Genetic modification by overexpression of target gene in mesenchymal stromal cell for treating liver diseases

Different hepatoxic factors cause irreversible liver injury, leading to liver failure, cirrhosis, and cancer in mammals. Liver transplantation is the only effective strategy, which can improve the prognosis of patients with end-stage liver diseases, but it is limited by liver donor shortage, expensive costs, liver graft rejection and dysfunction, and recurring liver failure. Recently, mesenchymal stromal cells (MSCs) isolated from various tissues are regarded as the main stem cell type with therapeutic effects in liver diseases because of their hepatogenic differentiation, anti-inflammatory, immuoregulatory, anti-apoptotic, antifibrotic, and antitumor capacities. To further improve the therapeutic effects of MSCs, multiple studies showed that genetically engineered MSCs have increased regenerative capacities and are able to more effectively inhibit cell death. Moreover, they are able to secrete therapeutic proteins for attenuating liver injury in liver diseases. In this review, we mainly focus on gene overexpression for reprogramming MSCs to increase their therapeutic effects in treating various liver diseases. We described the potential mechanisms of MSCs with gene overexpression in attenuating liver injury, and we recommend further expansion of experiments to discover more gene targets and optimized gene delivery methods for MSC-based regenerative medicine. We also discussed the potential hurdles in genetic engineering MSCs. In conclusion, we highlight that we need to overcome all scientific hurdles before genetically modified MSC therapy can be translated into clinical practices for patients with liver diseases.