Probable role of exosomes in the extension of fibrotic alterations from affected to normal cells in systemic sclerosis

Abstract

SSc is a systemic autoimmune disease of unknown etiology characterized by frequently progressive cutaneous and internal organ fibrosis causing severe disability, organ failure and high mortality. A remarkable feature of SSc is the extension of the fibrotic alterations to nonaffected tissues. The mechanisms involved in the extension of fibrosis have remained elusive. We propose that this process is mediated by exosome microvesicles released from SSc-affected cells that induce an activated profibrotic phenotype in normal or nonaffected cells. Exosomes are secreted microvesicles involved in an intercellular communication system. Exosomes can transfer their macromolecular content to distant target cells and induce paracrine effects in the recipient cells, changing their molecular pathways and gene expression. Confirmation of this hypothesis may identify the molecular mechanisms responsible for extension of the SSc fibrotic process from affected cells to nonaffected cells and may allow the development of novel therapeutic approaches for the disease.

Keywords: SSc; cellular phenotype; endothelial cells; exosomes; fibrosis; myofibroblasts; paracrine.

Fig. 1

Hypothetical role of exosome-mediated paracrine effects in the extension of tissue fibrosis and in SSc Exosomes released from affected SSc cells reach normal target cells through the interstitial fluid or the circulation and become internalized by the target cells. The exosomes release their macromolecular cargo that induces the paracrine conversion of the target cells into activated myofibroblasts. Activated myofibroblasts cause the deposition of fibrotic tissue, as illustrated for skin and lungs.

Fig. 2

Exosome profibrotic paracrine effects on target cells Exosome microvesicles are generated by intracellular budding of early endosomes followed by loading of multiple macromolecules generating MVBs. MVBs fuse with the plasma membrane for exosome release. Alternatively, MVBs may fuse with lysosomes and undergo degradation. Following their release, exosomes reach distant target cells through the interstitial fluid or the circulation, bind to the normal target cells, become internalized and release their macromolecular cargo. The exosome macromolecules induce potent molecular and biological effects in the target cells through paracrine mechanisms, resulting in tissue fibrosis.