Kaini Liang

Probiotics, recognized for their cost‐effective production, easy storage, and straightforward delivery, are a key focus in developing innovative delivery systems for disease treatment. However, the limited delivery efficacy of probiotics and potential safety issues have hastened their broader application. In this study, a hydrogel encapsulation system is developed to improve the therapeutic efficiency of probiotics through subcutaneous administration. This encapsulation approach is proven to protect the probiotics, thus prolonging their lifetime and enhancing delivery efficiency. Besides, the growth of probiotics is limited within the hydrogel microparticle, which may reduce the adverse effects on the surrounding tissues. This probiotic therapy regimen is demonstrated in Exendin‐4 delivery for diabetic treatment, as well as the delivery of thrombopoietin mimetic peptide for thrombocytopenia treatment. In summary, this system has shown the promising potential of probiotic encapsulation in improving the efficacy and safety of probiotic therapy in various diseases.

Cirrhosis-associated portal hypertension drives vascular injury, yet the pathogenesis mediated by abnormal hydrostatic pressure (HP) remains unclear due to the absence of in vitro models replicating the cirrhotic perivascular mechanical microenvironment. Here, we developed 2D static and 3D dynamic “hepatic hypertension on-a-chip” (HH chip) systems replicating cirrhotic hemodynamics and matrix properties. The HH chip realized integration and decoupled regulation of HP, shear stress, and matrix stiffness. Liver sinusoidal endothelial cells (LSECs) exhibited HP-induced damage exclusively on stiff matrices, recapitulating cirrhotic degeneration phenotypes and genotypes. Using the HH chip, we identified GPR116 as the key HP mechanosensor in LSECs and delineated its downstream mechanotransduction pathway driving cellular injury. Genetic silencing of GPR116 protected endothelial cells from HP-induced damage both in vitro and in cirrhotic murine models. Cell- and gene-based therapies targeting GPR116 significantly attenuated cirrhosis progression. The HH chip can accelerate pathological investigation, target identification, and therapeutic development for hypertension-associated diseases.

Nonunions and delayed unions pose significant challenges in orthopedic treatment, with current therapies often proving inadequate. Bone tissue engineering (BTE), particularly through endochondral ossification (ECO), emerges as a promising strategy for addressing critical bone defects. This study introduces mesenchymal stem cells overexpressing Exendin-4 (MSC-E4), designed to modulate bone remodeling via their autocrine and paracrine functions. We established a type I collagen (Col-I) sponge-based in vitro model that effectively recapitulates the ECO pathway. MSC-E4 demonstrated superior chondrogenic and hypertrophic differentiation and enhanced the ECO cell fate in single-cell sequencing analysis. Furthermore, MSC-E4 encapsulated in microscaffold, effectively facilitated bone regeneration in a rat calvarial defect model, underscoring its potential as a therapeutic agent for bone regeneration. Our findings advocate for MSC-E4 within a BTE framework as a novel and potent approach for treating significant bone defects, leveraging the intrinsic ECO process.

Deposition of extracellular matrix (ECM) in the liver is an important feature of liver cirrhosis. Recovery from liver cirrhosis is physiologically challenging, partially due to the ECM in scar tissue showing resistance to cell‐mediated degradation by secreted matrix metalloproteinases (MMPs). Here, a cell‐mediated ECM‐degradation screening system (CEDSS) in vitro is constructed for high‐throughput searching for cells with tremendous degradation ability. ECM‐degrading liver sinusoidal endothelial cells (dLSECs) are screened using CEDSS, which exhibit 17 times the ability to degrade collagen when compared to other cells. The degradation ability of dLSECs is mediated by the upregulation of MMP9. In particular, mRNA expression of MMP9 shows an 833‐fold increase in dLSECs compared to normal endothelial cells (nLSECs), and MMP9 is regulated by transcription factor c‐Fos. In vivo, single intrasplenic injection of dLSECs alleviates advanced liver fibrosis in mice, while intraperitoneal administration of liver‐targeting peptide‐modified dLSECs shows enhanced fibrosis‐targeting effects. Degradative human umbilical vein endothelial cells (dHUVECs) prove their enhanced potential of clinical translation. Together, these results highlight the potential of ECM‐degrading endothelial cells in alleviating advanced liver fibrosis, thus providing remarkable insights in the development of ECM‐targeting therapeutics.

Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.

This study revealed the enhanced therapeutic effects and mechanisms of Exendin-4–engineered MSCs for type 2 diabetes treatment.