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Spinal cord injury (SCI) is a severe central nerve diseases which lacks effective of treatment. Oxidative stress is a major pathological factor for SCI. It may induce mitochondrial damage, which further lead to ferroptosis and apoptosis in neural cells during SCI. Thus, targeting oxidative stress may be the key strategy for SCI treatment. In this study, we carried out screening experiment in the natural product library against oxidative stress in neural cells. It was identified that idebenone (IDE) may potently suppress oxidative stress induced cell death in neural cells. Furthermore, we successfully developed a multifunctional nanovesicles, which we named IDE@PPNs, by encapsulating IDE within proanthocyanidin polyphenol nanovesicles (PPNs). IDE@PPNs exhibited lysosomal escape capability and mitochondrial ROS responsiveness; meanwhile, they may suppress ferroptosis and apoptosis in neural cells. In vivo study demonstrated that IDE@PPNs may promote motor function recovery in rats and suppress ferroptosis and apoptosis in neurons. It may also show high biocompatibility in in vivo study. In summary, we fabricated a novel natural product loaded ROS responsive nanovesicles, IDE@PPNs may have the great potential for SCI therapy.

Objective: It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated. Methods: A blood-induced rat model was established and the impact of blood infiltration on inflammation and HO of the injured tendon was assessed. Cell adhesion, viability, apoptosis, and gene expression were measured to evaluate the effect of blood treatment on tendon stem/progenitor cells (TSPCs). Then RNA-seq was used to assess transcriptomic changes in tendons in a blood infiltration environment. At last, the small molecule drug PI3K inhibitor LY294002 was used for in vivo and in vitro HO treatment. Results: Blood caused acute inflammation in the short term and more severe HO in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenonic gene expression of TSPCs. Furthermore, blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenonic genes was significantly upregulated. At last, we also found that LY294002 treatment significantly reduced the tendon HO in the rat blood-induced model. Conclusion: Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO.

Summary: The global prevalence and burden of musculoskeletal (MSK) disorders are immense. Advancements in next-generation sequencing (NGS) have generated vast amounts of data, accelerating the research of pathological mechanisms and the development of therapeutic approaches for MSK disorders. However, scattered datasets across various repositories complicate uniform analysis and comparison. Here, we introduce MSdb, a database for visualization and integrated analysis of next-generation sequencing data from human musculoskeletal system, along with manually curated patient phenotype data. MSdb provides various types of analysis, including sample-level browsing of metadata information, gene/miRNA expression, and single-cell RNA-seq dataset. In addition, MSdb also allows integrated analysis for cross-samples and cross-omics analysis, including customized differentially expressed gene/microRNA analysis, microRNA-gene network, scRNA-seq cross-sample/disease integration, and gene regulatory network analysis. Overall, systematic categorizing, standardized processing, and freely accessible knowledge features MSdb a valuable resource for MSK research community.

Although aging is an increasingly severe healthy, economic, and social global problem, it is far from well-modeling aging due to the aging process’s complexity. To promote the aging modeling, here we did the quantitative measurement based on aging blood transcriptome. Specifically, the aging blood transcriptome landscape was constructed through ensemble modeling in a cohort of 505 people, and 1138 age-related genes were identified. To assess the aging rate in the linear dimension of aging, we constructed a simplified linear aging clock, which distinguished fast-aging and slow-aging populations and showed the differences in the composition of immune cells. Meanwhile, the non-linear dimension of aging revealed the transcriptome fluctuations with a crest around the age of 40 and showed that this crest came earlier and was more vigorous in the fast-aging population. Moreover, the aging clock was applied to evaluate the rejuvenation effect of molecules in vitro, such as Nicotinamide Mononucleotide (NMN) and Metformin. In sum, this study developed a de novo aging clock to evaluate age-dependent precise medicine by revealing its fluctuation nature based on comprehensively mining the aging blood transcriptome, promoting the development of personal aging monitoring and anti-aging therapies.

Objective: The magnitude of the therapeutic effects of intra-articular injection of platelet-rich plasma (PRP) on osteoarthritis (OA) is still under debate. The goal of this study that was a systematic review of randomised controlled trials ​of PRP injections for the treatment of OA was to elucidate the therapeutic efficacy of PRP. Methods: Electronic databases of PubMed, CENTRAL, EMBASE, EBSCO, ClinicalTrials.gov, and International Clinical Trials Registry Platform ​were searched from inception to June 2018 for RCTs that compared PRP injections to controls in patients with OA. A random-effects approach was used to compile data and subgroups according to trial size (large trials versus small trials), patient profile (age and gender), and PRP preparation method was performed. Results: Thirty trials met the inclusion criteria and were analysed. All results had unexplained statistical heterogeneity. Patients treated with PRP compared with control showed statistically relevant pain relief and function improvement at short term (standardised mean difference [SMD] ​= ​−0.62, 95% confidence interval [CI]: −0.98 to −0.27, P ​= ​0.0006, SMD ​= ​−0.74, 95% CI: −1.11 to 0.36, P ​= ​0.0001, respectively), medium term (SMD ​= ​−0.53, 95% CI: −0.83 to −0.23, P ​= ​0.0006, SMD ​= ​−0.50, 95% CI: −0.75 to −0.25, P ​= ​0.0006), and long term (SMD ​= ​−0.69, 95% CI: −1.08 to −0.30, P ​= ​0.0006, SMD ​= ​−0.68, 95% CI: −0.1.09 to −0.27, P ​= ​0.001, respectively). A subgroup analysis of the data from large trials and from trials composed of less than 50% female patients revealed that therapeutic effects of the treatment are insignificant. Conclusions: According to the currently available data, PRP injections are beneficial for pain relief and function improvement in patients with OA. This meta-analysis, however, demonstrated that the efficacy of PRP is related to sample size and gender composition. Thus, more randomised controlled trials of high quality and larger patient size, also including gender aspects, are required to understand this phenomenon. The translational potential of this article: The translation potential of this meta-analysis is that provided another perspective to analyse the treatment effect of PRP for OA. In future research, phenotypes subpopulation and gender difference of OA patient should be considered for PRP treatment.

Summary: Articular cartilage injury and degeneration causing pain and loss of quality-of-life has become a serious problem for increasingly aged populations. Given the poor self-renewal of adult human chondrocytes, alternative functional cell sources are needed. Direct reprogramming by small molecules potentially offers an oncogene-free and cost-effective approach to generate chondrocytes, but has yet to be investigated. Here, we directly reprogrammed mouse embryonic fibroblasts into PRG4+ chondrocytes using a 3D system with a chemical cocktail, VCRTc (valproic acid, CHIR98014, Repsox, TTNPB, and celecoxib). Using single-cell transcriptomics, we revealed the inhibition of fibroblast features and activation of chondrogenesis pathways in early reprograming, and the intermediate cellular process resembling cartilage development. The in vivo implantation of chemical-induced chondrocytes at defective articular surfaces promoted defect healing and rescued 63.4% of mechanical function loss. Our approach directly converts fibroblasts into functional cartilaginous cells, and also provides insights into potential pharmacological strategies for future cartilage regeneration. : In this article, Ouyang and colleagues develop a chemical-driven direct reprogramming of mouse embryonic fibroblasts into PRG4+ chondrocytes, with a screen-defined cocktail VCRTc. Their induced chondrocytes promote in vivo cartilage functional regeneration. The dynamical cellular phenotypes were analyzed by single-cell RNA sequencing, illustrating the inhibition of fibroblast features and activation of chondrogenesis pathways in early reprogramming. Keywords: chemical reprogramming, single-cell analysis, cartilage regeneration, drug discovery

Summary: A low surface expression level of human leukocyte antigen class I (HLA-I) ensures that the mesenchymal stem cells (MSCs) escape from the allogeneic recipients' immunological surveillance. Here, we discovered that both transcriptional and synthesis levels of HLA-I in MSCs increased continuously after interferon (IFN)-γ treatment, whereas interestingly, their surface HLA-I expression was downregulated after reaching an HLA-I surface expression peak. Microarray data indicated that the post-transcriptional process plays an important role in the downregulation of surface HLA-I. Further studies identified that IFN-γ-treated MSCs accelerated HLA-I endocytosis through a clathrin-independent dynamin-dependent endocytosis pathway. Furthermore, cells that have self-downregulated surface HLA-I expression elicit a weaker immune response than they previously could. Thus uncovering the plasticity of MSCs in the regulation of HLA-I surface expression would reveal insights into the membrane transportation events leading to the maintenance of low surface HLA-I expression, providing more evidence for selecting and optimizing low-immunogenic MSCs to improve the therapeutic efficiency. : Biological Sciences; Immunology; Cell Biology; Stem Cells Research Subject Areas: Biological Sciences, Immunology, Cell Biology, Stem Cells Research

Bearing compression from adjacent joints, the articular cartilage is cumulatively pressured in daily life, thus making it prone to injuries; however, once damaged, the self-healing capacity of articular cartilage is limited owing to its low metabolic property. Autologous chondrocyte implantation, a three-step repairing technique for articular lesions, has received satisfactory short-term clinical outcomes, whereas its long-term effect remains controversial. Currently, improved stem-cell therapies and novel biomaterials have shed new lights on autologous chondrocyte implantation. We would, therefore, synthesize these optimization strategies in order of their presences in the three-step protocol, seeking to find and amplify synergic effects between these strategies. The translational potential of this article: Autologous chondrocytes implantation serves as an alternative for the treatment of articular cartilage lesions to avoid potentially detrimental effects of applying microfracture. The optimized ACI should improve the cost-effectiveness of repairing articular cartilage while circumventing latent complications like osteophyte. This article synthesized optimization strategies for ACI and provided appropriate applying approaches to maximize their synergic effects. It will be a pioneering trial for combinedly using stem cells and nanotechnology to regenerate cartilage. Keywords: Autologous chondrocyte implantation, Scaffold, Stem cell, Nanotechnology

Osteoarthritis (OA) is a leading cause of physical disability among aging populations, with no available drugs able to efficiently restore the balance between cartilage matrix synthesis and degradation. Also, OA has not been accurately classified into subpopulations, hindering the development toward personalized precision medicine.In the present study, we identified a subpopulation of OA patients displaying high activation level of epidermal growth factor receptor (EGFR). With Col2a1-creERT2; Egfrf/f mice, it was found that the activation of EGFR, indicated by EGFR phosphorylation (pEGFR), led to the destruction of joints. Excitingly, EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration. The Food and Drug Administration (FDA)-approved drug gefitinib could efficiently inhibit EGFR functions in OA joints and restore cartilage structure and function in the mouse model as well as the clinical case report.Overall, our findings suggested the concept of the EGFR activated OA subpopulation and illustrated the mechanism of EGFR signaling in regulating cartilage homeostasis. Gefitinib could be a promising disease-modifying drug for this OA subpopulation treatment. Keywords: Osteoarthritis, Disease subpopulation, Epidermal growth factor receptor, Gefitinib

The endometrial layer comprises luminal and glandular epithelia that both develop from the same simple layer of fetal uterine epithelium. Mechanisms of uterine epithelial progenitor self-renewal and differentiation are unclear. This study aims to systematically analyze the molecular and cellular mechanisms of uterine epithelial development by single-cell analysis. An integrated set of single-cell transcriptomic data of uterine epithelial progenitors and their differentiated progenies is provided. Additionally the unique molecular signatures of these cells, characterized by sequential upregulation of specific epigenetic and metabolic activities, and activation of unique signaling pathways and transcription factors, were also investigated. Finally a unique subpopulation of early progenitor, as well as differentiated luminal and glandular lineages, were identified. A complex cellular hierarchy of uterine epithelial development was thus delineated. Our study therefore systematically decoded molecular markers and a cellular program of uterine epithelial development that sheds light on uterine developmental biology.

Background: Intra-articular injections of hyaluronic acid (HA), the United States Food and Drug Administration approved treatment and widely utilized to delay or reserve the progression of the osteoarthritis (OA) involves. However, this treatment has shown controversial results through various clinical practice guidelines and meta-analysis evaluations, warrants more advanced researches on its safety and effectiveness., Methods: A novel strategy of integrating medical informatics and bioinformatics was utilized. An updated meta-analysis of 16 randomized controlled trials (RCTs) out of 1820 articles was conducted, in combination with a high throughput body-wide-organ-transcriptomic (BOT) RNA-sequencing (RNA-seq) and in vitro and vivo experiments to evaluate the effect of HA at local and systemic levels, revealing the underlying mechanism., Results: A sensitivity analysis was performed restricting to high quality RCTs, no significant effect of HA treatment was found on pain relief and functional improvement. Descriptive analysis of RNA-seq using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed biological process related to innate immune responses and apoptosis; BOT analysis revealed differential gene expressions (DEGs) in cartilage, lymph node, spleen, kidney, and liver, with immune cell proliferation in immune-related organs. In vitro, HA-coated plates were shown to induce macrophage responses; in vivo histological images revealed knee joint, liver, and kidney with damaged/abnormal morphologies, while immune cell proliferation was observed in the lymph node and spleen and it was found that there was no significant difference in the treatment effect for OA animal model., Conclusion: Conclusively, integration of meta-analysis with bioinformatics analysis exhibited that HA induces inflammatory responses both locally and systematically and not benefit for OA treatment, thus limiting the regeneration and leading to some organ-specific pathogenesis. The strategy and findings will be of important for guiding future long-term clinical studies., The Translational Potential of This Article: This study illustrated that the administered HA activated both systemic and local pro-inflammatory immune responses, possibly limiting its efficacy. This novel unique strategy proposed in this study can be utilized and adapted for future meta-analysis and bioinformatics study., Competing Interests: We declare no competing interests., (© 2021 The Authors.)