Increased PRL-1 in BM-derived MSCs triggers anaerobic metabolism via mitochondria in a cholestatic rat model

Jae Yeon Kim; Se Ho Kim; Jin Seok; Si Hyun Bae; Seong-Gyu Hwang; Gi Jin Kim

doi:10.1016/j.omtn.2023.01.017

Increased PRL-1 in BM-derived MSCs triggers anaerobic metabolism via mitochondria in a cholestatic rat model

Mol Ther Nucleic Acids. 2023 Feb 4:31:512-524. doi: 10.1016/j.omtn.2023.01.017. eCollection 2023 Mar 14.

Authors

Jae Yeon Kim^{1

2}, Se Ho Kim¹, Jin Seok^{1

2}, Si Hyun Bae³, Seong-Gyu Hwang⁴, Gi Jin Kim^{1

2}

Affiliations

¹ Department of Biomedical Science, CHA University, 689, Sampyeong-dong, Bundang-gu, Seongnam-si 13488, Republic of Korea.
² Research Institute of Placental Science, CHA University, Seongnam 13488, Republic of Korea.
³ Department of Internal Medicine, Catholic University Medical College, Seoul 03312, Republic of Korea.
⁴ Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, 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-MSCs^PRL-1) and to investigate their therapeutic effects on mitochondrial anaerobic metabolism in a bile duct ligation (BDL)-injured cholestatic rat model. BM-MSCs^PRL-1 were generated with lentiviral and nonviral gene delivery systems and characterized. Compared with naive cells, BM-MSCs^PRL-1 showed an improved antioxidant capacity and mitochondrial dynamics and decreased cellular senescence. In particular, mitochondrial respiration in BM-MSCs^PRL-1 generated using the nonviral system was significantly increased as well as mtDNA copy number and total ATP production. Moreover, transplantation of BM-MSCs^PRL-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-MSCs^PRL-1 indicated significant alterations in mtDNA copy number and ATP production, activating anaerobic metabolism. In conclusion, BM-MSCs^PRL-1 generated by a nonviral gene delivery system enhanced anaerobic mitochondrial metabolism in a cholestatic rat model, improving hepatic function.

Keywords: BM-MSCs; MT: Delivery strategies; PRL-1; cholestasis; mitochondria; stem cell therapy.