adaptation hijacked by growth-promoting signalling pathways in situations of oncogenic pathway activity.
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