Fig. 11

Schematic diagram of exosomes from 3D-hESCs with suppression for fibrosis through modulating TGFβRII signaling-related small RNA expression. a During the development of liver fibrosis, the stellate cells was activated, acquired the capacity of the proliferation and became myofibroblasts, which produced and released excessive extracellular matrix (ECM) causing the pathological change of the livers; meanwhile, M1 macrophage was activated, and secreted a large number of pro-inflammatory factors and promoted the inflammation, leading to the progression of the liver fibrosis. The delivery of hESC-derived exosomes inhibited the proliferation of activated stellate cells, decreased the deposition of ECM, reduced the expression of pro-inflammatory factors; and M2 macrophage were increased, and played anti-inflammatory roles, reversing the liver fibrosis. Thus, hESC-derived exosomes exhibited anti-fibrotic effect by alleviating activation of stellate cells and suppressing the progression of liver fibrosis. b The internalized miR-6766-3p enriched from hESC-Exosomes bond the 3ʹUTR of TGFβRII and inhibited the expression of TGFβRII, consequently repressing the expression of nuclear phosphorylated p-SMAD2, p-SMAD3 and SMAD4, the downstream genes of TGFβRII. These decreased SMADs pathway-associated proteins failed to form homologous oligomers, and could not enter the nucleus of the target cells to regulate the transcriptional activities including proliferation, migration, and inflammation, suppressing the progression of liver fibrosis. Thus, the molecular mechanism by which miR-6766-3p enriched from hESC-derived exosome ameliorated liver fibrosis was to attenuate activated stellate cells through targeting TGFβRII-SMAD2/3 pathway