Clinical application of hepatocyte transplantation: current status, applicability, limitations, and future outlook

ABSTRACT

Introduction: Hepatocyte transplantation (HT) is a promising alternative to liver transplantation for the treatment of liver-based metabolic diseases and acute liver failure (ALF). However, shortage of good-quality liver tissues, early cell loss post-infusion, reduced cell engraftment and function restricts clinical application.

Areas covered: A comprehensive literature search was performed to cover pre-clinical and clinical HT studies. The review discusses the latest developments to address HT limitations: cell sources from marginal/suboptimal donors to neonatal livers, differentiating pluripotent stem cells into hepatocyte-like cells, in vitro expansion, prevention of immune response to transplanted cells by encapsulation or using innate immunity-inhibiting agents, and enhancing engraftment through partial hepatectomy or irradiation.

Expert opinion: To date, published data are highly encouraging specially the alginate-encapsulated hepatocyte treatment of children with ALF. Hepatocyte functions can be further improved through co-culturing with mesenchymal stromal cells. Moreover, ex–vivo genetic correction will enable the use of autologous cells in future personalized medicine.

KEYWORDS:

• Hepatocyte transplantation
• mature hepatocytes
• neonatal hepatocytes
• mesenchymal stromal cells
• encapsulation
• engraftment
• cryopreservation
• alpha-1 antitrypsin
• in vitro expansion
• partial hepatectomy
• irradiation

Article highlights

• Hepatocyte transplantation is a highly promising alternative to whole liver transplantation with excellent therapeutic benefit for patients suffering from numerous liver diseases

• One of the major limitations of hepatocyte transplantation is up to 70% massive early cell loss after infusion but a recent study suggests that alpha-1 antitrypsin can significantly reduce immune response responsible for that by inhibiting the coagulation and complement pathways

• Neonatal-derived hepatocytes have been shown to be superior to adult mature hepatocytes with higher cell viability and yield on isolation and overall better recovery post-thawing with greater maintained hepatic functions

• Engraftment of transplanted hepatocytes can be improved through selective and highly proliferative stimulus following partial hepatectomy

• Current strategies to advance transplantation of hepatocytes include large-scale production of cells through in vitro expansion, differentiation of pluripotent stem cells into hepatic lineages and cell encapsulation

• Primary hepatocytes can be alginate-embedded and have proved great efficacy in providing treatment to patients with liver-based metabolic disorders, ‘bridge’ to liver transplantation and temporary therapy while native liver can regenerate thus discarding the need for whole organ replacement

• Human hepatocyte microbeads have demonstrated high safety and efficacy in children with acute liver failure

• The source of cells for transplantation is starting to come from patients themselves where successful correction and infusion of autologous cells will not trigger any immune rejection

Declaration of interest

A Dhawan is an advisor to Ambys Pharma, Sana Labs, and Promethera Labs.

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper has not been funded.