State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650504, China.
Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
Stem Cell Res Ther. 2024 Sep 19;15(1):315. doi: 10.1186/s13287-024-03934-7.
Liver fibrosis can progress to end-stage cirrhosis and liver cancer. Mesenchymal stem cells (MSCs) were considered the most promising therapeutic strategy, but most of the MSCs injected intravenously traditionally are trapped in the lungs, rapidly reducing their survival ability. MSC spheroids cultured in 3D have shown higher tolerance to fluid shear stress and better survival than dissociated MSCs. Simulating the route of orthotopic liver transplantation, transplanting MSC spheroids into the liver via hepatic portal vein may impact superior therapeutic effects.
In the present study, human umbilical cord-derived MSC spheroids (hUC-MSC) were transplanted into rhesus monkey models of liver fibrosis via B-ultrasound-guided percutaneous portal vein puncture with minimized body invasion. The therapeutic effect is evaluated through hematology, ultrasound, and pathology. To study the effect of hUC-MSC on gene expression in rhesus monkeys with liver injury, transcriptome sequencing analysis was performed on the livers of rhesus monkeys. The distribution of transplanted hUC-MSC was traced with RNA scope technology.
We found that hUC-MSC significantly restored liver function, including ALT, AST, ALB, GLOB and bilirubin. hUC-MSC also significantly reduced liver collagen deposition and inflammatory infiltration, and promote dismission of liver ascites. Subsequently, the therapeutic effects were further validated in TGF-β1/Smad pathway by global transcription profile. The distribution of transplanted hUC-MSC were also tracked, and we found that hUC-MSC distributed in the liver in a sphere status at 1 h after transplantation. After 16 days, the hUC-MSC were dispersed into dissociated cells that were predominantly distributed in the spleen, and a significant number of dissociated cells were still present in the liver.
This study reveals the distributions of transplanted hUC-MSC after liver portal vein transplantation, and provides a novel approach and new insights into the molecular events of potential molecular events underlying the treatment of liver fibrosis with hUC-MSC.
肝纤维化可进展为终末期肝硬化和肝癌。间充质干细胞（MSCs）被认为是最有前途的治疗策略，但传统上静脉内注射的大多数 MSCs 会被困在肺部，迅速降低其生存能力。在 3D 中培养的 MSC 球体比分离的 MSC 具有更高的耐流体剪切力和更好的生存能力。模拟原位肝移植的途径，通过肝门静脉将 MSC 球体移植到肝脏中可能会产生更好的治疗效果。
在本研究中，通过 B 超引导经皮门静脉穿刺，以最小的身体入侵将人脐带间充质干细胞球体（hUC-MSC）移植到恒河猴肝纤维化模型中。通过血液学、超声和病理学评估治疗效果。为了研究 hUC-MSC 对肝损伤恒河猴基因表达的影响，对恒河猴肝脏进行转录组测序分析。使用 RNAscope 技术追踪移植的 hUC-MSC 的分布。
我们发现 hUC-MSC 显著恢复了肝功能，包括 ALT、AST、ALB、GLOB 和胆红素。hUC-MSC 还显著减少了肝胶原沉积和炎症浸润，并促进了肝腹水的消退。随后，通过全球转录谱进一步验证了 TGF-β1/Smad 通路的治疗效果。还追踪了移植的 hUC-MSC 的分布，我们发现 hUC-MSC 在移植后 1 小时以球体状态分布在肝脏中。16 天后，hUC-MSC 分散为分离细胞，主要分布在脾脏中，仍有大量分离细胞存在于肝脏中。
本研究揭示了肝门静脉移植后移植的 hUC-MSC 的分布情况，并为 hUC-MSC 治疗肝纤维化的潜在分子事件提供了一种新的方法和新的见解。
