Mesenchymal stromal cell therapy in liver disease: opportunities and lessons to be learnt?

Abstract

End-stage liver disease is responsible for 30,000 deaths per year in the United States alone, and it is continuing to increase every year. With liver transplantation the only curative treatment currently available, new therapies are in great demand. Mesenchymal stem cells (MSC) offer an opportunity to both treat liver inflammatory damage, as well as reverse some of the changes that occur following chronic liver injury. With the ability to regulate both the innate and adaptive immune system, as well as both inhibit and promote apoptosis of effector inflammatory cells, there are numerous therapeutic opportunities for MSC in acute and chronic liver disease. This article critically appraises the potential therapeutic roles of MSC in liver disease, as well as the barriers to their adoption into clinical practice.

Keywords: liver disease; mesenchymal stem cell; mesenchymal stromal cell.

Fig. 1.

Immune cells influenced by mesenchymal stem cells (MSC). MSC exert an effect on a range of cells involved in the immune response. There is a direct effect exerted on CD4⁺, CD8⁺, γδT-Cells, FoxP3⁺ T-reg cells, neutrophils, and monocytes, while they also exert an indirect effect on natural killer (NK) cells via their action on dendritic cells. (Stock images provided by Servier medical for use under the Creative Commons Attribution 3.0 Unported License).

Fig. 2.

Mechanisms of MSC action in liver inflammation/ischemia. MSC are able to inhibit CD4, CD8, and γδ T lymphocytes using a variety of cytokines, including LHA-G5, IDO, HO1, TGFβ, and PGE₂. MSC may also differentiate into hepatocytes, although this occurs in low numbers. Hepatocyte apoptosis is inhibited by MSC, secreting HGF, and finally MSC may adhere to hepatocytes and reduce TNF-α and phosphor-JNK. (Stock images provided by Servier medical for use under the Creative Commons Attribution 3.0 Unported License).

Fig. 3.

Mechanisms of MSC action in fibrotic liver disease. MSC can exert effects on hepatic stellate cells by secreting nerve growth factor (NGF), which binds to p75 expressed on activated stellate cells. This leads to stellate cell apoptosis and, therefore, a reduction in the stellate cell secreted ECM. MSC may also secrete MMP9, which has a direct effect of cleaving collagen in the ECM. MSC also act via an unknown mechanism to reduce the secretion of stellate cell αSMA and TGFβ. (Stock images provided by Servier medical for use under the Creative Commons Attribution 3.0 Unported License).