Lung mesenchymal cell diversity rapidly increases at birth and is profoundly altered by hyperoxia

Zanini, Fabio; Che, Xibing; Suresh, N.; Knutsen, Carsten; Klavina, Paula A.; Xie, Yike; Domingo-Gonzales, R.; Jones, Robert C.; Quake, Stephen R.; Alvira, Cristina M.; Cornfield, David N.

doi:10.1101/2021.05.19.444776

Cited by 5 publications

(2 citation statements)

References 98 publications

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“…All Lin – fibroblasts were gated for PDGFRA + and Ki-67 (proliferation) ( Supplemental Figure 2B ). Total Lin – fibroblasts were significantly reduced in hyperoxia at PN7 ( Supplemental Figure 2C ), replicating observations that the development of the mesenchyme is impaired in BPD ( 1 , 45 , 49 ). Lin – fibroblasts can be divided into PDGFRA– and PDGFRA + fibroblasts, which we hypothesized would have a different proliferative and activation response to hyperoxia ( 16 , 17 ).…”

Section: Resultssupporting

confidence: 80%

Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation

Riccetti¹,

Ushakumary²,

Waltamath³

et al. 2022

JCI Insight

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Infants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha–positive (PDGFRA + ) fibroblasts are critical for alveolarization and that PDGFRA + fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal population–targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O 2 postnatal days 0–7, PN0–PN7) and performed studies on sorted PDGFRA + cells during injury and room air recovery. After hyperoxia injury, PDGFRA + matrix and myofibroblasts decreased and PDGFRA + lipofibroblasts increased by transcriptional signature and population size. PDGFRA + matrix and myofibroblasts recovered during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA + sorted fibroblasts had reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA + fibroblasts from hyperoxia in mice exhibited reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA + matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia-exposed fibroblasts, WNT activation by CHIR increased the size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation.

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Section: Resultssupporting

confidence: 80%

Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation

Riccetti¹,

Ushakumary²,

Waltamath³

et al. 2022

JCI Insight

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“…In addition, we assessed scPSD performance on three in-house, well-characterized single cell transcriptomics datasets ( Supplementary Table S2 ) where scRNA-seq combined with fluorescent multiplexed in situ hybridization and flow cytometry were used to characterize changes in composition of immune cells ( 48 ) (5,234 cells and 16 cell subtypes), mesenchymal cells ( 49 ) (5479 cells and 16 subtypes), and endothelial cells ( 50 ) (2930 cells and 10 subtypes) in the murine lung during early postnatal development. Across three datasets, sequencing reads were obtained following the same protocol (Smart-Seq2) and bioinformatics pipeline resulting identical sequencing coverage.…”

Section: Resultsmentioning

confidence: 99%

Disentangling single-cell omics representation with a power spectral density-based feature extraction

Zandavi

Koch

Vijayan

et al. 2022

Nucleic Acids Research

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Emerging single-cell technologies provide high-resolution measurements of distinct cellular modalities opening new avenues for generating detailed cellular atlases of many and diverse tissues. The high dimensionality, sparsity, and inaccuracy of single cell sequencing measurements, however, can obscure discriminatory information, mask cellular subtype variations and complicate downstream analyses which can limit our understanding of cell function and tissue heterogeneity. Here, we present a novel pre-processing method (scPSD) inspired by power spectral density analysis that enhances the accuracy for cell subtype separation from large-scale single-cell omics data. We comprehensively benchmarked our method on a wide range of single-cell RNA-sequencing datasets and showed that scPSD pre-processing, while being fast and scalable, significantly reduces data complexity, enhances cell-type separation, and enables rare cell identification. Additionally, we applied scPSD to transcriptomics and chromatin accessibility cell atlases and demonstrated its capacity to discriminate over 100 cell types across the whole organism and across different modalities of single-cell omics data.

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Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during a period of rapid postnatal growth

Zanini

Che

Knutsen

et al. 2021

Preprint

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BackgroundEndothelial cells (EC) sit at the forefront of dramatic physiologic changes occurring in the pulmonary circulation during late embryonic and early postnatal life. First, as the lung moves from the hypoxic fetal environment to oxygen-rich postnatal environment, marked changes in pulmonary EC structure and function facilitate a marked increase in blood flow from the placenta to the lungs. Subsequently, pulmonary angiogenesis expands the microvasculature to drive exponential distal lung growth during early postnatal life. Yet, how these marked physiologic changes alter distinct EC subtypes to facilitate the transition of the pulmonary circulation and regulate vascular growth and remodeling remains incompletely understood.MethodsIn this report, we employed single cell RNA-transcriptomics and in situ RNA imaging to profile pulmonary EC in the developing mouse lung from just before birth through this period of rapid postnatal growth.ResultsMultiple, transcriptionally distinct macro- and microvascular EC were identified in the late embryonic and early postnatal lung, with gene expression profiles distinct from their adult EC counterparts. A novel arterial subtype, unique to the developing lung localized to the distal parenchyma and expressed genes that regulate vascular growth and patterning. Birth particularly heightened microvascular diversity, inducing dramatic shifts in the transcriptome of distinct microvascular subtypes in pathways related to proliferation, migration and antigen presentation. Two distinct waves of EC proliferation were identified, including one just prior to birth, and a second during early alveolarization, a time of exponential pulmonary angiogenesis. Chronic hyperoxia, an injury that impairs parenchymal and vascular growth, induced a common gene signature among all pulmonary EC, unique alterations to distinct microvascular EC subtypes, and disrupted EC-EC and EC-immune cell cross talk.ConclusionsTaken together, these data reveal tremendous diversity of pulmonary EC during a critical window of postnatal vascular growth, and provide a detailed molecular map that can be used to inform both normal vascular development and alterations in EC diversity upon injury. These data have important implications for lung diseases marked by dysregulated angiogenesis and pathologic pulmonary vascular remodeling.

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Lung mesenchymal cell diversity rapidly increases at birth and is profoundly altered by hyperoxia

Cited by 5 publications

References 98 publications

Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation

Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation

Disentangling single-cell omics representation with a power spectral density-based feature extraction

Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during a period of rapid postnatal growth

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