Proteomic Analysis of Human Lung Development

IntroductionPulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis, but their role in PAH is incompletely understood. We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH.MethodsLung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a−/–mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).ResultsHealthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a−/–mice under either chronic hypoxia and SuHx, global Wnt7a+/–mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/–PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.ConclusionsWnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.

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“…Notably, confocal analysis of hyperoxia lungs demonstrated immunoreactivity for Wnt7a throughout the distal lung (Supplement Fig. XIII) [32].…”

Section: Fig Ix)mentioning

confidence: 99%

Wnt7a deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension

et al. 2023

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“…This transformation makes the biological research of lung diseases more efficient. Proteomic analysis of human lungs at 10 distinct time points from birth to 8 years indicates the existence of distinct molecular substages of alveolar development and predicts the age of independent human lung samples 203 . Currently, the main clinical sample sources for studying lung diseases include biopsy samples, lung transplantation samples, autopsy samples, and alveolar lavage fluid.…”

Section: Research Models Of Lung Injury and Regenerationmentioning

confidence: 99%

Lung regeneration: diverse cell types and the therapeutic potential

Chen,

Li,

et al. 2024

MedComm

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Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

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“…A person’s exercise capacity is largely dependent on their respiratory and cardiovascular performance and the profound, functional, and anatomical interplay between both ( 7 – 9 ). The respiratory performance of children is determined by vascular and alveolar development in the lungs, where 95% of alveoli form during the first 7 years of life in humans ( 10 , 11 ). Fetal studies demonstrated that pulmonary blood flow modulates the development of fetal pulmonary parenchyma and vessels ( 12 , 13 ), yet little is known about whether pulmonary blood flow modulates postnatal lung development.…”

Section: Introductionmentioning

confidence: 99%

“…Fetal studies demonstrated that pulmonary blood flow modulates the development of fetal pulmonary parenchyma and vessels ( 12 , 13 ), yet little is known about whether pulmonary blood flow modulates postnatal lung development. Moreover, although a clinical study of adult patients with congenital pulmonary valve stenosis, which leads to RPF, revealed that these patients had smaller lungs than healthy controls ( 11 ), whether the smaller lungs found in such patients are caused by RPF remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

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Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA-sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of CHD patients with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.

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Proteomic Analysis of Human Lung Development

Cited by 16 publications

References 34 publications

Wnt7a deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension

Wnt7a deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension

Lung regeneration: diverse cell types and the therapeutic potential

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms

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