从信号通路到临床试验:间充质干细胞在肝硬化治疗中作为多模式再生构建者
From signaling pathways to clinical trials: mesenchymal stem cells as multimodal regenerative architects in liver cirrhosis therapy.
作者信息
Bozorgi Vida, Babaahmadi Mahnaz, Salehi Mohammad, Vafaeimanesh Jamshid, Hajizadeh-Saffar Ensiyeh
机构信息
Clinical Research Development Center, Qom University of Medical Sciences, Qom, Iran.
Qom Gastroenterology and Hepatology Disease Research Center, Qom University of Medical Sciences, Qom, Iran.
出版信息
Stem Cell Res Ther. 2025 Aug 5;16(1):421. doi: 10.1186/s13287-025-04535-8.
Liver cirrhosis, a chronic disease distinguished by extensive scarring in the liver, results in liver dysfunction and fatal complications such as portal hypertension and liver cancer. Although early interventions can retard or reverse early injury, advanced stages often call for liver transplantation-a therapy undermined by donor shortage and logistical setbacks. Emerging cell therapies, particularly those based on mesenchymal stem cells (MSCs), offer a novel approach to addressing these clinical needs. MSCs, self-renewing multipotent stromal cells, can differentiate into many cell types, including hepatocyte-like cells. Immune regulation, regenerative signaling, and anti-scarring effects are three mechanisms that underlie their therapeutic promise. MSCs modulate immune cells, suppressing inflammation and promoting tissue healing. MSCs release several growth factors and cytokines, including hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinases (MMPs), which participate in tissue regeneration. Among these, HGF is bivalent, as it supports hepatocyte proliferation while also inhibiting fibrosis and apoptosis, thereby allowing the tissue to repair and protect itself. Recent advances identify extracellular vesicles from MSCs (MSC-EVs) as a cell-free alternative. The vesicles contain bioactive cargo, including microRNAs and proteins, that regulate immune function, inhibit cell death, and facilitate liver repair. Preclinical models of cirrhosis in animals have demonstrated MSC-EVs to enhance liver function, reduce scarring, and improve survival. This review integrates current knowledge of MSC-based therapies, their mechanisms, clinical potential, and challenges associated with their deployment. More than 50 clinical trials are registered or planned to evaluate MSC-based treatments for liver cirrhosis. Preclinical and clinical outcomes are encouraging; however, further work is needed to optimize delivery strategies, confirm safety, and facilitate the universal clinical use of this approach. Advances in MSC-guided regenerative medicine have the potential to revolutionize therapy for end-stage liver disease, offering hope where traditional treatments fail.
肝硬化是一种以肝脏广泛瘢痕形成为特征的慢性疾病,会导致肝功能障碍以及诸如门静脉高压和肝癌等致命并发症。尽管早期干预可以延缓或逆转早期损伤,但晚期阶段往往需要进行肝移植——这种治疗方法因供体短缺和后勤障碍而受到影响。新兴的细胞疗法,尤其是基于间充质干细胞(MSC)的疗法,为满足这些临床需求提供了一种新方法。MSC是自我更新的多能基质细胞,可分化为多种细胞类型,包括类肝细胞。免疫调节、再生信号传导和抗瘢痕形成作用是其治疗前景的三种机制。MSC调节免疫细胞,抑制炎症并促进组织愈合。MSC释放多种生长因子和细胞因子,包括肝细胞生长因子(HGF)、血管内皮生长因子(VEGF)、表皮生长因子(EGF)和基质金属蛋白酶(MMP),它们参与组织再生。其中,HGF具有双重作用,因为它既支持肝细胞增殖,又抑制纤维化和细胞凋亡,从而使组织能够自我修复和保护。最近的进展将来自MSC的细胞外囊泡(MSC-EV)确定为一种无细胞替代物。这些囊泡含有生物活性物质,包括微小RNA和蛋白质,可调节免疫功能、抑制细胞死亡并促进肝脏修复。动物肝硬化的临床前模型已证明MSC-EV可增强肝功能、减少瘢痕形成并提高生存率。本综述整合了基于MSC的疗法的当前知识、其机制、临床潜力以及与应用相关的挑战。超过50项临床试验已注册或计划用于评估基于MSC的肝硬化治疗方法。临床前和临床结果令人鼓舞;然而,需要进一步开展工作以优化给药策略、确认安全性并促进这种方法的普遍临床应用。MSC引导的再生医学进展有可能彻底改变终末期肝病的治疗方法,在传统治疗失败时带来希望。