The ability of articular cartilage to repair itself is limited because it lacks blood vessels, nerves, and lymph tissue. Once damaged, it can lead to joint swelling and pain, accelerating the progression of osteoarthritis. To date, complete regeneration of hyaline cartilage exhibiting mechanical properties remains an elusive goal, despite the many available technologies. The inflammatory milieu created by cartilage damage is critical for chondrocyte death and hypertrophy, extracellular matrix breakdown, ectopic bone formation, and progression of cartilage injury to osteoarthritis. In the inflammatory microenvironment, mesenchymal stem cells (MSCs) undergo aberrant differentiation, and chondrocytes begin to convert or dedifferentiate into cells with a fibroblast phenotype, thereby resulting in fibrocartilage with poor mechanical qualities. All these factors suggest that inflammatory problems may be a major stumbling block to cartilage repair. To produce a milieu conducive to cartilage repair, multi-dimensional management of the joint inflammatory microenvironment in place and time is required. Therefore, this calls for elucidation of the immune microenvironment of cartilage repair after injury. This review provides a brief overview of: (1) the pathogenesis of cartilage injury; (2) immune cells in cartilage injury and repair; (3) effects of inflammatory cytokines on cartilage repair; (4) clinical strategies for treating cartilage defects; and (5) strategies for targeted immunoregulation in cartilage repair. STATEMENT OF SIGNIFICANCE: Immune response is increasingly considered the key factor affecting cartilage repair. It has both negative and positive regulatory effects on the process of regeneration and repair. Proinflammatory factors are secreted in large numbers, and necrotic cartilage is removed. During the repair period, immune cells can secrete anti-inflammatory factors and chondrogenic cytokines, which can inhibit inflammation and promote cartilage repair. However, inflammatory factors persist, which accelerate the degradation of the cartilage matrix. Furthermore, in an inflammatory microenvironment, MSCs undergo abnormal differentiation, and chondrocytes begin to transform or dedifferentiate into fibroblast-like cells, forming fibrocartilage with poor mechanical properties. Consequently, cartilage regeneration requires multi-dimensional regulation of the joint inflammatory microenvironment in space and time to make it conducive to cartilage regeneration.

Articular cartilage is susceptible to damage but hard to self-repair due to its avascular nature. Traditional treatment methods are not able to produce satisfactory effects. Mesenchymal stem cells (MSCs) have shown great promise in cartilage repair. However, the therapeutic effect of MSCs is often unstable partly due to their heterogeneity. Understanding the heterogeneity of MSCs and the potential of different types of MSCs for cartilage regeneration will facilitate the selection of superior MSCs for treating cartilage damage. This review provides an overview of the heterogeneity of MSCs at the donor, tissue source and cell immunophenotype levels, including their cytological properties, such as their ability for proliferation, chondrogenic differentiation and immunoregulation, as well as their current applications in cartilage regeneration. This information will improve the precision of MSC-based therapeutic strategies, thus maximizing the efficiency of articular cartilage repair.

Articular cartilage (AC) injury repair has always been a difficult problem for clinicians and researchers. Recently, a promising therapy based on mesenchymal stem cells (MSCs) has been developed for the regeneration of cartilage defects. As endogenous articular stem cells, synovial MSCs (SMSCs) possess strong chondrogenic differentiation ability and articular specificity. In this study, a cartilage regenerative system was developed based on a chitosan (CS) hydrogel/3D-printed poly(ε-caprolactone) (PCL) hybrid containing SMSCs and recruiting tetrahedral framework nucleic acid (TFNA) injected into the articular cavity. TFNA, which is a promising DNA nanomaterial for improving the regenerative microenvironment, could be taken up into SMSCs and promoted the proliferation and chondrogenic differentiation of SMSCs. CS, as a cationic polysaccharide, can bind to DNA through electrostatic action and recruit free TFNA after articular cavity injection in vivo. The 3D-printed PCL scaffold provided basic mechanical support, and TFNA provided a good microenvironment for the proliferation and chondrogenic differentiation of the delivered SMSCs and promoted cartilage regeneration, thus greatly improving the repair of cartilage defects. In conclusion, this study confirmed that a CS hydrogel/3D-printed PCL hybrid scaffold containing SMSCs could be a promising strategy for cartilage regeneration based on chitosan-directed TFNA recruitment and TFNA-enhanced cell proliferation and chondrogenesis.

Articular cartilage defect repair is a problem that has long plagued clinicians. Although mesenchymal stem cells (MSCs) have the potential to regenerate articular cartilage, they also have many limitations. Recent studies have found that MSC-derived exosomes (MSC-Exos) play an important role in tissue regeneration. The purpose of this study was to verify whether MSC-Exos can enhance the reparative effect of the acellular cartilage extracellular matrix (ACECM) scaffold and to explore the underlying mechanism. The results of in vitro experiments show that human umbilical cord Wharton's jelly MSC-Exos (hWJMSC-Exos) can promote the migration and proliferation of bone marrow-derived MSCs (BMSCs) and the proliferation of chondrocytes. We also found that hWJMSC-Exos can promote the polarization of macrophages toward the M2 phenotype. The results of a rabbit knee osteochondral defect repair model confirmed that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration. We demonstrated that hWJMSC-Exos can regulate the microenvironment of the articular cavity using a rat knee joint osteochondral defect model. This effect was mainly manifested in promoting the polarization of macrophages toward the M2 phenotype and inhibiting the inflammatory response, which may be a promoting factor for osteochondral regeneration. In addition, microRNA (miRNA) sequencing confirmed that hWJMSC-Exos contain many miRNAs that can promote the regeneration of hyaline cartilage. We further clarified the role of hWJMSC-Exos in osteochondral regeneration through target gene prediction and pathway enrichment analysis. In summary, this study confirms that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration.

In the absence of timely and proper treatments, injuries to articular cartilage (AC) can lead to cartilage degeneration and ultimately result in osteoarthritis. Regenerative medicine and tissue engineering techniques are emerging as promising approaches for AC regeneration and repair. Although the use of cell-seeded scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent, these approaches are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. Recently developed acellular scaffold approaches that rely on the recruitment of endogenous cells to the injured sites avoid these drawbacks and offer great promise for in situ AC regeneration. Multiple endogenous stem/progenitor cells (ESPCs) are found in joint-resident niches and have the capability to migrate to sites of injury to participate in AC regeneration. However, the natural recruitment of ESPCs is insufficient, and the local microenvironment is hostile after injury. Hence, an endogenous cell recruitment strategy based on the combination of chemoattractants and acellular scaffolds to effectively and specifically recruit ESPCs and improve local microenvironment may provide new insights into in situ AC regeneration. This review provides a brief overview of: (1) the status of endogenous cell recruitment strategy; (2) the subpopulations, potential migration routes (PMRs) of joint-resident ESPCs and their immunomodulatory and reparative effects; (3) chemoattractants and their potential adverse effects; (4) scaffold-based drug delivery systems (SDDSs) that are utilized for in situ AC regeneration; and (5) the challenges and future perspectives of endogenous cell recruitment strategy for AC regeneration. STATEMENT OF SIGNIFICANCE: Although the endogenous cell recruitment strategy for articular cartilage (AC) regeneration has been investigated for several decades, much work remains to be performed in this field. Future studies should have the following aims: (1) reporting the up-to-date progress in the endogenous cell recruitment strategies; (2) determining the subpopulations of ESPCs, the cellular and molecular mechanisms underlying the migration of these cells and their anti-inflammatory, immunomodulatory and reparative effects; (3) elucidating the chemoattractants that enhance ESPC recruitment and their potential adverse effects; and (4) developing advanced SDDSs for chemoattractant dispatch. Herein, we present a systematic overview of the aforementioned issues to provide a better understanding of endogenous cell recruitment strategies for AC regeneration and repair.