Clinical Hepatocyte Transplantation: What Is Next?

Squires, James E.; Soltys, Kyle; McKiernan, Patrick; Squires, Robert H.; Strom, Stephen C.; Fox, Ira J.; Soto-Gutiérrez, Alejandro

doi:10.1007/s40472-017-0165-6

Cited by 29 publications

(32 citation statements)

References 122 publications

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“…Allogenic transplantation of primary adult hepatocytes, the major functional cell‐type of the liver, is considered a viable solution in certain clinical indications . Lack of sufficient numbers of high‐quality hepatocytes; a result of isolating cells from tissue deemed unsuitable for transplantation, has limited the success of this programme . Derivation of human embryonic stem cells (hESCs) and their related induced pluripotent stem cells (hiPSCs) , however, has generated growing optimism that the development of cellular therapies, such as would be suitable for liver disease, is finally an obtainable goal .…”

Section: Introductionmentioning

confidence: 99%

Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

Blackford

Segal

et al. 2018

Stem Cells Translational Medicine

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Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC‐Heps) afford tremendous possibilities for treatment of patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite for such applications but have only recently been established. Whether such cGMP lines are capable of hepatic differentiation is not known. To address this knowledge gap, we examined the proficiency of three recently derived cGMP lines (two hiPSC and one hESC) to differentiate into hepatocytes and their suitability for therapy. hPSC‐Heps generated using a chemically defined four‐step hepatic differentiation protocol uniformly demonstrated highly reproducible phenotypes and functionality. Seeding into a 3D poly(ethylene glycol)‐diacrylate fabricated inverted colloid crystal scaffold converted these immature progenitors into more advanced hepatic tissue structures. Hepatic constructs could also be successfully encapsulated into the immune‐privileged material alginate and remained viable as well as functional upon transplantation into immune competent mice. This is the first report we are aware of demonstrating cGMP‐compliant hPSCs can generate cells with advanced hepatic function potentially suitable for future therapeutic applications. stem cells translational medicine 2019;8:124&14

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Section: Introductionmentioning

confidence: 99%

Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

Blackford

Segal

et al. 2018

Stem Cells Translational Medicine

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“…Currently, the only clinically viable approach to acute and acute‐on‐chronic liver failure is liver transplantation. Although theoretically attractive, ( 43 ) fully functioning human hepatocytes cannot be generated in vitro at scale for both therapeutic and investigational purposes. Although several protocols have been generated to produce hepatocyte‐like cells from various progenitor populations, these cells do not capture the complexity of metabolic and synthetic functions of mature hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development

et al. 2020

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Background and Aims During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver required to maintain organismal homeostasis. The developmental cues controlling the differentiation of committed progenitors into these cell types, however, are incompletely understood. Here, we discover an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. Approach and Results Exposure of zebrafish embryos to 17β‐estradiol (E2) during liver development significantly decreased hepatocyte‐specific gene expression, liver size, and hepatocyte number. In contrast, pharmacological blockade of estrogen synthesis or nuclear estrogen receptor (ESR) signaling enhanced liver size and hepatocyte marker expression. Transgenic reporter fish demonstrated nuclear ESR activity in the developing liver. Chemical inhibition and morpholino knockdown of nuclear estrogen receptor 2b (esr2b) increased hepatocyte gene expression and blocked the effects of E2 exposure. esr2b−/− mutant zebrafish exhibited significantly increased expression of hepatocyte markers with no impact on liver progenitors, other endodermal lineages, or vasculature. Significantly, E2‐stimulated Esr2b activity promoted biliary epithelial differentiation at the expense of hepatocyte fate, whereas loss of esr2b impaired biliary lineage commitment. Chemical and genetic epistasis studies identified bone morphogenetic protein (BMP) signaling as a mediator of the estrogen effects. The divergent impact of estrogen on hepatobiliary fate was confirmed in a human hepatoblast cell line, indicating the relevance of this pathway for human liver development. Conclusions Our studies identify E2, esr2b, and downstream BMP activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant clinical implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy.

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“…Based on several successful survival studies in large animals [38][39][40], cell transplantation has been studied as an alternative way of filling the treatment gap at the ICU for ESLF patients [41].…”

Section: Hepatocyte or Stem Cell Transplantationmentioning

confidence: 99%

End-stage liver failure: filling the treatment gap at the intensive care unit

Chamuleau

Hoekstra

2019

J Artif Organs

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End-stage liver failure is a condition of collapsing liver function with mortality rates up to 80. Liver transplantation is the only lifesaving therapy. There is an unmet need for therapy to extend the waiting time for liver transplantation or regeneration of the native liver. Here we review the state-of-the-art of non-cell based and cell-based artificial liver support systems, cell transplantation and plasma exchange, with the first therapy relying on detoxification, while the others aim to correct also other failing liver functions and/or modulate the immune response. Meta-analyses on the effect of non-cell based systems show contradictory outcomes for different types of albumin purification devices. For bioartificial livers proof of concept has been shown in animals with liver failure. However, large clinical trials with two different systems did not show a survival benefit. Two clinical trials with plasma exchange and one with transplantation of mesenchymal stem cells showed positive outcomes on survival. Detoxification therapies lack adequacy for most patients. Correction of additional liver functions, and also modulation of the immune system hold promise for future therapy of liver failure.

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Clinical Hepatocyte Transplantation: What Is Next?

Cited by 29 publications

References 122 publications

Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development

End-stage liver failure: filling the treatment gap at the intensive care unit

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