Department of Surgery, Jichi Medical University, Shimotsuke, Japan.
Division of Translational Research, Jichi Medical University, Shimotsuke, Japan.
Stem Cell Res Ther. 2024 Nov 4;15(1):395. doi: 10.1186/s13287-024-03993-w.
Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis.
Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV).
The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division.
MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.
全球范围内代谢相关脂肪性肝病（MASLD）的患病率正在上升，因此迫切需要开发创新疗法，以促进此类疾病行肝切除术后的肝脏再生。手术切除是治疗肝脏肿瘤的关键方法，具有治愈潜力。然而，肝脂肪变性会导致肝脏再生延迟和术后并发症风险增加。间充质干细胞条件培养基（MSC-CM）被认为是富含旁分泌因子的来源，可修复组织并恢复受损器官的功能。同时，水凝胶已被广泛认为可负载 MSC 分泌组并实现持续释放。本研究旨在评估水凝胶包封的 MSC-CM 对饮食诱导的肝脂肪变性啮齿动物模型肝部分切除（PHx）后肝脏再生的治疗效果。
雄性 Lewis 大鼠给予蛋氨酸和胆碱缺乏饮食。喂养 3 周后行 PHx，大鼠随机分为两组，通过肠系膜上静脉（SMV）的肠系膜内空间分别给予水凝胶包封的 MSC-CM 或载体。
PHx 后 30 和 168 小时，残肝再生明显加快，增殖细胞核抗原表达明显增强。MSC-CM 治疗可显著增加 PHx 后 168 小时的肝 ATP 和β-羟丁酸含量，表明 MSC-CM 不仅促进体积再生，而且促进功能再生。PHx 后 9 小时，MSC-CM 组每个 TUNEL 和 cleaved caspase-3 阳性核的肝细胞数量明显减少，提示 MSC-CM 抑制细胞凋亡。MSC-CM 增加 PHx 后 30 小时的血清免疫调节细胞因子白细胞介素-10 和白细胞介素-13。此外，MSC-CM 组有丝分裂数和 cyclin D1 表达减少，肝细胞体积增大，提示这种再生模式主要通过细胞肥大而不是细胞分裂。
MSC-CM 为需要 PHx 的 MASLD 患者提供了一种新的治疗方法。
