Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell–derived hepatocytes

Soto-Gutiérrez, Alejandro; Kobayashi, Naoya; Rivas‐Carrillo, Jorge David; Navarro-Alvarez, Nalú; Zhao, Debaio; Okitsu, Teru; Noguchi, Hirofumi; Basma, Hesham; Tabata, Yashuhiko; Chen, Yong; Tanaka, Kazunori; Narushima, Michiki; Miki, Atsushi; Ueda, Tomoya; Lee, Youn-Jung; Yoon, Ji Won; Lebkowski, Jane; Tanaka, Noriaki; Fox, Ira J.

doi:10.1038/nbt1257

Cited by 201 publications

(174 citation statements)

References 43 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…Mouse ES-derived hepatocytes co-cultured with human liver nonparenchymal cell lines showed higher metabolic capacity compared with mouse ES-derived hepatocytes differentiated without co-culture (see ref. 17 and Fig. 3).…”

Section: |mentioning

confidence: 85%

“…Differentiated ES cells secrete albumin; metabolize ammonia, lidocaine and diazepam; contain glycogen rosettes and express no pancreatic exocrine proteins. Mice with liver failure treated with an implantable liver assist device containing the ES cell-derived hepatocytes survived better and had improved liver function earlier than mice treated with the implantable assist device containing control cells 17 . The present hepatic differentiation strategy appears to require further optimization to eliminate AFP-positive cells and to produce a more homogeneous population of hepatocyte-like cells.…”

Section: Protocols Have Been Developed To Differentiate and Enrich Vamentioning

confidence: 94%

See 1 more Smart Citation

Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines

et al. 2007

Self Cite

View full text Add to dashboard Cite

This protocol describes a co-culture system for the in vitro differentiation of mouse embryonic stem cells into hepatocyte-like cells. Differentiation involves four steps: (i) formation of embryoid bodies (EB), (ii) induction of definitive endoderm from 2-d-old EBs, (iii) induction of hepatic progenitor cells and (iv) maturation into hepatocyte-like cells. Differentiation is completed by 16 d of culture. EBs are formed, and cells can be induced to differentiate into definitive endoderm by culture in Activin A and fibroblast growth factor 2 (FGF-2). Hepatic differentiation and maturation of cells is accomplished by withdrawal of Activin A and FGF-2 and by exposure to liver nonparenchymal cell-derived growth factors, a deleted variant of hepatocyte growth factor (dHGF) and dexamethasone. Approximately 70% of differentiated embryonic stem (ES) cells express albumin and can be recovered by albumin promoter-based cell sorting. The sorted cells produce albumin in culture and metabolize ammonia, lidocaine and diazepam at approximately two-thirds the rate of primary mouse hepatocytes.

show abstract

Section: |mentioning

confidence: 85%

Section: Protocols Have Been Developed To Differentiate and Enrich Vamentioning

confidence: 94%

Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…These cells could also provide a source of cellular therapies for the replacement of damaged or destroyed tissues [10][11][12][13][14][15], and tissues derived from hESC could be used in drug discovery and toxicology studies [16,17]. The success of these applications, however, depends on our capacity to provide an adequate supply of hESC for research and development purposes.…”

Section: Introductionmentioning

confidence: 99%

Proliferation and Pluripotency of Human Embryonic Stem Cells Maintained on Type I Collagen

Jones

Chu

Pendleton

et al. 2010

Stem Cells and Development

View full text Add to dashboard Cite

Human embryonic stem cells (hESC) require a balance of growth factors and signaling molecules to proliferate and retain pluripotency. Conditioned medium (CM) from a human embryonic germ-cell-derived cell culture, SDEC, was observed to support the growth of hESC on type I collagen (COL I) and on Matrigel (MAT) biomatricies. After 1 month, the population doubling of hESC grown in SDEC CM on COL I was equivalent to that of hESC grown in mouse embryonic fibroblast (MEF) CM on MAT. hESC grown in SDEC CM on COL I expressed OCT4, NANOG, SSEA-4, alkaline phosphatase (AP), and TRA-1-60; retained a normal karyotype; and were capable of forming teratomas. DNA microarray analysis was used to compare the transcriptional profiles of SDEC and the less supportive WI38 and Detroit 551 human cell lines. The mRNA level of secreted frizzledrelated protein (sFRP-1), a known antagonist of the WNT=b-catenin signaling pathway, was significantly reduced in SDEC as compared with the other 2 cell lines, whereas the mRNA levels of prostaglandin-endoperoxide synthase 2 (PTGS2 or COX-2) and prostaglandin I 2 synthase (PGIS), two prostaglandin biosynthesis genes, were significantly increased in SDEC. The level of sFRP-1 protein was significantly reduced, and levels of 2 prostaglandins that are downstream products of PTGS2 and PGIS, prostaglandin E 2 and 6-keto-prostaglandin F 1a , were significantly elevated in SDEC CM compared with WI38, Detroit 551, and MEF CM. Further, addition of purified sFRP-1 to SDEC CM reduced the proliferation of hESC grown on COL I as well as MAT in a dosedependent manner.

show abstract

“…1D). Coencapsulation of the human liver endothelial cell (LEC) line TMNK-1 (28,29) was the most beneficial to rat hepatocellular function ( Fig. 1 E and F), whereas additional mouse FIB were moderately and transiently supportive, and the human hepatic stellate cell (HSC) line TWNT-1 (30) had no effect (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Human liver-derived nonparenchymal cells provide soluble signals important for hepatocyte development and maintenance (28). To investigate the effects of paracrine signaling on HEAL stability, we mixed human liver nonparenchymal cell lines with HEP/FIB clusters prior to encapsulation, entrapping HEP/FIB near, but not clustered with, the nonparenchymal cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Humanized mice with ectopic artificial liver tissues

Chen

Thomas

Ong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

145

148

View full text Add to dashboard Cite

"Humanized" mice offer a window into aspects of human physiology that are otherwise inaccessible. The best available methods for liver humanization rely on cell transplantation into immunodeficient mice with liver injury but these methods have not gained widespread use due to the duration and variability of hepatocyte repopulation. In light of the significant progress that has been achieved in clinical cell transplantation through tissue engineering, we sought to develop a humanized mouse model based on the facile and ectopic implantation of a tissue-engineered human liver. These human ectopic artificial livers (HEALs) stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds. In contrast to current methods, HEALs can be efficiently established in immunocompetent mice with normal liver function. Mice transplanted with HEALs exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction, and drug-induced liver injury. Here, mice with HEALs are used to predict the disproportionate metabolism and toxicity of "major" human metabolites using multiple routes of administration and monitoring. These advances may enable manufacturing of reproducible in vivo models for diverse drug development and research applications.P reclinical models provide a critical window into human physiology and are important for determining drug safety and efficacy. Bioengineering advances have produced in vivo platforms with improved disease modeling (1, 2), absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) (3, 4), and circulation-mimicking capabilities (4). "Human-on-a-chip" systems, however, show limited recapitulation of pharmacokinetics and cannot support clinically relevant administration routes. Elsewhere, humanized mice, based on genetic manipulation or transplantation of human cells, have also been highly enabling (5). Mice with chimeric livers show encouraging drug responsiveness (6, 7) and pathogen susceptibility (8-12). However, these models are confined to liver-injury, immunodeficient recipients and depend on the coordinated injection of high-quality human hepatocytes, which must home to the liver from the injection site, engraft, and expand over weeks to months within the injured host (13,14). Given the limitations of current preclinical models, human metabolites and their downstream effects often go undetected until clinical trials, the most costly and dangerous phase of drug development (15).Here we develop an improved humanized mouse model by implantation of tissue-engineered human ectopic artificial livers (HEALs). In the field of tissue engineering, polymeric scaffolds are widely used for cell and drug delivery in vivo (16,17). Primary hepatocytes, however, are challenging to maintain and implant via biomaterials due to their unstable phenotype, variable engraftment efficiencies, and high metabolic needs (18). Use of partial hepatectomy with portal-caval ...

show abstract

Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell–derived hepatocytes

Cited by 201 publications

References 43 publications

Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines

Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines

Proliferation and Pluripotency of Human Embryonic Stem Cells Maintained on Type I Collagen

Humanized mice with ectopic artificial liver tissues

Contact Info

Product

Resources

About