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Updated: Aug 8, 2025
Partial Bile Duct Ligation in the Mouse: A Controlled Model of Localized Obstructive Cholestasis
Published on: March 28, 2018
Increased PRL-1 in BM-derived MSCs triggers anaerobic metabolism via mitochondria in a cholestatic rat model
Jae Yeon Kim1,2, Se Ho Kim1, Jin Seok1,2
1Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea.
Abstract:
Mesenchymal stem cell (MSC) therapy in chronic liver disease is associated with mitochondrial anaerobic metabolism. Phosphatase of regenerating liver-1 (PRL-1), known as protein tyrosine phosphatase type 4A, member 1 (PTP4A1), plays a critical role in liver regeneration. However, its therapeutic mechanism remains obscure. The aim of this study was to establish genetically modified bone marrow (BM)-MSCs overexpressing PRL-1 (BM-MSCsPRL-1) and to investigate their therapeutic effects on mitochondrial anaerobic metabolism in a bile duct ligation (BDL)-injured cholestatic rat model. BM-MSCsPRL-1 were generated with lentiviral and nonviral gene delivery systems and characterized. Compared with naive cells, BM-MSCsPRL-1 showed an improved antioxidant capacity and mitochondrial dynamics and decreased cellular senescence. In particular, mitochondrial respiration in BM-MSCsPRL-1 generated using the nonviral system was significantly increased as well as mtDNA copy number and total ATP production. Moreover, transplantation of BM-MSCsPRL-1 generated using the nonviral system had predominantly antifibrotic effects and restored hepatic function in a BDL rat model. Decreased cytoplasmic lactate and increased mitochondrial lactate upon the administration of BM-MSCsPRL-1 indicated significant alterations in mtDNA copy number and ATP production, activating anaerobic metabolism. In conclusion, BM-MSCsPRL-1 generated by a nonviral gene delivery system enhanced anaerobic mitochondrial metabolism in a cholestatic rat model, improving hepatic function.
Insights
Genetically modified mesenchymal stem cells (MSCs) overexpressing Phosphatase of Regenerating Liver-1 (PRL-1) enhanced mitochondrial anaerobic metabolism. This therapy improved liver function in a cholestatic rat model.
Area of Science:
- Stem cell biology
- Mitochondrial metabolism
- Liver disease research
Background:
- Mesenchymal stem cell (MSC) therapy for chronic liver disease involves mitochondrial anaerobic metabolism.
- Phosphatase of Regenerating Liver-1 (PRL-1), also known as PTP4A1, is crucial for liver regeneration, but its therapeutic role is unclear.
Purpose of the Study:
- To create genetically modified bone marrow (BM)-MSCs overexpressing PRL-1 (BM-MSCsPRL-1).
- To investigate the therapeutic effects of BM-MSCsPRL-1 on mitochondrial anaerobic metabolism in a bile duct ligation (BDL)-induced cholestatic rat model.
Main Methods:
- BM-MSCsPRL-1 were generated using lentiviral and nonviral gene delivery systems.
- The modified MSCs were characterized for antioxidant capacity, mitochondrial dynamics, and senescence.
- Therapeutic effects were assessed in a BDL rat model, focusing on hepatic function and mitochondrial metabolism.
Main Results:
- BM-MSCsPRL-1 exhibited enhanced antioxidant capacity, improved mitochondrial dynamics, and reduced senescence compared to naive cells.
- Nonviral BM-MSCsPRL-1 significantly increased mitochondrial respiration, mtDNA copy number, and ATP production.
- Transplantation of nonviral BM-MSCsPRL-1 demonstrated antifibrotic effects and restored liver function in BDL rats, with altered lactate distribution indicating enhanced anaerobic metabolism.
Conclusions:
- Nonviral gene delivery to generate BM-MSCsPRL-1 effectively enhances anaerobic mitochondrial metabolism.
- This approach shows significant therapeutic potential for improving hepatic function in cholestatic liver disease models.
