Therapeutic targets for liver regeneration after acute severe injury: a preclinical overview

ABSTRACT

Introduction: Liver transplantation is the only viable treatment with a proven survival benefit for acute liver failure (ALF). Donor organ shortage is, however, a major hurdle; hence, alternative approaches that enable liver regeneration and target acute severe hepatocellular damage are necessary.

Areas covered: This article sheds light on therapeutic targets for liver regeneration and considers their therapeutic potential. ALF following extensive hepatocyte damage and small-for-size syndrome (SFSS) are illuminated for the reader while the molecular mechanisms of liver regeneration are assessed in accordance with relevant therapeutic strategies. Furthermore, liver background parameters and predictive biomarkers that might associate with liver regeneration are reviewed.

Expert opinion: There are established and novel experimental strategies for liver regeneration to prevent ALF resulting from SFSS. Granulocyte-colony stimulating factor (G-CSF) is a promising agent targeting liver regeneration after acute severe injury. Autophagy and hepatocyte senescence represent attractive new targets for liver regeneration in acute severe hepatic injury. Liver support strategies, including tissue engineering, constitute novel regenerative means; the success of this is dependent on stem cell research advances. However, there is no firm clinical evidence that these supportive strategies may alleviate hepatocellular damage until liver transplantation becomes available or successful self-liver regeneration occurs.

KEYWORDS:

• Acute liver failure
• liver regeneration
• liver transplantation
• hepatocyte senescence
• autophagy

Article Highlights

• Hepatocytes fail to proliferate after severe liver injury, and this results in liver failure

• Liver transplantation remains the only treatment option with a proven survival benefit for ALF, but the acute donor organ shortage restricts patients receiving the life-saving procedure

• Successful liver regeneration can lead to recovery from acute liver failure

• There are established and preclinical strategies for liver regeneration to prevent acute liver failure caused by small-for-size syndrome. G-CSF is a promising therapeutic agent for liver regeneration after acute severe liver injury

• Recent reports on cell senescence and autophagy in ALF settings provide a rationale for novel therapeutic targets in liver regeneration.

• Progress of stem cell research has the potential to enable the clinically relevant cell-based therapy, including liver engineering as supplying abundant human cell sources

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of JW Kupiec-Weglinski has been supported by National Institute of Health Grants [P01 AI120944, R01 DK062357, DK107533, DK102110].