Stem and progenitor cells in the synovial joint as targets for regenerative therapy
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Engineering bone/cartilage organoids: strategy, progress, and application
The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.
Cross-talk of inflammation and cellular senescence: a new insight into the occurrence and progression of osteoarthritis
Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.
CCN2 mediates fibroblast-macrophage interaction in knee arthrofibrosis based on single-cell RNA-seq analysis
Knee arthrofibrosis, characterized by excessive matrix protein production and deposition, substantially impairs basic daily functions, causing considerable distress and financial burden. However, the underlying pathomechanisms remain unclear. Here, we characterized the heterogeneous cell populations and cellular pathways by combination of flow cytometry and single-cell RNA-seq analysis of synovial tissues from six patients with or without knee arthrofibrosis. Increased macrophages and fibroblasts were observed with decreased numbers of fibroblast-like synoviocytes, endothelial cells, vascular smooth muscle cells, and T cells in the arthrofibrosis group compared with negative controls. Notably, fibroblasts were discovered to interact with macrophages, and lead to fibrosis through TGF-β pathway induced CCN2 expression in fibroblasts. CCN2 was demonstrated to be required for fibroblast pro-fibrotic functions (activation, proliferation, and migration) through TGFBR/SMAD pathway. The expression of CCN2 was positively correlated with the collagen volume and TGF-β expression and negatively associated with patient-reported outcome measures in another cohort of patients with knee arthrofibrosis. Our study reveals the role of CCN2 in the fibroblast-macrophage interaction through TGF-β pathway which might help to shed light on CCN2 as a potential biomarker.
Cardiac conduction system regeneration prevents arrhythmias after myocardial infarction
Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. How insult to the cardiac conduction system causes arrhythmias following MI is poorly understood. Here, we demonstrate conduction system restoration during neonatal mouse heart regeneration versus pathological remodeling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganized bundling of conduction fibers after MI and global His–Purkinje disruption. Single-cell RNA sequencing (scRNA-seq) revealed specific molecular changes to regenerate the conduction network versus aberrant electrical alterations during fibrotic repair. This manifested functionally as a transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modeling in the infarcted human heart implicated the non-regenerative phenotype as causative for heart block, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration and reveal how MI-induced damage elicits clinical arrhythmogenesis.
Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases
Degenerative spine and joint diseases, including intervertebral disc degeneration (IDD), ossification of the spinal ligaments (OSL), and osteoarthritis (OA), are common musculoskeletal diseases that cause pain or disability to the patients. However, the pathogenesis of these musculoskeletal disorders is complex and has not been elucidated clearly to date. As a matter of fact, the spine and joints are not independent of other organs and tissues. Recently, accumulating evidence demonstrates the association between obesity and degenerative musculoskeletal diseases. Obesity is a common metabolic disease characterized by excessive adipose tissue or abnormal adipose distribution in the body. Excessive mechanical stress is regarded as a critical risk factor for obesity-related pathology. Additionally, obesity-related factors, mainly including lipid metabolism disorder, dysregulated pro-inflammatory adipokines and cytokines, are reported as plausible links between obesity and various human diseases. Importantly, these obesity-related factors are deeply involved in the regulation of cell phenotypes and cell fates, extracellular matrix (ECM) metabolism, and inflammation in the pathophysiological processes of degenerative spine and joint diseases. In this study, we systematically discuss the potential cellular and molecular mechanisms underlying obesity in these degenerative musculoskeletal diseases, and hope to provide novel insights for developing targeted therapeutic strategies.
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