Clinical Hepatocyte Transplantation: Practical Limits and Possible Solutions

Abstract

Since the first human hepatocyte transplants (HTx) in 1992, clinical studies have clearly established proof of principle for this therapy as a treatment for patients with acquired or inherited liver disease. Although major accomplishments have been made, there are still some specific limitations to this technology, which, if overcome, could greatly enhance the efficacy and implementation of this therapy. Here, we describe what in our view are the most significant obstacles to the clinical application of HTx and review the solutions currently proposed. The obstacles of significance include the limited number and quality of liver tissues as a cell source, the lack of clinical grade reagents, quality control evaluation of hepatocytes prior to transplantation, hypothermic storage of cells prior to transplantation, preconditioning treatments to enhance engraftment and proliferation of donor cells, tracking or monitoring cells after transplantation, and the optimal immunosuppression protocols for transplant recipients.

Critical location of cell viability loss during the cell injection process in hepatocyte transplantation using a rectangular microchannel model

“…Hepatocyte transplantation can cure inborn error diseases, biliary atresia, cirrhosis, fulminant hepatic failure, and viral hepatitis (cirrhosis) (Gramignoli et al, 2015). The benefits of hepatocyte transplantation are that cells can be received by multiple recipients through simple administration using cryopreserved cells, and the cells can be repeatedly transplanted (Forbes et al, 2015).…”

Clinical Hepatocyte Transplantation: What Is Next?

“…Ultimately, definitive assessment of hepatocyte quality is critical prior to proceeding with HT. Novel approaches with the capacity to quickly and affordably assess a variety of hepatic functions, as a reflection of quality, are enabling more personalization of HT preparations (26, 60, 61). Future work aimed at the standardization of the procedural techniques ranging from isolation through cryopreservation, thawing, and functional assessment of hepatocytes prior to HT will enable the incorporation of various center experiences into longitudinal studies advancing the field of HT in humans.…”

“…Once hepatocytes have engrafted in the liver sinusoids, transplanted hepatocytes should be induced to repopulate the liver parenchymal by providing growth advantage and a regenerative stimulus. Published reports describe a range of variability (6, 11, 15, 26) and efforts to provide donor cells a selective growth advantage over the host liver include partial hepatectomy (26, 63) (short-term regenerative stimulus), preoperative portal vein occlusion (32, 64, 65) (short-term regenerative stimulus), and native liver irradiation (26, 66–69) (growth advantage). However, it is acknowledged that some of these techniques, such as major hepatectomy and chemotherapeutic irradiation, carry unacceptably high risks for human patients limiting their use (13, 32, 33, 68, 69).…”

“…Thus, in many ways HT has yet to live up to its expectations. This is underscored by the declining number of active hepatocyte transplantation programs (26, 27). …”

“…(Table 1) A recent review of the clinical outcomes of the first 100 patients treated with HT has been published (30) and an additional 43 patient experiences have been reported (26). While a detailed clinical report is beyond the scope of this article, it is noted that significant barriers persist limiting broader HT implementation (26, 31, 32) explicitly highlighted in a recent report that included a preclinical and clinical approach (25). The identification of these impediments has led to recent advancements looking to overcome the limitations.…”