University of South China

The structural and functional homeostasis of the vascular wall critically depends on vascular smooth muscle cells (VSMCs) and their secreted extracellular matrix. As the primary cellular component of the vascular tunica media, VSMCs work in concert with elastic fiber networks to maintain vascular tension through their contractile properties. However, the most remarkable characteristic of VSMCs lies in their exceptional phenotypic plasticity. When subjected to mechanical injury or biochemical stimulation, differentiated contractile VSMCs undergo dedifferentiation, transforming into an intermediate state with highly synthetic activity. This phenotypic switching enables VSMCs to dedifferentiate into various functional subtypes, including fibroblast-like, macrophage-like, osteoblast-like, and adipocyte-like VSMCs. While this process confers proliferative and synthetic capabilities to repair vascular damage, it may conversely accelerate vascular pathology under disease conditions. Recent breakthroughs in single-cell RNA sequencing and lineage tracing technologies have revealed that most of lesional macrophages in atherosclerotic plaques are derived from macrophage-like cells (MLCs) dedifferentiated from the VSMCs lineage. These MLCs significantly compromise plaque stability by promoting pathological changes such as necrotic core expansion and fibrous cap thinning. This review systematically elucidates the dynamic roles of VSMC-to-MLC conversion throughout the progression of atherosclerosis. Building on these findings, future research should focus on deciphering the molecular switches that maintain VSMC phenotypic homeostasis. The identification of these key regulatory nodes will provide a theoretical foundation for developing novel therapeutic strategies aimed at stabilizing atherosclerotic plaques.

The restricted self-healing capacity of articular cartilage, combined with the inflammatory response and oxidative stress that follow injury, makes articular cartilage restoration a challenging therapeutic problem. We engineered an injectable porous microgel system (BMSC-Met@MGs) utilizing microfluidic technology comprising GelMA, CSMA, and PVA, which co-encapsulate bone marrow mesenchymal stem cells (BMSCs) and metformin via hydrogen-bonded sustained release. This structure uniquely integrates immune modulation (downregulation of MMP3/MMP13), antioxidation (clearance of reactive oxygen species and restoration of the mitochondrial membrane potential), and cartilage regeneration (upregulation of COL2A1) in vitro. Preliminary in vivo results suggest that BMSC-Met@MGs facilitated hyaline cartilage repair in rats. Our study introduced a comprehensive therapeutic approach with anti-inflammatory, antioxidant, and regenerative effects, marking the inaugural use of metformin in the repair of cartilage defects. This synergistic material/drug/cell method offers novel insights into cartilage repair.

Personalized gene circuit is a robust mode of cellular regulation that can manipulate intracellular gene expression to achieve desired functional regulation. However, the construction of logic circuits that automatically sense the characteristics of a particular environment within a cell is often difficult and lacking in sensitivity. Here, we synthesize from scratch specific promoters capable of sensing in cells, and use the combination of different types of promoters to construct smart gene circuits that can regulate gene expression in specific cell types sensitively. In detail, the tumour-specific promoter and the prostate tissue-specific promoter were constructed to be combined together into generating an artificial AND-gate gene circuit using the CRISPR-Cas9 system which could identify prostate cancer selectively. We then utilized this artificial gene circuit to drive targeted genes expression, such as P21, E-cadherin and Bax, to inhibit multifunctional prostate cancer cells but not other cells. Moreover, we applied gene circuits to redirect endogenous genes within cells and significantly and specifically suppressed the tumor growth of prostate cancer in vivo. Overall, these results highlight the clinical potential of these gene circuits as specific tools for prostate cancer detection and treatment, which is a new method for specifically reprogramming prostate cancer cells in vivo and may serve as a promising treatment strategy.