Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure
Wang et al. Stem Cell Research & Therapy
Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure
Kun Wang 0 1 3
Yuwen Li 0 2
Tiantian Zhu 1 3
Yongting Zhang 1
Wenting Li 3
Wenyu Lin 4
Jun Li 1
Chuanlong Zhu 1
0 Equal contributors
1 Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University , Nanjing , China
2 Department of Pediatrics, the First Affiliated Hospital with Nanjing Medical University , Nanjing , China
3 Department of Infectious Disease, Anhui Provincial Hospital, Anhui Medical University , Hefei , China
4 Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts , USA
Background: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has emerged as a novel therapy for acute liver failure (ALF). However, the homing efficiency of BMSCs to the injured liver sites appears to be poor. In this study, we aimed to determine if overexpression of c-Met in BMSCs could promote the homing ability of BMSCs to rat livers affected by ALF. Methods: Overexpression of c-Met in BMSCs (c-Met-BMSCs) was attained by transfection of naive BMSCs with the lenti-c-Met-GFP. The impact of transplanted c-Met-BMSCs on both homing and repair of ALF was evaluated and compared with lenti-GFP empty vector transfected BMSCs (control BMSCs). Results: After cells were transfected with the lenti-c-Met-GFP vector, the BMSCs displayed very high expression of c-Met protein as demonstrated by Western blot. In addition, in vitro transwell migration assays showed that the migration ability of c-Met-BMSCs was significantly increased in comparison with that of control BMSCs (P < 0.05), and was dependent on hepatocyte growth factor (HGF). Furthermore, rats with ALF that received transplanted cMet-BMSCs showed significantly improved homing ability to the injured liver; this was accompanied by elevated survival rates and liver function in the ALF rats. Parallel pathological examination further confirmed that transplantation of c-Met-BMSCs ameliorated liver injury with reduced hepatic activity index (HAI) scores, and that the effects of c-Met-BMSCs were more profound than those of control BMSCs. Conclusions: Overexpression of c-Met promotes the homing of BMSCs to injured hepatic sites in a rat model of ALF, thereby improving the efficacy of BMSC therapy for ALF repair.
c-Met; Bone marrow mesenchymal stem cells; Liver injury; Acute liver failure; Lentiviral vector
Background
Acute liver failure (ALF) is the rapid loss of liver
function due to severe damage to the liver, with common
causative factors including viruses (particularly hepatitis
B and C), toxins, prescribed drugs, and alcohol. ALF can
lead to jaundice, coagulopathy, multiple organ failure,
hepatic encephalopathy, and even death [
1
]. Currently,
liver transplantation (LT) is considered the most effective
therapy for this disease. However, its application for ALF is
limited by a shortage of available donor organs and the
procedure is invasive [
2
]. Bone marrow-derived mesenchymal
stem cells (BMSCs) are multipotent stem cells that exhibit
differentiation activity and significant potential for
selfrenewal. Furthermore, these cells can differentiate into a
variety of cell types, including osteoblasts, chondrocytes,
adipocytes, and hepatocytes. It has also been reported that
transfection of exogenous genes and consequent protein
expression appear to be readily manipulated in BMSCs [
3
].
Considering the aforementioned advantages of BMSCs,
they have been employed for the repair of damaged tissues
or organs including the liver. In fact, BMSCs have been
shown to be effective in the treatment of hepatic cirrhosis
and liver failure. In addition, studies with BMSCs have
demonstrated that they can repair ALF by regulating
inflammatory responses and secreting trophic factors such
as hepatocyte growth factor (HGF) and basic fibroblast
growth factor (bFGF). However the ability of BMSCs to
home to the injured liver has been reported as being poor.
Consequently, this has posed challenges for development of
their application [
4
]. Given the significant morbidity and
mortality associated with ALF, there is an urgent need to
enhance the homing capabilities of BMSCs in order to
improve the efficacy of these potent cell types.
c-Met is encoded by the MET gene and belongs to the
tyrosine protein kinase family. The c-Met protein is a
member of the transmembrane tyrosine kinase receptor
superfamily and has independent phosphorylation
activity [
5
]. HGF is commonly known as the ligand of c-Met.
The HGF/c-Met signaling pathway is considered to play
an important role in the homing ability of BMSCs to the
liver, which permits stem cell-mediated repair of the
liver. BMSCs have been shown to influence both the
differentiation of BMSCs into hepatocytes, and liver
regeneration [
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