Liver transplantation: Issues for the next 20 years

Perera, M Thamara P R; Mirza, Darius F.; Elias, Elwyn

doi:10.1111/j.1440-1746.2009.06081.x

Cited by 47 publications

(26 citation statements)

References 102 publications

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“…Liver transplantation is currently the only definitive and curative treatment for acute and chronic liver failure [2]. First accomplished in 1967 by Thomas Starzl, liver transplantation has been an unquestioned clinical success; however, the demand for liver transplantation has significantly outstripped the supply of donor organs [2-4]. As a consequence, multiple attempts to expand the availability of donor organs have been employed: opt-out organ donation programs, the use of suboptimal donor organs (deceased cardiac donors or steatotic (fatty) livers), split donor transplantation, and living donor liver transplantation [4].…”

Section: Introductionmentioning

confidence: 99%

Pluripotent stem cell-derived hepatocyte-like cells

Schwartz¹,

Fleming²,

Khetani

2014

Biotechnology Advances

237

212

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Liver disease is an important clinical problem, impacting over 30 million Americans and over 600 million people worldwide. It is the 12th leading cause of death in the United States and the 16th worldwide. Due to a paucity of donor organs, several thousand Americans die yearly while waiting for liver transplantation. Unfortunately, alternative tissue sources such as fetal hepatocytes and hepatic cell lines are unreliable, difficult to reproduce, and do not fully recapitulate hepatocyte phenotype and function. As a consequence, alternative cell sources that do not have these limitations have been sought. Human embryonic stem (hES) cell- and induced pluripotent stem (iPS) cell-derived hepatocyte-like cells may enable cell based therapeutics, the study of the mechanisms of human disease and human development, and provide a platform for pharmacology and toxicology drug screening. iPS cells can be differentiated in a stepwise fashion with high efficiency and reproducibility into hepatocyte-like cells that exhibit morphologic and phenotypic characteristics of hepatocytes. In addition, iPS-derived hepatocyte-like cells possess some functional hepatic activity as they secrete urea, alpha-1-antitrypsin, and albumin. However, the combined phenotypic and functional traits exhibited by iPS-derived hepatocyte-like cells resemble a relatively immature hepatic phenotype that more closely resembles that of fetal hepatocytes rather than adult hepatocytes. Specifically, iPS-derived hepatocyte-like cells express fetal markers such as alpha fetoprotein and lack key mature hepatocyte functions, as reflected by drastically reduced activity (0.1%) of many detoxification enzymes (i.e. CYP2A6, CYP3A4). These key differences between iPS-derived hepatocyte-like cells and adult hepatocytes have limited the use of stem cells as a renewable source of functional adult human hepatocytes for in vitro and in vivo applications. Unfortunately, the developmental pathways that control hepatocyte maturation from a fetal into an adult hepatocyte are poorly understood, which has hampered the field in its efforts to induce further maturation of iPS-derived hepatic lineage cells. This review analyzes recent developments in the derivation of hepatocyte-like cells, and proposes important points to consider and assays to perform during their characterization. In the future, we envision that iPS-derived hepatocyte-like cells will be used as in vitro models of human disease, and in the longer term, provide an alternative cell source for drug testing and clinical therapy.

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Section: Introductionmentioning

confidence: 99%

Pluripotent stem cell-derived hepatocyte-like cells

Schwartz¹,

Fleming²,

Khetani

2014

Biotechnology Advances

237

212

View full text Add to dashboard Cite

show abstract

“…Since donor organ scarcity is the major limitation of liver transplantation (1), novel therapeutic approaches are urgently needed to treat chronic and genetic-based liver diseases. In this regard, considerable attention has been focused on the possibility to restore liver function through cell transplantation (2,3).…”

Section: Introductionmentioning

confidence: 99%

Activin A, p15INK4b Signaling, and Cell Competition Promote Stem/Progenitor Cell Repopulation of Livers in Aging Rats

et al. 2011

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Background & Aims Highly proliferative fetal liver stem/progenitor cells (FLSPC) repopulate livers of normal recipients by cell competition. We investigated the mechanisms by which FLSPC repopulate livers of older, compared with younger rats. Methods Fetal liver cells were transplanted from DPPIV+ F344 rats into DPPIV− rats of different ages (2, 6, 14, or 18 months); liver tissues were analyzed 6 months later. Cultured cells and liver tissues were analyzed by reverse transcription PCR, immunoblot, histochemistry, laser-capture microscopy, and TUNEL analyses. Results We observed 4–5-fold increases in liver repopulation when FLSPC were transplanted into older, compared with younger, rats. mRNA levels of cyclin-dependent kinase inhibitors increased progressively in livers of older rats; hepatocytes from 20-month old rats had 6.1-fold higher expression of p15INK4b and were less proliferative, in vitro, than hepatocytes from 2-month old rats. Expression of p15INK4b in cultured hepatocytes was upregulated by activin A, which increased in liver during aging. Activin A inhibited proliferation of adult hepatocytes, whereas FLSPC were unresponsive because they had reduced expression of activin receptors (e.g. ALK-4). In vivo, expanding cell clusters derived from transplanted FLSPC had lower levels of ALK-4 and p15INK4b and increased levels of Ki-67, compared with the host parenchema. Liver tissue of older rats had 3-fold more apoptotic cells than of younger rats. Conclusions FLSPC, resistant to activin A signaling, repopulate livers of older rats; hepatocytes in older rats have less proliferation, because of increased activin A and p15INK4b levels, and increased apoptosis than of younger rats. These factors and cell types might be manipulated to improve liver cell transplantation strategies in patients with liver diseases in which activin A levels are increased.

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“…The increasing gap between organ donation and supply to severely-ill patients has fostered an increased interest in alternative organ sources[6]. For the development and differentiation of full organs suitable for human transplant, structures that provide microvasculature for the delivery of nutrients to all cells must be developed[7-9].…”

Section: Introductionmentioning

confidence: 99%

Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion

et al. 2010

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BackgroundDespite advances in transplant surgery and general medicine, the number of patients awaiting transplant organs continues to grow, while the supply of organs does not. This work outlines a method of organ decellularization using non-thermal irreversible electroporation (N-TIRE) which, in combination with reseeding, may help supplement the supply of organs for transplant.MethodsIn our study, brief but intense electric pulses were applied to porcine livers while under active low temperature cardio-emulation perfusion. Histological analysis and lesion measurements were used to determine the effects of the pulses in decellularizing the livers as a first step towards the development of extracellular scaffolds that may be used with stem cell reseeding. A dynamic conductivity numerical model was developed to simulate the treatment parameters used and determine an irreversible electroporation threshold.ResultsNinety-nine individual 1000 V/cm 100-μs square pulses with repetition rates between 0.25 and 4 Hz were found to produce a lesion within 24 hours post-treatment. The livers maintained intact bile ducts and vascular structures while demonstrating hepatocytic cord disruption and cell delamination from cord basal laminae after 24 hours of perfusion. A numerical model found an electric field threshold of 423 V/cm under specific experimental conditions, which may be used in the future to plan treatments for the decellularization of entire organs. Analysis of the pulse repetition rate shows that the largest treated area and the lowest interstitial density score was achieved for a pulse frequency of 1 Hz. After 24 hours of perfusion, a maximum density score reduction of 58.5 percent had been achieved.ConclusionsThis method is the first effort towards creating decellularized tissue scaffolds that could be used for organ transplantation using N-TIRE. In addition, it provides a versatile platform to study the effects of pulse parameters such as pulse length, repetition rate, and field strength on whole organ structures.

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Liver transplantation: Issues for the next 20 years

Cited by 47 publications

References 102 publications

Pluripotent stem cell-derived hepatocyte-like cells

Pluripotent stem cell-derived hepatocyte-like cells

Activin A, p15INK4b Signaling, and Cell Competition Promote Stem/Progenitor Cell Repopulation of Livers in Aging Rats

Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion

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