Liver cirrhosis (LC) is a serious health problem worldwide, and the only therapeutic option is orthotopic liver transplantation. Stem cell therapy can overcome this limitation [1]. For example, mesenchymal stem cells (MSCs), such as liver-derived MSCs (MLpvNG2+ cells) [2] or bone marrow-derived MSCs (BMMSCs) [3,4], have emerged as novel alternatives for the treatment of LC in animals and humans. MSCs derived from adipose tissues, umbilical cord blood, etc., for liver disease treatment have also been well studied [5,6]. However, in clinical settings, transplanted stem cells are required to improve injured liver function [7,8] and be safe [9]. To date, many clinical studies have shown that the efficacy of stem cell treatment improves cirrhotic liver function in patients, but long-term survival to promote long-term efficacy of the cell treatment has still not been achieved, which limits the development of definite conclusions about the efficacy of this treatment for LC [10]. Similar evidence has also been shown in model animals induced by the chemical reagent diethylnitrosamine (DEN), which is a well-defined animal model [11,12]. This model is similar to the development of liver disease in humans (fibrosis/cirrhosis/cancer) [13], and most reparative cells, including stem cells and immune cells, die via apoptosis in the cirrhotic liver environment [12,14]. Interestingly, in an animal study, we showed that intrahepatic stem cells proliferated aggressively in the fibrotic liver environment (between weeks 3–6) [12], but with the progression from the fibrotic to cirrhotic phase (7–10 weeks after DEN administration), more of these cells died via apoptosis [12]. It seems that there is zone of cell death between 6 and 7 weeks [12], and the mechanism remains unclear. Inspired by a previous study [15], we demonstrated that the mechanism of cell death in the cirrhotic liver niche may involve increased levels of hepatocyte growth factor (HGF) signaling. These studies prompted us to hypothesize that regulating or inhibiting c-Met (HGF only receptor) signaling may rescue stem cells and promote their therapeutic efficacy. To this end, we designed the present study.

In the present study, we used the DEN-induced liver fibrosis/cirrhosis mouse model and interfered with c-Met signaling before stem cell transplantation with adeno-associated virus (AAV)-positive [Ad-cMet (−)] and control [Ad-lacZ] vectors to silence the c-Met gene or a neutralizing antibody to functionally block the c-Met receptor (24 h before donor cell injection). The cells were transplanted between 6 and 7 weeks after DEN administration (a zone of stem cell survival and death) [12] to determine whether the specific short-term inhibitory approaches during the fibrotic/cirrhotic phase could rescue stem cells and allow them to perform repair functions. Additionally, since fewer transplanted cells were used to mitigate thromboembolic events caused by an increased number of transplanted cells [16], these findings are also expected to provide a strategy for transplanting fewer (5 × 104) stem cells.