Milk fat globule-epidermal growth factor 8 (MFG-E8) is a secreted glycoprotein primarily produced by phagocytes, such as macrophages and microglia, and is widely distributed in multiple mammalian tissues and organs. MFG-E8 exerts a wide range of biological effects, extensively influencing the outcomes of tissue repair by modulating key processes such as efferocytosis, macrophage polarization, angiogenesis, and oxidative stress. While mostly exerting beneficial effects, its detrimental roles in different pathological contexts, such as tumor progression and vascular wall injury, cannot be overlooked. Therefore, a comprehensive understanding of the effects of MFG-E8 in tissue repair is significant for the future development of safe and effective therapeutic strategies. This review summarizes the diverse biological effects of MFG-E8, with a focus on its roles and the underlying molecular mechanisms in the tissue repair of the nervous, musculoskeletal, cardiovascular, and digestive systems. Furthermore, it explores the potential of MFG-E8 as a therapeutic target and its possibilities for clinical application.

Intervertebral disc degeneration (IVDD) is a predominant cause of low back pain, and mesenchymal stem cell (MSC) transplantation represents a promising therapeutic strategy. However, its efficacy is severely limited by the harsh oxidative microenvironment of the degenerative disc, which rapidly triggers ferroptosis, an iron-dependent form of cell death, in transplanted MSCs. This review critically appraised current ferroptosis-inhibition strategies, highlighting their transient or single-axis limitations. We then synthesized a hierarchical framework for engineering robust MSC resistance, progressing from dual-target gene circuits and genetic-pharmacological alliances to smart, protective biomaterial niches. Conventional approaches provide only partial protection. In contrast, advanced multi-layered strategies, including dual-target gene circuits (e.g., the Prominin-2/FBXO22/BACH1 axis) potentiated by genetic-pharmacological alliances (e.g., with TBE56), confer superior, cell-intrinsic resilience, increasing MSC survival by approximately 1.5-fold and significantly improving regenerative outcomes in IVDD models. Furthermore, encapsulating engineered MSCs in responsive biomaterials establishes a protective niche, ensuring sustained function. The paradigm is shifting from passive protection to active cellular empowerment. Engineering MSCs with multi-layered, comprehensive ferroptosis shielding is fundamental to unlocking their full therapeutic potential. This engineered cellular empowerment strategy represents a paradigm shift from palliative care to potentially curative, regenerative treatment for IVDD, with the potential to fundamentally change clinical management by addressing the root cause of MSC therapy failure.

Macrophages contribute to osteoarthritis (OA) pathogenesis, but how specific macrophage states influence chondrocyte senescence remains unclear. Using single-cell RNA sequencing of naturally aged mouse joints, we identified a PTGS2-high macrophage subset associated with joint senescence. In a surgically induced OA model, lineage tracing revealed a marked increase of these macrophages, and their selective depletion using a diphtheria toxin receptor-based mouse model attenuated cartilage senescence and disease progression. PTGS2+ macrophage-derived THBS1 promoted chondrocyte senescence through SDC4-associated pericellular interactions and, at least in part, TGF-β-dependent signaling. Macrophage-specific deletion of Thbs1 reduced chondrocyte senescence markers and attenuated OA-like degeneration. Mechanistically, elevated glycolytic lactate enhanced THBS1 lactylation at lysine 262 (K262), which reduces NEDD4-dependent ubiquitination and stabilizes THBS1 protein. Intra-articular targeting of PTGS2-high macrophages attenuated chondrocyte senescence and OA progression. These findings link macrophage metabolic remodeling to a pro-senescent secreted pathway and suggest a locally delivered strategy for OA.

Platelet-rich plasma-derived exosomes (PRP-Exos) have recently been considered an optimized strategy for diabetic wound treatment, yet the potential role of PRP-Exos in diabetic wound healing is still unclear. This study aims to investigate the potential mechanisms of PRP-Exos in diabetic wound healing and to utilize the hydrogel Pluronic F127 as a carrier to maintain the sustained release of encapsulated PRP-Exos. PRP-Exos were isolated from the blood of healthy individuals and characterized, followed by co-culturing with isolated diabetic human skin fibroblasts (Diabetes HSF). RNA sequencing (RNA-seq) was used to analyze the effect of PRP-Exos on the transcriptome of normal and Diabetes HSF, screening and validating the crucial mechanism and target gene. Then, a hydrogel composed of Pluronic F127 and PRP-Exos (PRP-Exos/Gel) was constructed and applied in the diabetic mouse models to evaluate the effect and mechanism. RNA-seq analysis revealed that PRP-Exos significantly upregulated the expression of FosB in Diabetes HSF. Further intervention in the expression of FosB in Diabetes HSF showed that knocking down FosB induced ferroptosis in Diabetes HSF, characterized by decreased cell viability, increased oxidative stress, and increased iron ion levels, along with downregulation of GPX4 and SLC7A11 expression, while ACSL4 expression was increased; conversely, overexpression of FosB had the opposite effect. Subsequently, adding PRP-Exos to FosB-knocked down Diabetes HSF significantly weakened the inhibitory effect of PRP-Exos on ferroptosis in diabetic fibroblasts. The synthesized PRP-Exos/Gel exhibited significant thermosensitivity and sustained release of exosomes. In animal experiments, the PRP-Exos/Gel showed significant anti-inflammatory effects, evidenced by an increased proportion of M2 macrophages and a decreased proportion of central granule cells in wound tissue, and inhibited fibroblast ferroptosis, thereby accelerating wound healing. Overall, the constructed PRP-Exos/Gel displays a continuous release of exosomes and promotes diabetic wound healing by suppressing inflammatory responses and fibroblast ferroptosis, which provides new insights and methods for the treatment of diabetic wounds.

Osteoarthritis (OA) is a prevalent joint disease characterized by pain, disability, and loss of physical function, posing a challenge to public health. However, molecular mechanisms of OA pathogenesis have not been fully described. We report that tripartite motif containing 15 (TRIM15) is a regulator in chondrocyte senescence and OA. Our study revealed heightened expression of TRIM15 in chondrocytes of senescent cartilage from patients with OA and in aged wild-type mice. Using gain- and loss-of-function studies, we found that TRIM15 facilitated human chondrocyte senescence. Conditional deletion of Trim15 in mouse chondrocytes severely impaired skeletal growth, partially because of impaired embryonic chondrocyte senescence. Compared with conditionally knocked out Col2a1-CreERT2/Trim15flox/flox mice, Trim15flox/flox control mice exhibited accelerated OA phenotypes, increased senescence markers, and senescence-associated secretory phenotype during aging. Mechanistically, TRIM15 bound with yes-associated protein (YAP) and mediated K48-linked YAP ubiquitination at K254, which interrupted the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. Dysregulation of TRIM15-YAP and transcriptional coactivator with PDZ-binding motif (TAZ) signaling promoted OA progression in both the surgery-induced and natural aging-induced mouse OA model. Intra-articular injection of adeno-associated virus 5 (AAV5)-Trim15 shRNA decelerated OA progression in mice. In particular, YAP and TAZ protein amounts were increased in chondrocytes of patients with OA. Our preclinical results demonstrated that the AAV5-TRIM15 shRNA treatment protected human OA explants against degeneration through inhibiting chondrocyte senescence. Together, our findings underscore the potential of targeting TRIM15 in reshaping the aging cartilage microenvironment and suggest a promising therapeutic avenue for OA.

The advancement of nanomedicine requires a thorough understanding of the intrinsic bioactivity and molecular interactions of nanomaterials for safe and effective clinical applications, which remains lacking for most currently developed nanomaterials. Here, we uncover the unique intrinsic bioactivity and regulatory mechanisms of carbon-based fullerol nanomaterials through high-throughput molecular analysis and explore their therapeutic potential for tissue regeneration using tissue engineering approaches. Fullerol exhibits intrinsic pro-differentiation and antioxidant properties that enhance the osteogenesis and chondrogenesis of MSCs. Mechanistically, proteomic analysis combined with small-molecule inhibition studies reveals that fullerol is internalized by MSCs via clathrin-mediated endocytosis and activates NRF2 signaling, thereby exerting antioxidant effects that restore impaired MSC viability and differentiation under oxidative stress. Leveraging these unique bioactivities, we develop a fullerol-functionalized hydrogel with feasible physicochemical properties and triple biological functions in antioxidant, pro-osteogenic, and pro-chondrogenic effects and confirm its great regenerative capacity for both cartilage and subchondral bone by promoting structural restoration and improving functional recovery in a rat osteochondral defect model. Our findings offer new insights into the intricate interactions between stem cells and nanomaterials at the cellular and molecular levels and broaden the potential biomedical applications of fullerol for future cartilage and bone regeneration therapies.

Stem cell-based cartilage regeneration remains a major clinical challenge due to the need for temporally coordinated immunomodulation and chondrogenic induction. This study designed a composite G5-IM/Mn nanoparticle system by covalently conjugating the anti-inflammatory drug indomethacin (IM) onto the surface of fifth-generation poly(amidoamine) (G5) dendrimers and encapsulating chondrogenic manganese ions (Mn) within their internal cavities. The G5-IM/Mn nanoparticles enable the rapid release of IM followed by sustained release of Mn, precisely matching the temporal requirements for inflammation control and subsequent chondrogenesis. In vitro studies demonstrated that G5-IM/Mn nanoparticles exerted significant anti-inflammatory effects. These nanoparticles were further incorporated into a GelMA hydrogel to fabricate a GelMA@G5-IM/Mn system. Moreover, experiments showed that the bone marrow stem cell (BMSC)-loaded GelMA@G5-IM/Mn system exhibited excellent biocompatibility and significantly upregulated the expression of chondrogenic markers, including SOX9, ACAN, and Col2a1. In a rabbit subcutaneous implantation model, the BMSC-loaded GelMA@G5-IM/Mn system markedly reduced CD3+ and CD68+ inflammatory cell infiltration. Furthermore, it enhanced collagen type II expression and cartilage matrix deposition. Biochemical analyses revealed increased glycosaminoglycan and collagen II content, as well as improved Young’s modulus in the GelMA@G5-IM/Mn group. In summary, this time-programmed G5-IM/Mn nanoparticle system first establishes an immuno-favorable microenvironment and subsequently promotes robust cartilage regeneration.

Background:Metabolic syndrome (MetS) is a combination of interconnected conditions, including insulin resistance, abdominal obesity, high blood pressure, and abnormal blood lipid levels. The objective of this research was to investigate the impact of MetS on the quality of life and clinical outcomes following total knee arthroplasty (TKA) in patients with osteoarthritis (OA). Methods:A retrospective descriptive study was conducted to enroll OA patients who underwent primary TKA at Zhongda Hospital, Southeast University from January 2015 to August 2019. A total of 83 OA patients who did and 144 (MetS group) who did not have MetS (non-MetS group) were included. An analysis was conducted on the patient's clinical data. Results:The two groups had similar results in terms of lengths of stay (P=0.93), hospital costs (P=0.24), and overall complication rates (P=0.99). There was no significant difference in the average erythrocyte sedimentation rate and C-reactive protein levels between the groups. However, the MetS group exhibited notably lower Hospital for Special Surgery knee scores and Short Form [36] health survey (SF-36) scores compared to the non-MetS group (both P>0.05) during the one-year follow-up period. Conclusions:OA patients who have MetS had significantly worse knee joint function and quality of life after TKA. There are certain constraints in the current research. First, it belongs to a single-center retrospective study. Further study will be necessary to determine the generality of this conclusion. Second, this study is retrospective, and the number of patients included is not large. Third, due to the diverse clinical groups in our hospital, it is challenging to comprehensively document all the clinical data of the patients involved in this study. Forth, this study did not compare the preoperative differences between the two groups, as well as analyze the postoperative improvement changes in depth. We will compare the preoperative and postoperative differences between the two groups in more depth in future large sample studies.

In the field of sports medicine, repair surgery for anterior cruciate ligament (ACL) and rotator cuff (RC) injuries are remarkably common. Despite the availability of relatively effective treatment modalities, outcomes often fall short of expectations. This comprehensive review aims to thoroughly examine current strategies employed to promote tendon-bone healing and analyze pertinent preclinical and clinical research. Amidst ongoing investigations, tendon-derived stem cells (TDSCs), which have comparatively limited prior exploration, have garnered increasing attention in the context of tendon-bone healing, emerging as a promising cell type for regenerative therapies. This review article delves into the potential of combining TDSCs with tissue engineering methods, with ACL reconstruction as the main focus. It comprehensively reviews relevant research on ACL and RC healing to address the issues of graft healing and bone tunnel integration. To optimize tendon-bone healing outcomes, our emphasis lies in not only reconstructing the original microstructure of the tendon-bone interface but also achieving proper bone tunnel integration, encompassing both cartilage and bone formation. In this endeavor, we thoroughly analyze the transcriptional and molecular regulatory variables governing TDSCs differentiation, incorporating a retrospective analysis utilizing single-cell sequencing, with the aim of unearthing relevant signaling pathways and processes. By presenting a novel strategy rooted in TDSCs-driven osteogenic and chondrogenic differentiation for tendon-bone healing, this study paves the way for potential future research avenues and promising therapeutic applications. It is anticipated that the findings herein will contribute to advancing the field of tendon-bone healing and foster the exploration of TDSCs as a viable option for regenerative therapies in the future.

Osteochondral defects pose a severe threat to joint structure and function, leading to permanent joint dysfunction. Electrical stimulation provided by electroactive materials is one of the most effective tools for inducing tissue regeneration. Electrical stimulation can supplement the missing bioelectric microenvironment, which is particularly important for the piezoelectric skeletal muscle system. Piezoelectric biomaterials have garnered attention in the field of osteochondral tissue engineering due to their biocompatibility, biodegradability, and the ability to produce an electrical output in response to mechanical stress. This article first introduces the basic principles and biological significance of the piezoelectric effect, then discusses in detail the classification of piezoelectric biomaterials, including biopiezoelectric ceramics, biopiezoelectric polymers, and composite piezoelectric biomaterials. Furthermore, the article explores the development and application of piezoelectric scaffolds, especially the application of electrospinning technology and piezoelectric hydrogels in tissue engineering. In addition, the review also analyses the role of piezoelectric stimulation in promoting cell function, including simulating bioelectric signals, immune regulation, and the impact on the proliferation, differentiation, and migration of chondrocytes and osteoblasts. Finally, the article discusses the application of piezoelectric stimulation in the repair of osteochondral defects and provides commentary on future trends, challenges, and opportunities for implementing biodegradable piezoelectric polymers in biomedical applications.

Accumulating evidence suggests that microRNAs (miRNAs) play an important role in intervertebral disc degeneration (IDD), but the precise role of specific miRNAs involved in this disease remains elusive. The purpose of this study was to identify IDD-specific miRNAs, followed by functional validation of results. MiRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing Solexa sequencing and quantitative real-time PCR (qRT-PCR). Biological functions of differential expression miRNAs were further investigated in vitro and in vivo. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 28 miRNAs that were differentially expressed in patients compared with controls. Following qRT-PCR confirmation, miR-193a-3p was significantly down-regulated in degenerative NP tissues. Moreover, its level was correlated with grade of disc degeneration. Through gain- and loss-of-function studies, miR-193a-3p was demonstrated to significantly promote type II collagen expression in NP cells. Knockdown of MMP14 induced effects on NP cells similar to those induced by miR-193a-3p. Bioinformatics target prediction identified MMP14 as a putative target of miR-193a-3p. Furthermore, luciferase reporter assays and Western blotting demonstrated that miR-193a-3p directly targets MMP14. MiR-193a-3p inhibited IDD in vitro and in vivo. The downregulation of miR-193a-3p induces the expression of MMP14, which promotes loss of type II collagen and thereby contributes to the development of human IDD. Our findings extend the role of miR-193a-3p in the pathogenesis of IDD and provide a potential novel therapeutic target for degenerative disc disease.

Discoid lateral meniscus (DLM) is the most common congenital variant of the lateral meniscus, which is prone to degeneration and lesions, and often leads to knee osteoarthritis. At present, there is no consensus on the clinical practice of DLM, and this expert consensus and practice guidelines on DLM was developed and approved by Chinese Society of Sports Medicine according to the Delphi method. Among 32 statements drafted, 14 statements were excluded for redundant information, and 18 statements achieved consensus. This expert consensus focused on the definition, epidemiology, etiology, classification, clinical manifestations, diagnosis, treatment, prognosis, and rehabilitation of DLM. Restoring the normal shape, retaining appropriate width and thickness, and ensuring the stability of the remnant meniscus is critical to sustaining the physiological function of the meniscus and preserving the knee. The partial meniscectomy with or without repair should be the first-line treatment when possible, given that the clinical and radiological long-term outcomes of total or subtotal meniscectomy are worse.

Although mesenchymal stem cells (MSCs) have been effective in tendinopathy, the mechanisms by which MSCs promote tendon healing have not been fully elucidated. In this study, we tested the hypothesis that MSCs transfer mitochondria to injured tenocytes in vitro and in vivo to protect against Achilles tendinopathy (AT). Bone marrow MSCs and H2O2-injured tenocytes were co-cultured, and mitochondrial transfer was visualized by MitoTracker dye staining. Mitochondrial function, including mitochondrial membrane potential, oxygen consumption rate, and adenosine triphosphate content, was quantified in sorted tenocytes. Tenocyte proliferation, apoptosis, oxidative stress, and inflammation were analyzed. Furthermore, a collagenase type I-induced rat AT model was used to detect mitochondrial transfer in tissues and evaluate Achilles tendon healing. MSCs successfully donated healthy mitochondria to in vitro and in vivo damaged tenocytes. Interestingly, mitochondrial transfer was almost completely blocked by co-treatment with cytochalasin B. Transfer of MSC-derived mitochondria decreased apoptosis, promoted proliferation, and restored mitochondrial function in H2O2-induced tenocytes. A decrease in reactive oxygen species and pro-inflammatory cytokine levels (interleukin-6 and -1β) was observed. In vivo, mitochondrial transfer from MSCs improved the expression of tendon-specific markers (scleraxis, tenascin C, and tenomodulin) and decreased the infiltration of inflammatory cells into the tendon. In addition, the fibers of the tendon tissue were neatly arranged and the structure of the tendon was remodeled. Inhibition of mitochondrial transfer by cytochalasin B abrogated the therapeutic efficacy of MSCs in tenocytes and tendon tissues. MSCs rescued distressed tenocytes from apoptosis by transferring mitochondria. This provides evidence that mitochondrial transfer is one mechanism by which MSCs exert their therapeutic effects on damaged tenocytes.

Osteoarthritis (OA) is the most common joint disease globally, and its progression is irreversible. The mechanism of osteoarthritis is not fully understood. Research on the molecular biological mechanism of OA is deepening, among which epigenetics, especially noncoding RNA, is an emerging hotspot. CircRNA is a unique circular noncoding RNA not degraded by RNase R, so it is a possible clinical target and biomarker. Many studies have found that circRNAs play an essential role in the progression of OA, including extracellular matrix metabolism, autophagy, apoptosis, the proliferation of chondrocytes, inflammation, oxidative stress, cartilage development, and chondrogenic differentiation. Differential expression of circRNAs was also observed in the synovium and subchondral bone in the OA joint. In terms of mechanism, existing studies have mainly found that circRNA adsorbs miRNA through the ceRNA mechanism, and a few studies have found that circRNA can serve as a scaffold for protein reactions. In terms of clinical transformation, circRNAs are considered promising biomarkers, but no large cohort has tested their diagnostic value. Meanwhile, some studies have used circRNAs loaded in extracellular vesicles for OA precision medicine. However, there are still many problems to be solved in the research, such as the role of circRNA in different OA stages or OA subtypes, the construction of animal models of circRNA knockout, and more research on the mechanism of circRNA. In general, circRNAs have a regulatory role in OA and have particular clinical potential, but further studies are needed in the future.

适当终止炎症反应的放大可防止无菌性炎症、微生物炎症导致的不必要的组织损伤,对治疗炎症性疾病、恢复组织动态平衡和正常功能至关重要.胞葬作用特指在凋亡细胞发生进一步坏死、释放有毒物质,并引起炎症反应之前被以巨噬细胞为代表的吞噬细胞清除的过程.近年来的研究提示调控胞葬作用对炎症微环境具有深远的影响,因此,深入了解这两者之间的关系对于发展炎症性疾病的诊疗措施具有较大的意义.本文作者着重对胞葬作用和炎症反应进行综述,以期为基础科研和临床应用提供一定的参考.

Cardiovascular disease (CVD), a leading cause of morbidity and mortality, is among the most prevalent health problems worldwide and effective strategies for its prevention and treatment are urgently required. In this regard, increasing research has demonstrated that natural drugs offer antihypertensive, antiatherosclerotic, and cardioprotective activities, and many are applied widely for the treatment of CVD and its manifestations such as myocardial infarction, peripheral vascular diseases, and coronary heart disease. Natural drugs have significant advantages in the treatment of CVD due to their efficacy and safety profiles. Saponins are an important class of active components of plant natural products and play an important role in the treatment of CVD. This review covers the most up-to-date information on saponins concerning their cardioprotective effects and mechanisms of action.

Abstract Trial design: This study prospectively analyzes the effect of EPO combined with Iron sucrose on postoperative anemia prevention and prognosis of patients with TKA. Methods: Participants in this study will be randomly assigned to a treatment group or control group. Patients in the treatment group will receive EPO for ten days combined with iron sucrose injection for three days preoperative. The general data, hematological indexes, transfusion rate, total blood loss, and knee joint function score will be analyzed. Results: 92 patients met the inclusion criteria, including 46 patients in the treatment group and 46 in the control group. There were no significant statistical differences in descriptive characteristics of the population between the two groups. The results indicated that the anemic rate of the treatment group was significantly lower than the control group after treatment (67.4%vs93.5%, P=0.001). The hematological index also has a significant difference in the two groups, such as Postoperative Hb, RBC count, Hct. The treatment group, perioperative blood loss, was significantly lower than the control group (587.69±340.81ml vs. 812.72±329.7ml, P=0.002). The treatment group showed a better HSS score and WOMAC score (HSS score: P=0.007; WOMAC score: P=0.001), HSS score improved 3.37 points, and WOMAC scores improved 12.08 points after the operation than the control group. No postoperative blood transfusion and postoperative complications occurred in the study period. Conclusions: According to our study, we found that perioperative treatment of erythrocyte mobilization in patients with TKA can improve postoperative hemoglobin level, reduce postoperative total blood loss, and reduce postoperative anemic rate without increased drug costs on the hospitalization expenses. Patients who receive erythrocyte mobilization treatment can significantly accelerate erythropoiesis after surgery and promote the hemoglobin level to normal more quickly. The patients after treatment show an advantage in HSS score and WOMAC score.

Sirt6 has been implicated as a key regulator in aging-related diseases, including osteoarthritis. However, its functional role and molecular mechanism in chondrocyte senescence and osteoarthritis pathophysiology remain largely undefined. Here we show that Sirt6 deficiency exaggerates chondrocyte senescence and osteoarthritis progression, whereas intra-articular injection of adenovirus-Sirt6 markedly attenuates surgical destabilization of medial meniscus-induced osteoarthritis. Mechanistically, Sirt6 can directly interact with STAT5 and deacetylate STAT5, thus inhibiting the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus, which inactivates IL-15/JAK3/STAT5 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 163 on STAT5. Mutation of lysine 163 to arginine in STAT5 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in chondrocytes exacerbated osteoarthritis. Pharmacological activation of Sirt6 substantially alleviated chondrocyte senescence. Taken together, Sirt6 attenuates chondrocyte senescence by inhibiting IL-15/JAK3/STAT5 signaling. Targeting Sirt6 represents a promising new approach for osteoarthritis.