Single‐cell transcriptomics provides new insights into the role of fibroblasts during peritoneal fibrosis

Zhang, Jinhua; Chen, Yuxian; Chen, Tufeng; Miao, Benchun; Tang, Zuofu; Hu, Xiao; Luo, Yilun; Zheng, Tong; Na, Ning

doi:10.1002/ctm2.321

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…Publicly available datasets with both single-cell and single-nucleus data that contain adipocytes provided an ideal test case. While mesothelial cells seems to be present in some single-cell sequencing datasets [26, 27], in these datasets we used both adipocytes and mesothelial cells are shown to be lost during single-cell sequencing but the nuclei are preserved and profiled in single-nucleus sequencing [28]. In our experiment, the cell-type proportion in pseudobulks was defined based on cell types observed in single-cell data, while the expression profiles themselves were derived from single-nucleus counterpart.…”

Section: Resultsmentioning

confidence: 99%

Missing cell types in single-cell references impact deconvolution of bulk data but are detectable

Ivich,

Davidson,

Grieshober

et al. 2024

Preprint

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Advancements in RNA-sequencing have dramatically expanded our ability to study gene expression profiles of biological samples in bulk tissue and single cells. Deconvolution of bulk data with single-cell references provides the ability to study relative cell-type proportions, but most methods assume a reference is present for every cell type in bulk data. This is not true in all circumstances--cell types can be missing in single-cell profiles for many reasons. In this study, we examine the impact of missing cell types on deconvolution methods. Our experimental designs are simulation-based, using paired single-cell and single-nucleus data, since single-nucleus RNA-sequencing is able to preserve the nucleus of cell types that would otherwise be missing in a single-cell counterpart. These datasets allow us to examine the missing-cell-type phenomenon in deconvolution with realistic proportions. We apply three deconvolution methods that vary from straightforward to state-of-the-art: non-negative least squares, BayesPrism, and CIBERSORTx. We find that the performance of deconvolution methods is influenced by both the number and the similarity of missing cell types, consistent with prior results. Additionally, we find that missing cell-type profiles can be recovered from residuals using a simple non-negative matrix factorization strategy. We expect our simulation strategies and results to provide a starting point for those developing new deconvolution methods and help improve their to better account for the presence of missing cell types. Building off of our findings on simulated data, we then analyzed data from high-grade serous ovarian cancer; a tumor that has regions of highly variable levels of adipocytes dependent on the region from which it is sampled. We observe results consistent with simulation, namely that expression patterns from cell types likely to be missing appear present in residuals. Our results suggests that deconvolution methods should consider the possibility of missing cell types and provide a starting point to address this. Our source code for data simulation and analysis is freely available at https://github.com/greenelab/pred_missing_celltypes.

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Section: Resultsmentioning

confidence: 99%

Missing cell types in single-cell references impact deconvolution of bulk data but are detectable

Ivich,

Davidson,

Grieshober

et al. 2024

Preprint

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“…The functional importance of FAO in PD is further shown by improvement of the FAO in mesothelial cells, either by genetic or pharmacological restoration of CPT1A, which greatly attenuates the profibrotic effects and lessens the peritoneal fibrosis. In the setting of PD, the presence of a hyperglycolytic state in mesothelial cells has recently been described 6 , 26 . However, activity of other metabolic pathways in PD has not been studied.…”

Section: Discussionmentioning

confidence: 99%

Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis

Su,

Hu,

Zhong

et al. 2023

Theranostics

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Background: Peritoneal dialysis (PD) is limited by gradual fibrotic remodeling in the peritoneum, a process involving profibrotic response of mesothelial cells. However, the role of fatty acid oxidation (FAO) and carnitine palmitoyltransferase 1A (CPT1A) in this process remains unexplored. Methods: FAO and CPT1A expression were characterized in mesothelial cells from patients on long-term PD and from a mouse model of PD using multiple experimental methods, including single-cell sequencing, seahorse assay, real-time quantitative PCR, Western blot, and immunofluorescence staining. Overexpression of CPT1A was achieved in a human mesothelial cell line and in primary mouse mesothelial cells. Finally, genetic and pharmacological manipulations of CPT1A were performed in a mouse model of PD. Results: Herein, FAO and CPT1A expression were reduced in mesothelial cells from patients on long-term PD, which negatively correlated with expression of fibrogenic markers in these cells. This was corroborated in PD mice, as well as in mouse and human mesothelial cells incubated with transforming growth factor (TGF) β1. CPT1A overexpression in mesothelial cells, which prevented TGFβ1-induced suppression of mitochondrial respiration, restored cellular ATP levels and downregulated the expression of fibrogenic markers. Furthermore, restoration of FAO by overexpressing CPT1A in PD mice reversed profibrotic phenotype in mesothelial cells and reduced fibrotic lesions in the peritoneum. Treatment with the CPT1A activator C75 induced similar therapeutic benefit in PD mice. In contrast, inhibition of FAO with a CPT1 inhibitor caused more severe fibrosis in PD mice. Conclusions: A defective FAO is responsible for the profibrotic response of mesothelial cells and thus the peritoneal fibrogenesis. This aberrant metabolic state could be improved by modulating CPT1A in mesothelial cells, suggesting FAO enhancement in mesothelial cells is a potential treatment of peritoneal fibrosis.

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“…The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) pathway is activated in most real diseases ( 64 , 65 ). This signaling pathway plays an important role in macrophage adhesion, migration, invasion, metabolism, proliferation, and survival ( 66 – 68 ).…”

Section: The Pathways Of Macrophage Pro-inflammationmentioning

confidence: 99%

Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy

Chen

Liu²,

Zhuang³

2022

Front. Immunol.

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Acute kidney injury (AKI) is a renal disease with a high incidence and mortality. Currently, there are no targeted therapeutics for preventing and treating AKI. Macrophages, important players in mammalian immune response, are involved in the multiple pathological processes of AKI. They are dynamically activated and exhibit a diverse spectrum of functional phenotypes in the kidney after AKI. Targeting the mechanisms of macrophage activation significantly improves the outcomes of AKI in preclinical studies. In this review, we summarize the role of macrophages and the underlying mechanisms of macrophage activation during kidney injury, repair, regeneration, and fibrosis and provide strategies for macrophage-targeted therapies.

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Single‐cell transcriptomics provides new insights into the role of fibroblasts during peritoneal fibrosis

Abstract: 1. Landscape dynamics of cell populations during dialysis-related peritoneal fibrosis. 2. Description of pathophysiology in peritoneal fibrosis at single-cell resolution. 3. Elucidation of receptor-ligand interaction networks between fibroblasts and immune cells.

Cited by 11 publications

References 32 publications

Missing cell types in single-cell references impact deconvolution of bulk data but are detectable

Missing cell types in single-cell references impact deconvolution of bulk data but are detectable

Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis

Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy

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