MSCs cell fates in murine acute liver injury and chronic liver fibrosis induced by carbon tetrachloride

Chenhui Ma; Li Han; Jiajun Wu; Feng Tang; Qiangqiang Deng; Ting He; Zhitao Wu; Chen Ma; Wei Huang; Ruimin Huang; Guoyu Pan

doi:10.1124/dmd.122.000958

MSCs cell fates in murine acute liver injury and chronic liver fibrosis induced by carbon tetrachloride

Drug Metab Dispos. 2022 Jul 26:DMD-AR-2022-000958. doi: 10.1124/dmd.122.000958. Online ahead of print.

Authors

Chenhui Ma¹, Li Han², Jiajun Wu², Feng Tang¹, Qiangqiang Deng², Ting He³, Zhitao Wu⁴, Chen Ma⁵, Wei Huang⁶, Ruimin Huang⁶, Guoyu Pan⁶

Affiliations

¹ Shanghai Institute of Materia Medica, Chinese Academy of Sciences,University of Chinese Academy of Sciences, China.
² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences,School of Pharmaceutical Sciences, Nanjing Tech University, China.
⁴ Shanghai Institute of Materia Medica; Nanjing University of Chinese Medicine, China.
⁵ Shanghai Institute of Materia Medica, China.
⁶ Shanghai Institute of Materia Medica, Chinese Academy of Sciences,University of Chinese Academy of Sciences, China gypan@simm.ac.cn.

PMID: 35882404
DOI: 10.1124/dmd.122.000958

Abstract

Mesenchymal stem cells (MSCs) therapy has shown potential benefits in multiple diseases. However, their clinic performance is not as satisfactory as expected. This study aimed to provide an alternative explanation by comparing MSCs' fates in different liver diseases. The distribution and therapeutic effects of hMSCs were investigated in acute liver injury (ALI) and chronic liver fibrosis (CLF) mice models, respectively. The two models were induced by single or repeated injection of carbon tetrachloride (CCl₄) separately. The increase of hMSCs exposure in the liver (AUC_{liver 0-72 h}) were more significant in ALI than in CLF (177.1% vs. 96.2%). In the ALI model, the hMSCs exposures in the lung (AUC_lung _{0-72 h}) increased by nearly 50% while decreased by 60.7% in CLF. The efficacy satellite study indicated that hMSCs could significantly ameliorate liver injury in ALI, but its effects in CLF were limited. In the ALI, suppressed Natural Killer (NK) cell activities were observed, while NK cell activities were increased in CLF. The depletion of NK cells could increase hMSCs exposure in mice. For mice MSC (mMSCs), their cell fates in ALI were very similar to hMSCs in ALI: mMSCs' exposure in the liver and lung increased in ALI. In conclusion, our study revealed the distinct cell pharmacokinetic patterns of MSCs in ALI and CLF mice, which might be at least partially attributed to the different NK cell activities in the two liver diseases. This finding provided a novel insight into the varied MSCs' therapeutic efficacy in the clinic. Significance Statement Currently, there is little knowledge about the PK behavior of cell products like MSCs. This study was the first time investigating the influence of liver diseases on cell fates and efficacies of MSCs and the underneath rationale. The exposure was distinct between two representative liver disease models, which directly linked with the therapeutic performance that MSCs achieved. The difference could be attributed to the NK cells-mediated MSCs clearance.

Keywords: cell trafficking; liver disease; pharmacokinetic; stem cells.