Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar?

Abstract

The liver is unique in that it is able to regenerate. This regeneration occurs without formation of a scar in the case of non-iterative hepatic injury. However, when the liver is exposed to chronic liver injury, the purely regenerative process fails and excessive extracellular matrix proteins are deposited in place of normal liver parenchyma. While much has been discovered in the past three decades, insights into fibrotic mechanisms have not yet lead to effective therapies; liver transplant remains the only cure for advanced liver disease. In an effort to broaden the collection of possible therapeutic targets, this review will compare and contrast the liver wound healing response to that found in two types of wound healing: scarless wound healing of fetal skin and oral mucosa and scar-forming wound healing found in adult skin. This review will examine wound healing in the liver and the skin in relation to the role of humoral and cellular factors, as well as the extracellular matrix, in this process. While several therapeutic targets are similar between fibrotic liver and adult skin wound healing, others are unique and represent novel areas for hepatic anti-fibrotic research. In particular, investigations into the role of hyaluronan in liver fibrosis and fibrosis resolution are warranted.

Fig. (1)

Therapeutic targets for liver fibrosis. Several intervention points exist for which therapeutic strategies for liver fibrosis can be or are being developed. Some of the factors which contribute to liver fibrosis are written in black and found outside the circle. Some therapeutic strategies/targets are written in red and found inside the circle. From the discussion presented in this review, published evidence suggests that the extracellular matrix glycosaminoglycan, hyaluronan (HA), in its native, high molecular weight form, has the potential to reduce chronic inflammation, facilitate tissue repair and improve the extracellular matrix compliance. Leveraging HA’s anti-inflammatory and pro-homeostatic functions may ‘fetalize’ the liver response to chronic injury and therefore improve hepatic wound healing and attenuate fibrosis or facilitate fibrosis resolution.