A cMet Inhibitor Promotes the Survival and Long‐Term Efficacy of Transplanted Hepatic Stem/Progenitor Cells in Liver Cirrhosis
Min Yan, Deyu Hu, Jiejuan Lai, Quanyu Chen, Jiayu Yu, Mei Ding, Lu Li, Hongbo Shi, Hongyu Zhang, Yu Chen, Lianhua BaiBackground
Poor retention of transplanted stem cells in the liver cirrhosis milieu (LCM) which critically blunts long‐term efficacy, remains unexplained. This study investigated the effects of a small peptide chemical compound (icMet) delivered intravenously for cMet receptor inhibition at the diethylnitrosamine (DEN)‐induced middle‐to‐late cirrhotic liver stage (CLS 8/9 ), focusing on apoptosis prevention, endogenous hepatic regeneration and the long‐term efficacy of transplanted hepatic stem/progenitor cells (MLpvNG2 cells).
Methods
C57BL/6 mice with CLS 8/9 liver injury were used as recipients. icMet was used before or during MLpvNG2 cell therapy. Tissues from CLS 8/9 livers were also used to generate conditioned medium (CM, CLS 8/9 CM) to observe MLpvNG2 cell activity in response to the injured liver‐related cues. Results: Compared with CLS 8/9 mice without icMet, mice subjected to icMet administration showed increased survival rates of transplanted MLpvNG2 cells in the CLS 8/9 livers, as well as enhanced downstream hepatic repair and long‐term healing. In CLS 8/9 CM cultures, the survival of MLpvNG2 cells within icMet was similar to that observed in CLS 8/9 livers. In terms of the underlying mechanisms, it is possible that icMet pretreatment promotes proliferation and prevents apoptosis of grafted MLpvNG2 cells, activating host hepatic functional differentiation, particularly sinusoidal reconstruction, which can initiate hepatocyte regeneration. In addition, the relieved fibrotic load could also favor repopulation by donor cells, leading to long‐term treatment efficacy.
Conclusions
A strategy involving a pre‐ or during cell treatment that blocks the cMet receptor achieves apoptosis resistance of transplanted MLpvNG2 cells in the LCM and promotes endogenous hepatic regeneration, leading to long‐term treatment efficacy.