Heterogeneous microenvironment analysis to explore the potential regulatory role of endothelial-mesenchymal transition in idiopathic pulmonary fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease mainly caused by excessive proliferation of fibroblasts and activation of myofibroblasts. The cellular microenvironment is mainly composed of different types of cellular components and extracellular matrix (ECM), whose changes directly affect cellular heterogeneity, resulting in immensely complex cellular interactions. However, microenvironment study is mainly focused on the pathological process of tumors, and the microenvironment changes during IPF development remain unclear.Methods: The current study intends to employ IPF-related single-cell sequencing and gene expression profile data to analyze the scores of different cell clusters in the IPF microenvironment, and exploit the underlying interaction between cells to illustrate the fundamental mechanism causing IPF.Results: Our analysis revealed that the amount of endothelial cells was obviously decreased, and the amount of fibroblasts and myofibroblasts was increased during the development of IPF, suggesting a possible endothelial-mesenchymal transition (EndMT) process. Furthermore, we found that the hub genes obtained through IPF-related gene expression profile analysis may play a regulative role in the number and function of endothelial cells and fibroblasts/myofibroblasts during IPF.Conclusions: Our research represents a valuable analysis of the cellular microenvironment, and provides a novel mechanistic insight into the pathobiology of not only EndMT in IPF, but also other traumatic fibrotic disease disorders.

Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis

“…The microstructure shows that ECs in the fibrotic area of PF lose their endothelial characteristics, such as polarity and intercellular junctions, while acquiring mesenchymal cell characteristics, such as a spindle-shaped cell morphology and increased migration ability [38]. In addition, the results of immunofluorescence staining and single-cell sequencing also showed that the expression of mesenchymal cell marker proteins was also observed in these ECs [39,40]. It has been reported that vascular damage occurred first in radiationinduced lung fibrosis (RIPF), including narrowing and obliterating capillaries induced by EC swelling, fibrin deposition, and endothelial hyperplasia [41].…”

Advances in common in vitro cellular models of pulmonary fibrosis

“…52 Various fibrotic diseases, including PF, result from the abnormal activation of fibroblasts, primarily caused by the transformation of normal resident fibroblasts, as well as epithelial or endothelial cells within lung tissue. 53 Myofibroblast foci develop as a result of migration, proliferation and activation of mesenchymal cells induced by activated AECs. The excessive secretion of ECM proteins by myofibroblasts disrupts pulmonary homeostasis and structure, leading to pulmonary interstitial matrix sclerosis and pathological matrix deposition.…”

The contribution of endothelial cells to tissue fibrosis

“…In addition, increased expression of the myofibroblast markers N-cadherin, S100A4, and vimentin was reported in the arterial layers of IPF patients, suggesting that resident lung endothelial cells may transdifferentiate into mesenchymal/myofibroblast-like cells [ 28 ]. In a recent study employing single-cell analysis and gene expression profile data from lung tissues of IPF patients, the number of endothelial cells was found to be significantly decreased, while the number of fibroblasts and myofibroblasts significantly increased [ 29 ]. Moreover, gene expression profile in the IPF group revealed an increase in the biological processes related to fibroblast function (e.g., cellular response to fibroblast growth factor stimulation and collagen fibril organization), suggesting the occurrence of EndMT during IPF development [ 29 ].…”

“…In a recent study employing single-cell analysis and gene expression profile data from lung tissues of IPF patients, the number of endothelial cells was found to be significantly decreased, while the number of fibroblasts and myofibroblasts significantly increased [ 29 ]. Moreover, gene expression profile in the IPF group revealed an increase in the biological processes related to fibroblast function (e.g., cellular response to fibroblast growth factor stimulation and collagen fibril organization), suggesting the occurrence of EndMT during IPF development [ 29 ]. In another recent experimental work, endothelial-specific overexpression of sterol regulatory element-binding protein 2 (SREBP2), a protein with key role in oxidative stress-induced endothelial dysfunction, was shown to exacerbate vascular remodeling and induce pulmonary EndMT in bleomycin-treated mice [ 30 ].…”