Pluripotent stem cells to hepatocytes, the journey so far

Palakkan, Anwar Azad; Nanda, Jyoti; Ross, James A.

doi:10.3892/br.2017.867

Cited by 43 publications

(39 citation statements)

References 67 publications

(54 reference statements)

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“…With the aim of replicating liver development in vitro, several groups have succeeded in differentiating human iPSCs into hepatocyte-like cells following a stepwise differentiation protocol based on several chemical inhibitors 63. An alternative approach was pursued by the Suzuki and Hui labs, which forced the expression of pioneer liver transcription factors ( HNF4a and FOXA1,2,3 )64 or ( HNF4a , GATA4 and HNF1B )65 to induce the direct differentiation of iPSCs into hepatocyte-like cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Liver organoids: from basic research to therapeutic applications

Prior

Inácio

Huch

2019

Gut

258

201

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Organoid cultures have emerged as an alternative in vitro system to recapitulate tissues in a dish. While mouse models and cell lines have furthered our understanding of liver biology and associated diseases, they suffer in replicating key aspects of human liver tissue, in particular its complex architecture and metabolic functions. Liver organoids have now been established for multiple species from induced pluripotent stem cells, embryonic stem cells, hepatoblasts and adult tissue-derived cells. These represent a promising addition to our toolbox to gain a deeper understanding of this complex organ. In this perspective we will review the advances in the liver organoid field, its limitations and potential for biomedical applications.

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Section: Introductionmentioning

confidence: 99%

Liver organoids: from basic research to therapeutic applications

Prior

Inácio

Huch

2019

Gut

258

201

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“…We differentiated hiPSCs (human induced pluripotent stem cells) over 25 days ( 18, 19 ) into hepatocytes lineage during which the hepatoblast-to-hepatocyte differentiation took 6 days in vitro ( 20 ). During this hepatic lineage induction, we observed a mixed population of cells at different maturation stages ( 21 ). To assess hepatocyte maturity, we used the expression levels and localization of a small organic anion transporter MRP2 (Multidrug resistance-associated protein 2).…”

Section: Resultsmentioning

confidence: 95%

Autonomous induction of hepatic polarity to construct single cell liver

Zhang

Mets

Monzel

et al. 2019

Preprint

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20Symmetry breaking of protein distribution and cytoskeleton organization is an 21 essential aspect for development of apico--basal polarity. In embryonic cells this 22 process is largely cell autonomous, while differentiated epithelial cells collectively 23 polarize during epithelium formation. We report here that the de novo polarization 24 of mature hepatocytes is a cell autonomous process. Single hepatocytes developed 25 bona fide secretory hemi--apical lumens upon adhesion to finely tuned substrates 26 bio--functionalized with cadherin and extra cellular matrix. The creation of this single 27 cell liver allows unprecedented control and imaging resolution of the lumenogenesis 28 process. We demonstrate that the density and localization of cadherins along the 29 initial cell--cell contact acted as a key factor triggering the reorganization from lateral 30 to apical actin cortex. Consequently, we established why hepatocytes could form 31 asymmetric lumens in heterotypic doublets involving another ectopic epithelial cell 32 originating from kidney, breast, or colon. 33 34 stimulate the creation of a border brush with a partial localization of the polarity 50 complexes (17).The question then arises whether de novo establishment of epithelial 51 polarity is a cell autonomous response triggered by external cues or a collective 52 response associated to the concomitant development of polarity in neighboring 53 cells. Usual epithelial models (tissue, cell monolayer, or cysts) inherently fail to 54 address this question. Considering a cell polarizing in these multi--cellular contexts, 55 the concomitant reorganization of cell--cell contacts of the neighboring cells can act 56 as a polarization cue and as a response to its polarization establishment. 57This study presents a novel model where single primary hepatocytes develop 58 independent bona fide secretory apical poles when grown in synthetic 59 microenvironments. In this context, we demonstrate for the first time that de novo 60 apical lumen development is a genetically controlled cell autonomous process. It 61 depends mainly on actin cortex rearrangements triggered by the biophysical 62properties of the cadherin--mediated adherens junction along the initial lateral cell--63 cell contact. Subsequently, we demonstrate that, hepatocytes can form functional 64 lumen with a whole variety of epithelial cells. In particular, we show that mature 65 hepatocytes can polarize with immature hepatocytes during the differentiation 66 process. 67 68 Results: 69We investigated the de novo lumenogenesis of bile canaliculi to test if the apical 70 polarity development is a cell autonomous process triggered by simple cues sensed 71 by the cell along the non--polarized initial cell--cell contact. We used hepatocytes at 72 different maturation stages during differentiation. Mature hepatocytes develop 73 intercellular secretory apical lumen called bile canaliculi, connecting the hepatocytes 74 to the biliary system. They consist of small, elongated tubules (2 μm in diameter) 75 sealed...

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“…Hepatocyte-like cells derived from iPS cells (iPS-Heps) exhibit properties of hepatocytes, such as albumin secretion and metabolic functional properties. Several pathophysiological disorders can be reproduced using human iPS-Heps; on the contrary, the phenotypes of iPS-Heps are immature compared with adult mature hepatocytes with respect to albumin production, cytochrome P450 (CYP) activity and metabolic functions [18,19]. Recent reports have shown that patientderived iPS-Heps have been used to investigate the pathophysiology of genetic disorders, such as a1antitrypsin deficiency, glycogen storage disease type 1, Crigler-Najjar syndrome, hereditary tyrosinemia type 1, Gaucher disease, Niemann-Pick disease type C and Wilson's disease [14][15][16]20,21].…”

Section: Diseases Models Of Genetic Liver Diseasesmentioning

confidence: 99%

“…Human iPS-Hep cells with genetic modifications may be of value for research into various diseases as described above; however, previous studies also showed that the phenotypes of iPS-Hep cells are immature compared with adult hepatocytes with respect to albumin production, CYP activity and metabolic functions [4,5,18,19]. This problem of the immature nature of iPS-Hep cells as hepatocytes must be resolved.…”

Section: Disease Models Of Liver Fibrosismentioning

confidence: 99%

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

Kakinuma

Watanabe

2019

Immunological Medicine

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Results of recent studies have shown that disease models using human induced pluripotent stem (iPS) cells have recapitulated the pathophysiology of genetic liver diseases, viral hepatitis and hepatic fibrosis. The utilization of human iPS cells as a model of liver diseases has several substantial advantages compared with primary hepatocytes and cancer cell lines, such as the potential for unlimited expansion and similarity of biological characteristics to normal liver cells. In this review, we have focused on modeling liver diseases using human iPS cells and discussed the experimental evidence that supports the utility of such disease models, including that in our recent studies. Genetically modified or patient-derived human iPS cells can mimic congenital liver disease phenotypes. Human iPS-derived hepatic cells can be infected with the hepatitis viruses. The co-culture of human iPS-derived hepatocytes and mesenchyme partially mimics the process of liver fibrosis. Human iPS cell-derived hepatic cells and the co-culture system of such cells will contribute to the progress of studies on the pathophysiology of genetic and non-genetic liver diseases and development of novel therapeutic strategies for treating liver diseases.

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Pluripotent stem cells to hepatocytes, the journey so far

Cited by 43 publications

References 67 publications

Liver organoids: from basic research to therapeutic applications

Liver organoids: from basic research to therapeutic applications

Autonomous induction of hepatic polarity to construct single cell liver

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

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