Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the histopathological pattern of usual interstitial pneumonia and is associated with a high mortality rate. Recently, lung resident mesenchymal stem cells (LR-MSCs) have been identified as an important contributor to myofibroblast activation in pulmonary fibrosis. Macrophages are also believed to play a critical role in pulmonary fibrosis. However, the underlying connections between LR-MSCs and macrophages in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we investigated the interaction between LR-MSCs and macrophages using a bleomycin-induced mouse pulmonary fibrosis model and a coculture system. Here, we show that blocking pulmonary macrophage infiltration attenuated bleomycin-induced pulmonary fibrosis. In addition, as determined by flow cytometry, we discovered that the recruited macrophages in fibrotic lungs of bleomycin-treated mice were mainly M2 macrophages. In particular, we found that M2, rather than M1 macrophages, promoted myofibroblast differentiation of LR-MSCs. Moreover, we demonstrated that suppression of the Wnt/β-catenin signaling pathway could attenuate myofibroblast differentiation of LR-MSCs induced by M2 macrophages and bleomycin-induced pulmonary fibrosis. Tissue samples from IPF patients confirmed the infiltration of M2 macrophages and activation of Wnt/β-catenin signaling pathway. In summary, this study furthered our understanding of the pulmonary fibrosis pathogenesis and highlighted M2 macrophages as a critical target for treating pulmonary fibrosis.

Tissue engineering scaffolds are essential for repairing bone defects. The use of biomimetic scaffolds for bone tissue engineering has been investigated for decades. To date, the trend in this area has been moved toward the construction of biomimetic acellular scaffolds with effective modification to enhance the osteogenic differentiation efficiency of bone marrow mesenchymal stem cells (BMSCs). The exosomes derived from BMSCs have been shown as a potential therapeutic tool for repairing bone defects. In this study, we demonstrated the pro-osteogenic effects of exosomes derived form osteogenic differentiated BMSCs (OBMSC) and presented a novel exosmes-functionalized decellularized fish scale (DE-FS) scaffold for promoting bone regeneration in vivo. The DE-FS scaffolds were obtained through decellularization and decalcification processes, which exhibited high biocompatibility and low immunological rejection. The intrinsic anisotropic structures of DE-FS could enhance the adhesion and proliferation ability of BMSCs in vitro. In addition, we demonstrated that the porous structure of DE-FS endowed them with the capacity to load and release exosomes to BMSCs, resulting in the enhanced osteogenic differentiation of BMSCs. Concerning these pro-osteogenic effects, it was further proved that OBMSC exosome-modified DE-FS scaffolds could effectively promote bone regeneration in the mouse calvarial defect models. In conclusion, our work provided a new insight to design exosome-riched biomimetic scaffolds for bone tissue engineering and clinical applications.

Background: Sarcopenia is a common and progressive skeletal muscle disorder characterized by atrophic muscle fibres and contractile dysfunction. Accumulating evidence shows that the number and function of satellite cells (SCs) decline and become impaired during ageing, which may contribute to impaired regenerative capacity. A series of myokines/small extracellular vesicles (sEVs) released from muscle fibres regulate metabolism in muscle and extramuscular tissues in an autocrine/paracrine/endocrine manner during muscle atrophy. It is still unclear whether myokines/sEVs derived from muscle fibres can affect satellite cell function during ageing.Methods: Aged mice were used to investigate changes in the myogenic capacity of SCs during ageing‐induced muscle atrophy. The effects of atrophic myotube‐derived sEVs on satellite cell differentiation were investigated by biochemical methods and immunofluorescence staining. Small RNA sequencing was performed to identify differentially expressed sEV microRNAs (miRNAs) between the control myotubes and atrophic myotubes. The target genes of the miRNA were predicted by bioinformatics analysis and verified by luciferase activity assays. The effects of identified miRNA on the myogenic capacity of SCs in vivo were investigated by intramuscular injection of adeno‐associated virus (AAV) to overexpress or silence miRNA in skeletal muscle.Results: Our study showed that the myogenic capacity of SCs was significantly decreased (50%, n = 6, P < 0.001) in the tibialis anterior muscle of aged mice. We showed that atrophic myotube‐derived sEVs inhibited satellite cell differentiation in vitro (n = 3, P < 0.001) and in vivo (35%, n = 6, P < 0.05). We also found that miR‐690 was the most highly enriched miRNA among all the screened sEV miRNAs in atrophic myotubes [Log₂ (Fold Change) = 7, P < 0.001], which was verified in the atrophic muscle of aged mice (threefold, n = 6, P < 0.001) and aged men with mean age of 71 ± 5.27 years (2.8‐fold, n = 10, P < 0.001). MiR‐690 can inhibit myogenic capacity of SCs by targeting myocyte enhancer factor 2, including Mef2a, Mef2c and Mef2d, in vitro (n = 3, P < 0.05) and in vivo (n = 6, P < 0.05). Specific silencing of miR‐690 in the muscle can promote satellite cell differentiation (n = 6, P < 0.001) and alleviate muscle atrophy in aged mice (n = 6, P < 0.001).Conclusions: Our study demonstrated that atrophic muscle fibre‐derived sEV miR‐690 may inhibit satellite cell differentiation by targeting myocyte enhancer factor 2 during ageing.