Establishment of immortalized human hepatic stellate scavenger cells to develop bioartificial livers1

Watanabe, Takahiro; Shibata, Norikuni; Westerman, Karen A.; Okitsu, Teru; Allain, Jean E.; Sakaguchi, Masakiyo; Totsugawa, Toshinori; Maruyama, Masanobu; Matsumura, Tatsuro; Noguchi, Hirofumi; Yamamoto, Shinichiro; Hara, Masaki; Ohmori, Akira; Reth, Michael; Weber, Anne; Tanaka, Noriaki; Leboulch, Philippe; Kobayashi, Naoya

doi:10.1097/01.tp.0000064621.50907.a6

Cited by 63 publications

(39 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cytokine cross-talk is equally important and includes TGF-␤ (58, 419), TGF-␣ (284), insulin-like growth factors and binding proteins (72,211,607), HGF (108,305,469,709), VEGF (109), NGF (21, 454), CTGF (507), IL-6 (32), thrombospondin (430), as well as other paracrine factors derived from hepatic tumor cells (34, 148). Stellate cells may also support hepatocyte function ex vivo,which could advance the development of liver support devices (687). There is also evidence that HCV-infected hepatocytes may release fibrogenic factors towards stellate cells (578,647), which could explain how patients with normal serum transaminases infected with HCV can still develop hepatic fibrosis.…”

Section: Paracrine Interactions With Other Resident Liver Cellsmentioning

confidence: 99%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,386

2,549

View full text Add to dashboard Cite

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

show abstract

Section: Paracrine Interactions With Other Resident Liver Cellsmentioning

confidence: 99%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,386

2,549

View full text Add to dashboard Cite

show abstract

“…We devised a strategy for differentiation of ES cells into hepatocyte-like cells using a four-step differentiation protocol: (i) generation of EBs; (ii) induction of definitive endoderm from 2-d-old EBs by growth in Activin A and FGF-2; (iii) induction of hepatic progenitors by co-culture with human liver nonparenchymal cell lines (human liver endothelial (TMNK-1) 14 , stellate (TWNT-1) 15 and cholangiocyte (MMNK-1) 16 cell lines) and a deleted variant of HGF (dHGF); and (iv) maturation into hepaticlike cells by culture in DMSO and dexamethasone (Fig. 1).…”

Section: Protocols Have Been Developed To Differentiate and Enrich Vamentioning

confidence: 99%

“…Induction of hepatic progenitor cells (expressing both albumin and AFP) and maturation into hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines 12| Prepare human liver nonparenchymal cell lines [14][15][16] , which can be maintained in T75 tissue culture flasks in 10 ml of DMEM and 10% FBS. Passage confluent cultures every week, and change the medium every 3 d.…”

Section: |mentioning

confidence: 99%

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

“…hTERT lifespan extension is also being investigated for the treatment of Duchenne muscular dystrophy by using genetically modified muscle satellite cells (6,7). Other cell types that have been lifespan-extended by telomerase in anticipation of tissue engineering applications include retinal pigment epithelia (8)(9)(10)(11)(12), dermal fibroblasts (13,14), vascular endothelium (15)(16)(17), bone marrow stromal cells (18)(19)(20)(21), osteoblasts (22,23), mesenchymal stem cells (24), and hepatic stellate cells (25,26). Using retroviral delivery of hTERT to human saphenous vein SMC, it is possible to culture autologous blood vessels for patients as old as 74 years (2).…”

mentioning

confidence: 99%

Relevance and safety of telomerase for human tissue engineering

Klinger

Blum

Hearn

et al. 2006

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

View full text Add to dashboard Cite

Tissue engineering holds the promise of replacing damaged or diseased tissues and organs. The use of autologous donor cells is often not feasible because of the limited replicative lifespan of cells, particularly those derived from elderly patients. Proliferative arrest can be overcome by the ectopic expression of telomerase via human telomerase reverse transcriptase (hTERT) gene transfection. To study the efficacy and safety of this potentially valuable technology, we used differentiated vascular smooth muscle cells (SMC) and vascular tissue engineering as a model system. Although we previously demonstrated that vessels engineered with telomerase-expressing SMC had improved mechanics over those grown with control cells, it is critical to assess the phenotypic impact of telomerase expression in donor cells, because telomerase upregulation is observed in >95% of human malignancies. To study the impact of telomerase in tissue engineering, expression of hTERT was retrovirally induced in SMC from eight elderly patients and one young donor. In hTERT SMC, significant lifespan extension beyond that of control was achieved without population doubling time acceleration. Karyotype changes were seen in both control and hTERT SMC but were not clonal nor representative of cancerous change. hTERT cells also failed to show evidence of neoplastic transformation in functional assays of tumorigenicity. In addition, the impact of donor age on cellular behavior, particularly the synthetic capability of SMC, was not affected by hTERT expression. Hence, this tissue engineering model system highlights the impact of donor age on cellular synthetic function that appears to be independent of lifespan extension by hTERT.tumorigenicity ͉ smooth muscle cells ͉ vascular graft

show abstract

Establishment of immortalized human hepatic stellate scavenger cells to develop bioartificial livers1

Abstract: TWNT-1 cells could be valuable in the study of integrated liver functions and contribute to the optimization of liver cell therapies and bioartificial livers.

Cited by 63 publications

References 19 publications

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

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

Relevance and safety of telomerase for human tissue engineering

Contact Info

Product

Resources

About