You are hereFebruary 18, 2019 | ESCs/iPSCs
Moving Pluripotent Stem Cell-derived Hepatocytes One Step Closer to the Clinic
Review of “Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell‐Derived Hepatocytes for Cell‐Based Therapy” from STEM CELLS Translational Medicine by Stuart P. Atkinson
The transplantation of functionally mature hepatocytes differentiated from human pluripotent stem cells may represent a viable therapeutic option for patients with end‐stage chronic liver disease or acute liver failure. Encouragingly, recent studies have described the differentiation of both human embryonic stem cells and patient-specific induced pluripotent stem cells into hepatocytes that can repopulate the rodent liver following transplantation [1-3].
To propel human pluripotent stem cell-derived hepatocytes one step closer to therapeutic applications in human patients, researchers led by S. Tamir Rashid (King's College London, London, United Kingdom) recently tested the ability of hepatocytes differentiated from human pluripotent stem cells derived under current good manufacturing practice (cGMP) guidelines to form functional three‐dimensional liver constructs. The results of this new STEM CELLS Translational Medicine study from Blackford et al. highlights the suitability of this approach for future therapeutic applications in human patients . Are we now one step closer to the application of human pluripotent stem cell-derived hepatocytes in the clinic?
The authors differentiated three recently-derived cGMP lines, one human embryonic stem cell line and two induced pluripotent stem cell lines, via the application of a chemically defined four‐step hepatic differentiation protocol  that passed through definitive endoderm and hepatic endoderm stages before uniformly generating hepatic progenitor-like cells with highly reproducible phenotypes and functionality. Subsequent seeding of cGMP‐compliant hepatic progenitors into bio‐engineered scaffolds composed of a clinically approved material that mimics native liver tissue anatomy promoted further hepatic maturation and the generation of advanced three‐dimensional hepatic tissue structures in a scalable manner. Encouragingly, said hepatic structures displayed clinically relevant levels of functionality, while hepatocytes generated in this manner also expressed high levels of critically important genes, including albumin (ALB), and those coding for enzymes that metabolize potentially toxic compounds (CYP3A7 and CYP3A4)
The authors then encapsulated their cGMP‐compliant human pluripotent stem cell-derived three‐dimensional hepatic tissues in the immune‐privileged material alginate , which heightened viability and promoted high levels of functionality following transplantation into immunocompetent mice. This encouraging finding highlights the above-described strategy as a suitable approach for the treatment of end‐stage chronic liver disease or acute liver failure in human patients that would avoid potential allogenic immune rejection of the host.
Overall, the authors anticipate that their first report of the generation of advanced functional three‐dimensional hepatic tissue from clinical grade human pluripotent stem cells manufactured under cGMP conditions take the field a step closer to the treatment of human patients with pluripotent stem cell-derived hepatocytes.
For more on the production of clinically relevant and functional tissue constructs from human pluripotent stem cells, stay tuned to the Stem Cells Portal.
- Tolosa L, Caron J, Hannoun Z, et al., Transplantation of hESC-derived hepatocytes protects mice from liver injury. Stem Cell Research & Therapy 2015;6:246.
- Choi SM, Kim Y, Liu H, et al., Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells. Cell Cycle 2011;10:2423-7.
- Chen Y, Li Y, Wang X, et al., Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes. Stem Cell Reports 2015;5:22-30.
- Blackford SJI, Ng SS, Segal JM, et al., Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy. STEM CELLS Translational Medicine 2019;8:124-137.
- Hannan NRF, Segeritz C-P, Touboul T, et al., Production of hepatocyte-like cells from human pluripotent stem cells. Nature Protocols 2013;8:430.
- Strand BL, Coron AE, and Skjak‐Braek GJSctm, Current and future perspectives on alginate encapsulated pancreatic islet. STEM CELLS Translational Medicine 2017;6:1053-1058.