Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis

Abstract

End‐stage liver fibrosis frequently progresses to portal vein thrombosis, formation of oesophageal varices, hepatic encephalopathy, ascites, hepatocellular carcinoma and liver failure. Mesenchymal stem cells (MSCs), when transplanted in vivo, migrate into fibrogenic livers and then differentiate into hepatocyte‐like cells or fuse with hepatocytes to protect liver function. Moreover, they can produce various growth factors and cytokines with anti‐inflammatory effects to reverse the fibrotic state of the liver. In addition, only a small number of MSCs migrate to the injured tissue after cell transplantation; consequently, multiple studies have investigated effective strategies to improve the survival rate and activity of MSCs for the treatment of liver fibrosis. In this review, we intend to arrange and analyse the current evidence related to MSC transplantation in liver fibrosis, to summarize the detailed mechanisms of MSC transplantation for the reversal of liver fibrosis and to discuss new strategies for this treatment. Finally, and most importantly, we will identify the current problems with MSC‐based therapies to repair liver fibrosis that must be addressed in order to develop safer and more effective routes for MSC transplantation. In this way, it will soon be possible to significantly improve the therapeutic effects of MSC transplantation for liver regeneration, as well as enhance the quality of life and prolong the survival time of patients with liver fibrosis.

Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand?

“…The molecular mechanisms underlying these beneficial effects are manifold, but are believed to be derived from paracrine factors affecting apoptosis, immune responses, stellate cell activation, angiogenesis, etc. (as reviewed in [76][77][78]). Moreover, as for BM-HSCs and BMMs, fusion of human MSCs with host liver cells has been suggested [79].…”

“…Of note, however, even if we believe that undifferentiated MSC are not good candidates for liver repopulation, as there are only few studies describing spontaneous differentiation and repopulation after engraftment, they might hold potential for grafting together with hepatocytes from other cell sources that have the potential to regenerate the liver, because of their ability to protect the latter cells from immune rejection. In addition, undifferentiated MSCs may ameliorate liver fibrosis [76], even if there are also reports suggesting that they may aggravate fibrogenesis [81,84], making the case for in vitro differentiation prior to transplantation.…”

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

“…Liver cirrhosis is a continuous liver injury in which quiescent hepatic stellate cells (HSCs) transform into proliferative, α‐smooth muscle actin + myofibroblast‐like cells that deposit collagen in liver tissue. Hepatic stellate cell activation, extracellular matrix and collagen deposition and immune cell accumulation in liver tissue result in liver fibrosis or cirrhosis in mammals . MSCs effectively induced the apoptosis of HSCs and inhibited liver inflammation and collagen deposition to block hepatic fibrosis .…”

“…Hepatic stellate cell activation, extracellular matrix and collagen deposition and immune cell accumulation in liver tissue result in liver fibrosis or cirrhosis in mammals. 31 MSCs effectively induced the apoptosis of HSCs and inhibited liver inflammation and collagen deposition to block hepatic fibrosis. 32,33 Patients with hepatitis C virus-induced liver fibrosis also benefited from MSC transplantation, which prompted the down-regulation of fibrotic markers and inflammatory factors and the up-regulation of anti-inflammatory factors in liver tissue.…”

“…53 HLC transplantation also significantly attenuated liver fibrosis via up-regulating the expression levels of HGF and Bcl-2 in liver tissue and decreasing the levels of serum fibronectin and hepatic AFP. 54 Although HLCs are effective at repairing liver injury in various diseases, Hu et al 31,55 reported that undifferentiated MSCs can exert greater benefits than HLCs in liver diseases because HLCs are more sensitive to harsh in vitro and in vivo environments. these MSCs showed enhanced migration via the CXCR-4/CXCL-12 axis.…”