Bone marrow-derived mesenchymal stem cells (BMSCs) are widely used in tissue engineering for regenerative medicine due to their multipotent differentiation potential. However, their poor migration ability limits repair effects. Icariin (ICA), a major component of the Chinese medical herb Herba Epimedii, has been reported to accelerate the proliferation, osteogenic, and chondrogenic differentiation of BMSCs. However, it remains unknown whether ICA can enhance BMSC migration, and the possible underlying mechanisms need to be elucidated. In this study, we found that ICA significantly increased the migration capacity of BMSCs, with an optimal concentration of 1 μmol/L. Moreover, we found that ICA stimulated actin stress fiber formation in BMSCs. Our work revealed that activation of the MAPK signaling pathway was required for ICA-induced migration and actin stress fiber formation. In vivo, ICA promoted the recruitment of BMSCs to the cartilage defect region. Taken together, these results show that ICA promotes BMSC migration in vivo and in vitro by inducing actin stress fiber formation via the MAPK signaling pathway. Thus, combined administration of ICA with BMSCs has great potential in cartilage defect therapy.

This study explored the role played by combined ICA and bone mesenchymal stem cells (BMSCs) in repairing rabbit knee cartilage defects. Firstly, rabbit BMSCs were isolated and used to construct an in vitro cellular model of oxygen‐glucose deprivation/reoxygenation (OGD/R). Subsequently, ICA processing, Alcian blue staining, immunofluorescence and Western blot studies were performed to evaluate the ability of BMSCs to display signs of chondrogenic differentiation. Furthermore, a rabbit knee cartilage injury model was established in vivo. International Cartilage Repair Society (ICRS) macroscopic evaluations, H&E, Alcian blue and EdU staining, as well as immunohistochemistry, were analysed cartilage repair and pathological condition of the knee cartilage tissue. Our in vitro results showed that ICA promoted the chondrogenic differentiation of BMSCs, as well as aggrecan (AGR), bone morphogenetic protein 2 (BMP2) and COL2A1 protein expression in BMSCs. In vivo experiments showed that rabbits in the BMSCs or ICA treatment group had higher ICRS scores and displayed a better restoration of cartilage‐like tissue and chondrocyte expression on the surface of their cartilage defects. In conclusion, ICA or BMSCs alone could repair rabbit knee cartilage damage, and combined treatment with ICA and BMSCs showed a better ability to repair rabbit knee cartilage damage.

Mucosally induced tolerance is an attractive strategy for immunotherapy of autoimmune diseases. Treatment of nonobese diabetic (NOD) mice with a mixture of autoantigen peptides is better geared toward slowing the progression of late stage type 1 diabetes (T1D) than treatment with any of the peptides alone. In this study, we constructed a fusion protein CTB-GADIII. It contains cholera toxin B subunit (CTB) and three tandem peptides derived from glutamic acid decarboxylase 65 (GAD65), p217-236, p524-538 and p290-306. The purified renatured pentamer fusion protein was effective in inhibiting the development of diabetes in NOD mice when the mice were nasally immunized three times (8w, 10w and 12w). Prevention of diabetes was associated with special humoral immune tolerance against tandem peptides GADIII. These data indicate that using CTB as a vaccine carrier, tandem GAD65 peptides can prevent T1D in NOD mice at the late stage of disease.

Original Article Icariin promotes the repair of bone marrow mesenchymal stem cells in rabbit knee cartilage defects via the BMP/Smad pathway Feng Jiao, Wang Tang, Jie Wang, Donghua Liu, Hongyi Zhang, Dongming Tang

Objectives. Osteochondral defects (OCDs) are localized areas of damaged cartilage and underlying subchondral bone that can produce pain and seriously impair joint function. Literature reports indicated that icariin (ICA) has the effect of promoting cartilage repair. However, its mechanism remains unclear. Here, we explored the effects of icariin and extracellular vesicles (EVs) from rabbit synovial‐derived mesenchymal stem cells (rSMSCs) on repairing of OCDs. Materials and Methods. Rabbit primary genicular chondrocytes (rPGCs), knee skeletal muscle cells (rSMCKs), and rSMSCs, and extracellular vesicles derived from the latter two cells (rSMCK‐EVs and rSMSC‐EVs) were isolated and identified. The rPGCs were stimulated with ICA, rSMSC‐EVs either separately or in combination. The rSMCK‐EVs were used as a control. After stimulation, chondrogenic‐related markers were analyzed by quantitative RT‐PCR and western blotting. Cell proliferation was determined by the CCK‐8 assay. The preventative effects of ICA and SMSC‐EVs in vivo were determined by H&E and toluidine blue staining. Immunohistochemical analyses were performed to evaluate the levels of COL2A1 and β‐catenin in vivo. Results. In vitro, the proliferation of rPGCs was markedly increased by ICA treatment in a dose‐dependent manner. When compared with ICA or rSMSC‐EVs treatment alone, combined treatment with ICA and SMSC‐EVs produced stronger stimulative effects on cell proliferation. Moreover, combined treatment with ICA and rSMSC‐EVs promoted the expression of chondrogenic‐related gene, including COL2A1, SOX‐9, and RUNX2, which may be via the activation of the Wnt/β‐catenin pathway. In vivo, combined treatment with rSMSC‐EVs and ICA promoted cartilage repair in joint bone defects. Results also showed that ICA or rSMSC‐EVs both promoted the COL2A1 and β‐catenin protein accumulation in articular cartilage, and that was further enhanced by combined treatment with rSMSC‐EVs and ICA. Conclusion. Our findings highlight the promising potential of using combined treatment with ICA and rSMSC‐EVs for promoting osteochondral repair.