Trauma- or osteoarthritis-related cartilage damage resulted in functional decline of joints and heavy burden of public health. Recently, the reparative role of mesenchymal stem/progenitor cells (MSCs) in articular cartilage (AC) reconstruction is drawing more and more attention. To provide a review on (1) the locations and categories of joint-resident MSCs, (2) the regulation of chondrogenic capacities of MSCs, (3) the migratory approaches of MSCs to diseased AC and regulatory mechanisms. PubMed and Web of Science were searched for English-language articles related to MSC recruitment and migration for AC repair until June 2019. The presence of various MSCs in or around joints, the potential approaches to diseased AC` and the regenerative capacities of MSCs were reviewed. Various intra- and peri-articular MSCs, with inherent migratory potentials, are present in multiple stem cell niches in or around joints. The recruitment and migration of joint-resident MSCs play crucial roles in endogenous AC repair. Multiple recruiting signals, such as chemokines, growth factors, etc., emerge during the development of AC diseases and participate in the regulation of MSC mobilization. Motivated MSCs could migrate into cartilage lesions and then exert multiple reparative potentials, including extracellular matrix (ECM) reconstruction and microenvironment modulation. In general, AC repair based on endogenous MSC recruitment and migration is a feasible strategy, and a promising research field. Furthermore, endogenous AC repair mediated by native MSCs would provide new opportunities to efficient preventative or therapeutic options for AC diseases.

Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4–1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and off-target toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3⁺CD8⁺ T cells and CD62L⁺CCR7⁺ central memory T cells (T_CM) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the anti-tumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.

Osteonecrosis of the femoral head (ONFH) is a refractory orthopedic disease with a high disability rate. Long-term administration of steroids is the most common pathogenic factor for non-traumatic ONFH. Early diagnosis of steroid-induced osteonecrosis of the femoral head (SONFH) is difficult and mainly depends on imaging. The objectives of this review were to examine the pathological mechanisms of SONFH, summarize related markers of SONFH, and identify areas for future studies. We reviewed studies on pathological mechanisms and related markers of SONFH and discussed the relationship between them, as well as clinical applications and the outlook of potential markers. The pathological mechanisms of SONFH included decreased osteogenesis, lipid accumulation, increased intraosseous pressure, and microcirculation disruption. Differential proteomics and genomics play crucial roles in the occurrence, progression, and outcome of SONFH, providing novel insights into SONFH. Additionally, the biological functions of mesenchymal stem cells (MSCs) and exosomes (Exos) in SONFH have attracted increasing attention. The pathological mechanisms of SONFH are complex. The related markers mentioned in the current review can predict the occurrence and progression of SONFH, which will help provide effective early clinical prevention and treatment strategies for SONFH.

Bone healing is thought to be influenced by the cross-talk between bone forming and immune cells. In particular, macrophages play a crucial role in the regulation of osteogenesis. Curcumin, the major bioactive polyphenolic ingredient of turmeric, has been shown to regulate inflammatory response and osteogenic activities. However, whether curcumin could regulate macrophage polarization and subsequently influence osteogenesis remain to be elucidated. In this study, the potential immunomodulatory capability of curcumin on inflammatory response and phenotype switch of macrophages and the subsequent impact on osteogenic differentiation of MSCs are investigated. We demonstrated that curcumin exhibited significant anti-inflammatory effect by polarizing the macrophages toward anti-inflammatory phenotype, with increased expression of IL-4, IL-10, and CD206, and decreased expression of IL-1β, TNF-α, CCR7, and iNOS. In addition, curcumin could improve the osteo-immune microenvironment via promoting osteogenesis-related regenerative cytokine BMP-2 and TGF-β production. Moreover, the co-cultured test of macrophages and BMSCs showed that curcumin-modulated macrophages conditioned medium could promote osteogenic differentiation of BMSCs with increased gene (ALP, Runx-2, OCN, and OPN) and protein (Runx-2 and OCN) expression levels, enhanced ALP activity, and obvious formation of mineralized nodules. Taken together, with the interaction between curcumin-conditioned macrophage and curcumin-stimulated BMSCs, curcumin could remarkably enhance the osteogenic differentiation of BMSCs in LPS-activated inflammatory macrophage-BMSCs coculture system.

The senescence-associated secretory phenotype (SASP) is a generic term for the secretion of cytokines, such as pro-inflammatory factors and proteases. It is a crucial feature of senescent cells. SASP factors induce tissue remodeling and immune cell recruitment. Previous studies have focused on the beneficial role of SASP during embryonic development, wound healing, tissue healing in general, immunoregulation properties, and cancer. However, some recent studies have identified several negative effects of SASP on fracture healing. Senolytics is a drug that selectively eliminates senescent cells. Senolytics can inhibit the function of senescent cells and SASP, which has been found to have positive effects on a variety of aging-related diseases. At the same time, recent data suggest that removing senescent cells may promote fracture healing. Here, we reviewed the latest research progress about SASP and illustrated the inflammatory response and the influence of SASP on fracture healing. This review aims to understand the role of SASP in fracture healing, aiming to provide an important clinical prevention and treatment strategy for fracture. Clinical trials of some senolytics agents are underway and are expected to clarify the effectiveness of their targeted therapy in the clinic in the future. Meanwhile, the adverse effects of this treatment method still need further study.