Stem cell dysfunction and failure have been found in joints afflicted by osteoarthritis (OA). However, the exact factors in the OA microenvironment that impair stem cell functions and the role of stem cell dysfunction in OA development have not been fully clarified. In this study, we evaluated the functional status of synovial mesenchymal stem cells (SMSCs) from OA patients and explored the influence of OA-SMSCs on cartilage degradation in a rat model. We then screened 138 Wnt signaling-related genes in the synovium of OA patients, focusing on the effects of five WNT ligands on SMSC functions. The OA synovium showed mild hyperplasia, and we found a large number of CD90 + /CD105 + stem cells in synovial hyperplasia. The OA-SMSCs revealed a cellular senescence phenotype, with decreased proliferation and chondrogenic capacity, accompanied by enhanced migration, proinflammatory and matrix degradation activities. The intra-articular transplantation of these OA-SMSCs significantly aggravated the degradation and destruction of the articular cartilage. Of 138 Wnt signaling genes, the expression of 86 genes was consistently altered in the OA synovium, among which the increased expression of DVL2, WNT10A, and DKK3 was the most marked. In general, we found that canonical Wnt/b-catenin pathways were inhibited in the OA synovium, whereas noncanonical PCP and Wnt/Ca2 + pathways were activated. In vitro, WNT10A had an obvious antisenescence effect on SMSCs. WNT5B significantly inhibited the chondrogenic differentiation of SMSCs, and WNT10A and WNT5A increased the expression of inflammatory cytokines in SMSCs. In a rat model, WNT5A significantly aggravated joint degeneration, whereas WNT10A had a mild protective effect on cartilage integrity. In conclusion, stem cells in the OA synovium were functionally abnormal and promoted the development of OA, whereas dysregulation of the Wnt signaling pathway revealed a comprehensive influence on SMSC functions and cartilage degradation.

Aim: Diabetic wound healing is seriously interrupted, and administration of KGF for wound treatment is restricted by its inherent instability. We aim to develop an ideal way toward KGF stabilization, thus improving diabetic wound healing. Materials & methods: We conjugated KGF with gold nanoparticles (GNPs) and determined the stability and binding affinity. Biological effects of conjugates (KGF-GNPs) were evaluated in vitro and in an animal model. Results: KGF-GNPs revealed high stability under hostile circumstances because of the preserved secondary structure and possessed elevated binding affinity to KGF receptor. Moreover, application of KGF-GNPs contributed to accelerated wound recovery in diabetic rats, including re-epithelialization and contraction. Conclusion: KGF-GNPs were promising for future clinical application for diabetic wound therapy.

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BackgroundMacrophage is a central regulator of innate immunity. Its M2 subsets, such as interstitial synovial macrophages, have been found to play critical roles in suppressing chronic inflammation and maintaining homeostasis within the joint. These macrophages have great potential as a disease-modifying cell therapy for osteoarthritis (OA). However, this has not yet been studied.MethodsMacrophages were isolated from the bone marrow of rats. We constructed a stable macrophage that “locked” in anti-inflammatory and pro-regenerative M2a polarity (L-M2a) by simultaneously knocking out tumor necrosis factor receptor 1 (TNFR1) and overexpressing IL-4 using Cas9-ribonuclear proteins (Cas9-RNP) and electroporation. In vitro, these L-M2a macrophages were treated with OA synovial fluid or co-cultured with OA chondrocytes or fibroblast-like synoviocytes (FLS). In vivo, L-M2a macrophages were injected intra-articularly to evaluate their homing and engrafting abilities and therapeutic effects on OA progression using a rat model.ResultsL-M2a macrophages displayed a typical anti-inflammatory phenotype similar to that of M2 macrophages in vitro. In OA microenvironment, L-M2a macrophages maintained a stable anti-inflammatory phenotype, whereas unmodified M2 macrophages lost their phenotype and switched to M1 polarity. L-M2a macrophages demonstrated a potent anti-inflammatory effect in crosstalk with OA-FLSs and an anti-degenerative effect in crosstalk with senescent OA chondrocytes. In vivo, compared with M2 macrophages and exosomes, L-M2a macrophages exhibited significantly superior therapeutic effects in OA by successfully resolving inflammation, restoring tissue homeostasis, and promoting cartilage regeneration.ConclusionThe engineered L-M2a macrophages maintained a superior anti-inflammatory and pro-regenerative capacity in the inflammatory OA microenvironment and represents an ideal new strategy for the disease-modifying therapy of OA.