Role of Mesenchymal Stem Cells and Extracellular Vesicles in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.

Keywords: extracellular vesicles; lung damage; mesenchymal stem cells; mesenchymal stem cells derived extracellular vesicles; pulmonary fibrosis.

Figure 1

Pathways of myofibroblast formation during IPF. The figure shows the different cell types that respond to stimulation by profibrotic growth factors (TGF-β, CTGF), cytokines (IL-1, IL-13, IL-4, IL-6, TNF-α), signaling pathways (Wnt/β-catenin, Notch1/PDGFRβ/ROCK1), chemokines (CXCL12, SLC, CCL1), specific EMT transcription factors (Snail2, ZEB1, TWIST, p62/SQSTM1), adhesion molecules (ICAM-1,VCAM-1, FAK and CDH-11), hyperoxia, exposure to endothelin-1 and nicotine, overexpression of α-SMA, COL1α1 and fibronectin, upregulation of SMAD2, SMAD3, Sp1 and c-Myc differentiated into myofibroblasts [65,70,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102] (Created with BioRender.com, accessed on 4 July 2022).

Figure 2

Schematic representation of the lung tissue damage therapy mechanism in IPF by means of mesenchymal stem cell-derived extracellular vesicles. The footnotes in the figure indicate: the composition of EVs-MSCs—proteins (PRKCZ, TIMP-1, TIMP-2, BMP-7), transcription factors (NF-κβ p50, NF-κβ p65), miRNAs (miR-182-5p, miR-214-3p, miR-29b-3p, miR-23a-3p) and therapeutic effect of EVs-MSCs (Created with BioRender.com, accessed on 22 September 2022).