Perinatal expression of genes that may participate in lipid metabolism by lipid-laden lung fibroblasts

Chen, Heshun; Jackson, Sheila K.; Doro, Melissa M.; McGowan, Stephen E.

doi:10.1016/s0022-2275(20)33329-0

Cited by 33 publications

(3 citation statements)

References 47 publications

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“…Pulmonary lipofibroblasts, which can store lipid droplets within lung tissues, play an important role in maintaining lung homeostasis by involving in the production of surfactants by type II alveolar Frontiers in Cell and Developmental Biology frontiersin.org epithelial cells and alveolar development and regeneration associated with retinoic acid (vitamin A) storage (Tahedl et al, 2014). In contrast to age-related gain of fibrotic gene expression, the expression levels of lipogenesis-related genes including Pparg, Plin2, Fabp1, Fabp4, Fabp5, Lpl, and Lipa (Chen et al, 1998;Chen et al, 2012) as well as chemokines (Ccl2 and Cxcl12) were notably lost in aged pFBs compared to young pFBs as shown by our scRNA-seq data. These results suggest that pFBs may play critical roles in immune regulation, particularly warranting further investigation into their interactions with alveolar macrophages.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the age-dependent changes of pulmonary fibroblasts in mice by single-cell transcriptomics

Wu,

Zhang,

Zhang

et al. 2023

Front. Cell Dev. Biol.

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Background and objectives: The heterogeneity of pulmonary fibroblasts, a critical aspect of both murine and human models under physiological and pathological conditions, is well-documented. Yet, consensus remains elusive on the subtypes, lineage, biological attributes, signal transduction pathways, and plasticity of these fibroblasts. This ambiguity significantly impedes our understanding of the fibrotic processes that transpire in lung tissue during aging. This study aims to elucidate the transcriptional profiles, differentiation pathways, and potential roles of fibroblasts within aging pulmonary tissue.Methods: We employed single-cell transcriptomic sequencing via the 10x Genomics platform. The downstream data were processed and analyzed using R packages, including Seurat. Trajectory and stemness of differentiation analyses were conducted using the Monocle2 and CytoTRACE R packages, respectively. Cell interactions were deciphered using the CellChat R package, and the formation of collagen and muscle fibers was identified through Masson and Van Geison staining techniques.Results: Our analysis captured a total of 22,826 cells, leading to the identification of fibroblasts and various immune cells. We observed a shift in fibroblasts from lipogenic and immune-competent to fibrotic and myofibroblast-like phenotype during the aging process. In the aged stage, fibroblasts exhibited a diminished capacity to express chemokines for immune cells. Experimental validation confirmed an increase of collagen and muscle fiber in the aged compared to young lung tissues. Furthermore, we showed that TGFβ treatment induced a fibrotic, immunodeficient and lipodystrophic transcriptional phenotype in young pulmonary fibroblasts.Conclusion: We present a comprehensive single-cell transcriptomic landscape of lung tissue from aging mice at various stages, revealing the differentiation trajectory of fibroblasts during aging. Our findings underscore the pivotal role of fibroblasts in the regulation of immune cells, and provide insights into why age increases the risk of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Deciphering the age-dependent changes of pulmonary fibroblasts in mice by single-cell transcriptomics

Wu,

Zhang,

Zhang

et al. 2023

Front. Cell Dev. Biol.

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“…22,26,27,31,[37][38][39][40][41][42][43][44][45][46][47][48] During and after septation, lipofibroblasts align themselves with AT2 cells and support their proliferation and differentiation to AT1 cells. 34,[49][50][51][52][53][54][55] As the septa mature, matrix and myofibroblasts secrete metalloproteinases and other ECM-remodeling proteins to thin the septal tip ECM. 2,29,35,40,[56][57][58][59][60][61][62][63] The secondary-crest myofibroblast continues producing elastin, eventually undergoing apoptosis during adulthood.…”

Section: Significance Statementmentioning

confidence: 99%

Resident Interstitial Lung Fibroblasts and their Role in Alveolar Stem Cell Niche Development, Homeostasis, Injury, and Regeneration

Ushakumary

Riccetti

Perl

2021

Stem Cells Translational Medicine

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Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.

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“…In line with this, genetic modified mice with an ApoE deletion show reduced alveologenesis and abnormal pulmonary function with increased airway resistance as well as high dynamic and static compliance ( 124 ). PPARγ is a nuclear receptor and considered one of the master regulators of adipogenesis, showing a high expression pattern in adipose tissue and in the lung ( 125 – 127 ). PPARγ is essential for normal lung development via the induction of alveolar epithelial-mesenchymal paracrine signaling ( 128 , 129 ).…”

Section: The Impact Of Perinatal Nutritive Surplus On the Origins Of Chronic Lung Diseasementioning

confidence: 99%

Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

et al. 2021

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Lung development is not completed at birth, but expands beyond infancy, rendering the lung highly susceptible to injury. Exposure to various influences during a critical window of organ growth can interfere with the finely-tuned process of development and induce pathological processes with aberrant alveolarization and long-term structural and functional sequelae. This concept of developmental origins of chronic disease has been coined as perinatal programming. Some adverse perinatal factors, including prematurity along with respiratory support, are well-recognized to induce bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease that is characterized by arrest of alveolar and microvascular formation as well as lung matrix remodeling. While the pathogenesis of various experimental models focus on oxygen toxicity, mechanical ventilation and inflammation, the role of nutrition before and after birth remain poorly investigated. There is accumulating clinical and experimental evidence that intrauterine growth restriction (IUGR) as a consequence of limited nutritive supply due to placental insufficiency or maternal malnutrition is a major risk factor for BPD and impaired lung function later in life. In contrast, a surplus of nutrition with perinatal maternal obesity, accelerated postnatal weight gain and early childhood obesity is associated with wheezing and adverse clinical course of chronic lung diseases, such as asthma. While the link between perinatal nutrition and lung health has been described, the underlying mechanisms remain poorly understood. There are initial data showing that inflammatory and nutrient sensing processes are involved in programming of alveolarization, pulmonary angiogenesis, and composition of extracellular matrix. Here, we provide a comprehensive overview of the current knowledge regarding the impact of perinatal metabolism and nutrition on the lung and beyond the cardiopulmonary system as well as possible mechanisms determining the individual susceptibility to CLD early in life. We aim to emphasize the importance of unraveling the mechanisms of perinatal metabolic programming to develop novel preventive and therapeutic avenues.

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Perinatal expression of genes that may participate in lipid metabolism by lipid-laden lung fibroblasts

Cited by 33 publications

References 47 publications

Deciphering the age-dependent changes of pulmonary fibroblasts in mice by single-cell transcriptomics

Deciphering the age-dependent changes of pulmonary fibroblasts in mice by single-cell transcriptomics

Resident Interstitial Lung Fibroblasts and their Role in Alveolar Stem Cell Niche Development, Homeostasis, Injury, and Regeneration

Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

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