Therapeutic Potential of Exosomes in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is closely associated with the recruitment of fibroblasts from capillary vessels with damaged endothelial cells, the epithelial mesenchymal transition (EMT) of type II alveolar epithelial cells, and the transformation of fibroblasts to myofibroblasts. Recent studies suggest that EMT is a key factor in the pathogenesis of pulmonary fibrosis, as the disruption of EMT-related effector molecules can inhibit the occurrence and development of PF. With the numerous advancements made in molecular biology in recent years, researchers have discovered that exosomes and their cargos, such as miRNAs, lncRNAs, and proteins, can promote or inhibit the EMT, modulate the transformation of fibroblasts into myofibroblasts, contribute to the proliferation of fibroblasts and promote immunoregulatory and mitochondrial damage during pulmonary fibrosis. Exosomes are key factors regulating the differentiation of bone marrow mesenchymal stem cells (BMSCs) into myofibroblasts. Interestingly, exosomes derived from BMSCs under pathological and physiological conditions may promote or inhibit the EMT of type II alveolar epithelial cells and the transformation of fibroblasts into myofibroblasts to regulate pulmonary fibrosis. Thus, exosomes may become a new direction in the study of drugs for the treatment of pulmonary fibrosis.

Keywords: bone marrow mesenchymal stem cell; epithelial mesenchymal transition; exosome; myofibroblast; pulmonary fibrosis; type II alveolar epithelial cell.

FIGURE 1

Signaling pathway of EMT. GSK3β is an important negative regulator of the Wnt signaling pathway. Axin can interact with many important members of the Wnt signaling pathway to negatively regulating Wnt/β-catenin signaling. Wnt signaling pathway activation inhibits the phosphorylation of GSK3β, preventing GSK3β from phosphorylating β-catenin, leading to the inhibition of β-catenin degradation. GSK3β phosphorylation can promote axin autophosphorylation, increasing the affinity of axin and β-catenin and promoting β-catenin degradation. β-Catenin can promote the EMT of type II alveolar epithelial cells, promote the transformation of type II alveolar epithelial cells to myofibroblasts, and ultimately promote PF by activating the TGF-β1/Smad and Rho-ROCK signaling pathways.

FIGURE 2

Therapeutic potential of BMSC-derived exosomes for PF and the potential molecular mechanisms. BMSCs in the PF microenvironment can contribute to myofibroblasts formation through self-differentiation and secrete exosomes to facilitate the EMT of type II alveolar epithelial cells to promote PF. In contrast, BMSCs from healthy individuals can migrate to damaged organs to promote their repair and secrete exosomes to inhibit the EMT of type II alveolar epithelial cells via the interplay between the Wnt and TGF-β1/Smad signaling pathways. Exosomal cargos such as miRNAs can inhibit β-catenin and axin activity. Axin can negatively regulate the Wnt/β-catenin signaling pathway, inhibiting the phosphorylation of GSK3β and leading to the suppression of β-catenin degradation. β-Catenin can promote the transformation of type II alveolar epithelial cells into myofibroblasts via EMT. Finally, the downregulation of axin can inhibit the EMT of type II alveolar epithelial cells to inhibit PF. The self-differentiation of BMSCs may be mediated by miRNAs, caspase, TGF-β1, and Wnt signaling pathways.