Recent advances in the therapeutic efficacy of hepatocyte growth factor gene-modified mesenchymal stem cells in multiple disease settings

Abstract

Mesenchymal stem cell (MSC) therapy is considered a new treatment for a wide range of diseases and injuries, but challenges remain, such as poor survival, homing and engraftment rates, thus limiting the therapeutic efficacy of the transplanted MSCs. Many strategies have been developed to enhance the therapeutic efficacy of MSCs, such as preconditioning, co-transplantation with graft materials and gene modification. Hepatocyte growth factor (HGF) is secreted by MSCs, which plays an important role in MSC therapy. It has been reported that the modification of the HGF gene is beneficial to the therapeutic efficacy of MSCs, including diseases of the heart, lung, liver, urinary system, bone and skin, lower limb ischaemia and immune-related diseases. This review focused on studies involving HGF/MSCs both in vitro and in vivo. The characteristics of HGF/MSCs were summarized, and the mechanisms of their improved therapeutic efficacy were analysed. Furthermore, some insights are provided for HGF/MSCs' clinical application based on our understanding of the HGF gene and MSC therapy.

Keywords: HGF gene-modified MSCs (HGF/MSCs); clinical application; hepatocyte growth factor (HGF); mesenchymal stem cells (MSCs); therapeutic efficacy.

FIGURE 1

Main mechanisms of HGF/MSC therapy. HGF/MSCs were adopted in treatment for a variety of diseases, including ischaemic, heart, lung, liver, urinary system, bone and immune‐related diseases. (1) HGF/MSC promote cell migration and engraftment, in which SDF‐1α/CXCR‐4 axis and ERK1/2 signalling pathway were involved. (2) HGF/MSCs promote cell–cell connection restoration and soft tissue re‐epithelialization. (3) HGF/MSCs promote angiogenesis and neurogenesis. (4) HGF/MSCs promote anti‐fibrosis effect. (5) HGF/MSCs promote anti‐inflammatory effect. They can deactivate Th1 and Th17 cells and activate Treg cells. (6) HGF/MSCs promote anti‐apoptosis effect. (7) HGF/MSCs promote anti‐oxidation effect. Bcl, B‐cell lymphoma; COL, collagen; Cx43, connexin 43; CXCR4, chemokine (C‐X‐C motif) receptor 4; ERK1/2, extracellular regulated protein kinases 1/2; FGF, fibroblast growth factor; FN, fibronectin; GSH, antioxidant glutathione; ICAM, intercellular adhesion molecule; IFN‐γ, interferon gamma; IL, interleukin; MDA, antioxidant metabolite malondialdehyde; MMP, matrix metalloproteinase; S1PR1, sphingosine 1‐phosphate receptors 1; SDF‐1, stromal cell‐derived factor‐1; Smad, small mothers against decapentaplegic; SOD, superoxide dismutase; TGF‐β, transforming growth factor‐beta; Th1, T helper 1 cell; Th17, interleukin 17 (IL‐17)‐secreting helper T; TNF‐α, tumour necrosis factor alpha; Treg, regulatory T cell; VCAM, vascular cell adhesion protein; VEGF, vascular endothelial growth factor; ZO‐1, zonula occludens‐1; α‐SMA, alpha‐smooth muscle Actin; γ‐GCS, gama glutamylcysteine synthetase.