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• W2061765327 abstract "Forced lineage conversion of accessible cell types can supply scarce or inaccessible cells for research and therapy. Two papers in Nature now report the identification of transcription factors sufficient for inducing therapeutically effective hepatocyte function in fibroblasts (Huang et al., 2011Huang P. He Z. Ji S. Sun H. Xiang D. Liu C. Hu Y. Wang X. Hui L. Nature. 2011; 475: 386-389Crossref PubMed Scopus (603) Google Scholar, Sekiya and Suzuki, 2011Sekiya S. Suzuki A. Nature. 2011; 475: 390-393Crossref PubMed Scopus (591) Google Scholar). Forced lineage conversion of accessible cell types can supply scarce or inaccessible cells for research and therapy. Two papers in Nature now report the identification of transcription factors sufficient for inducing therapeutically effective hepatocyte function in fibroblasts (Huang et al., 2011Huang P. He Z. Ji S. Sun H. Xiang D. Liu C. Hu Y. Wang X. Hui L. Nature. 2011; 475: 386-389Crossref PubMed Scopus (603) Google Scholar, Sekiya and Suzuki, 2011Sekiya S. Suzuki A. Nature. 2011; 475: 390-393Crossref PubMed Scopus (591) Google Scholar). Hepatocytes are responsible for both function and regeneration of the adult liver. An unlimited source of human hepatocytes would be of great value for modeling and understanding liver diseases, drug efficacy and toxicity testing, and cell replacement therapy. Because primary human hepatocytes are scarce and, despite their ability to efficiently proliferate in vivo, cannot be expanded in vitro, much effort has been focused on generating surrogate hepatocytes from pluripotent stem cells. For this purpose, current protocols use growth factors that have been identified in studies of mouse liver development to guide the formation of ventral endoderm and subsequent differentiation steps that produce liver progenitors and mature hepatocytes (Si-Tayeb et al., 2010Si-Tayeb K. Lemaigre F.P. Duncan S.A. Dev. Cell. 2010; 18: 175-189Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, Zaret and Grompe, 2008Zaret K.S. Grompe M. Science. 2008; 322: 1490-1494Crossref PubMed Scopus (441) Google Scholar). Now Huang et al. and Sekiya et al. investigated whether the transcription factors activated by these growth factors can be used to induce direct hepatocyte differentiation of fibroblasts, a readily accessible, developmentally unrelated cell type. Prompted by pioneering work on reprogramming of fibroblasts to pluripotency or neuronal, cardiac, or hematopoietic differentiation (Chambers and Studer, 2011Chambers S.M. Studer L. Cell. 2011; 145: 827-830Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), both groups started by overexpressing in mouse fibroblasts a cohort of transcription factors previously reported to play a role in liver development and hepatocyte function (Kyrmizi et al., 2006Kyrmizi I. Hatzis P. Katrakili N. Tronche F. Gonzalez F.J. Talianidis I. Genes Dev. 2006; 20: 2293-2305Crossref PubMed Scopus (187) Google Scholar, Zaret and Grompe, 2008Zaret K.S. Grompe M. Science. 2008; 322: 1490-1494Crossref PubMed Scopus (441) Google Scholar). Then, using de novo hepatocyte-specific gene expression as a marker for the formation of induced hepatocyte-like (iHep) cells, they gradually eliminated those factors that were not essential for the reprogramming process (Table 1).Table 1iHep Cell Generation and CharacterizationHuang et al.Sekiya et al.CellsTTF, MEFMEF, MDF, KUM10Overexpression systemsvectorslentivirusretroviruspromotersEF1αMSCV LTRFactorsaFactors categorized based on the stage of mouse liver development at which they predominantly function (Kyrmizi et al., 2006; Zaret and Grompe, 2008). Underline denotes factors essential for iHep cell generation. Strikethrough denotes factors inhibiting hepatic gene expression and/or epithelial colony formation.ventral endodermFoxa1/2/3, Gata4Foxa1/2/3, Gata4/6, Hnf1βliver progenitorHex, Hnf1α, Hnf6Hex, Hnf1α, Hnf6, Tbx3hepatocyteCoup-TF1, Fxr, Hlf, Hnf4α, Jarid2, Lrh1, PxrC/epbα, Hnf4αproliferation and survivalp19Arf inactivationspontaneousconversion efficiency?0.3%Differentiation in vitroliver progenitor intermediate?Afp, Krt19 gene expressionAfp, Krt7, Krt19, Prom1, Sox9 gene expressionfibroblast differentiationsome residual fibroblast-specific gene expressionlack of the fibroblast-specific proteins α-SMA and vimentinhepatocyte differentiationbRelative to primary mouse hepatocyte cultures or transplants.partial deficiency in hepatocyte-specific functions, including lower albumin secretion and lower or lacking CYP-dependent drug metabolismpartial deficiency in hepatocyte-specific functions, including lower albumin secretion, glucose release, triglyceride synthesis, and CYP-dependent drug metabolismFunction in vivointrasplenic injection8 × 105 iHep cells per Fah- and Rag2-deficient mouse1 × 107 or 2 × 106 iHep cells per Fah-deficient mousesurvival after NTBC withdrawal5/12 mice at 8 weeks (TTF-injected controls dead by 6 weeks)6/14 mice at 10 weeks (MEF-injected controls dead by 4 weeks)liver repopulation5%–80%?normalization of plasmaliver disease markersbRelative to primary mouse hepatocyte cultures or transplants.tyrosine, bilirubin, ALT lowered to ∼3-fold elevationbilirubin and ALT lowered to ∼3-fold elevationAbbreviations: Afp, α-fetoprotein; ALT, alanine aminotransferase; α-SMA, α-smooth muscle actin; CYP, cytochrome P450; EF1α, human elongation factor-1α; Krt7/19, keratin 7/19; KUM10, adult mouse bone marrow mesenchymal cells; LTR, long terminal repeat; MDF, adult mouse dermal fibroblasts; MEF, mouse embryonic fibroblasts; MSCV, murine stem cell virus; NTBC, 2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione; Prom1, Prominin 1; Sox9, Sry-box containing gene 9; TTF, adult mouse tail-tip fibroblasts.a Factors categorized based on the stage of mouse liver development at which they predominantly function (Kyrmizi et al., 2006Kyrmizi I. Hatzis P. Katrakili N. Tronche F. Gonzalez F.J. Talianidis I. Genes Dev. 2006; 20: 2293-2305Crossref PubMed Scopus (187) Google Scholar, Zaret and Grompe, 2008Zaret K.S. Grompe M. Science. 2008; 322: 1490-1494Crossref PubMed Scopus (441) Google Scholar). Underline denotes factors essential for iHep cell generation. Strikethrough denotes factors inhibiting hepatic gene expression and/or epithelial colony formation.b Relative to primary mouse hepatocyte cultures or transplants. Open table in a new tab Abbreviations: Afp, α-fetoprotein; ALT, alanine aminotransferase; α-SMA, α-smooth muscle actin; CYP, cytochrome P450; EF1α, human elongation factor-1α; Krt7/19, keratin 7/19; KUM10, adult mouse bone marrow mesenchymal cells; LTR, long terminal repeat; MDF, adult mouse dermal fibroblasts; MEF, mouse embryonic fibroblasts; MSCV, murine stem cell virus; NTBC, 2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione; Prom1, Prominin 1; Sox9, Sry-box containing gene 9; TTF, adult mouse tail-tip fibroblasts. Remarkably, both groups found that the number of factors needed to induce hepatocyte differentiation in fibroblasts was small: overexpression of a Forkhead box A protein (Foxa), either alone or in combination with GATA-binding protein 4 (Gata4), was essential for iHep cell generation. This finding is not unexpected, considering that during development these so-called pioneer factors establish competence for liver specification by opening chromatin regions of liver-specific genes for binding of transcriptional activators (Si-Tayeb et al., 2010Si-Tayeb K. Lemaigre F.P. Duncan S.A. Dev. Cell. 2010; 18: 175-189Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). In addition to pioneer factors, iHep cell generation required only a single transcriptional activator, hepatocyte nuclear factor 1α (Hnf1α) in the study by Huang et al. and Hnf4α in the study by Sekiya et al. iHep cells exhibited many characteristics and functions of hepatocytes, although generally at lower levels than primary cells. Although both papers stress the point that liver progenitor intermediates were not produced in the reprogramming process, incomplete hepatocyte differentiation and expression of certain marker genes by iHep cells are compatible with an immature or progenitor-like state (Dorrell et al., 2011Dorrell C. Erker L. Schug J. Kopp J.L. Canaday P.S. Fox A.J. Smirnova O. Duncan A.W. Finegold M.J. Sander M. et al.Genes Dev. 2011; 25: 1193-1203Crossref PubMed Scopus (180) Google Scholar). Moreover, similar to adult liver progenitors (Shin et al., 2011Shin S. Walton G. Aoki R. Brondell K. Schug J. Fox A. Smirnova O. Dorrell C. Erker L. Chu A.S. et al.Genes Dev. 2011; 25: 1185-1192Crossref PubMed Scopus (111) Google Scholar), iHep cells efficiently proliferated in vitro. In fact, in contrast to other examples of direct reprogramming, proliferation may be a prerequisite for reprogramming to hepatocytes: Sekiya et al. observed that iHep cells could be passaged many more times than the embryonic fibroblasts from which they originated. Huang et al. succeeded in generating viable iHep cells only after inactivating the cell cycle inhibitor p19Arf in their starting fibroblast population. Furthermore, they observed increased iHep cell colony formation after eliminating Hnf4α from their reprogramming strategy. Hnf4α is known to inhibit proliferation (Lazarevich et al., 2004Lazarevich N.L. Cheremnova O.A. Varga E.V. Ovchinnikov D.A. Kudrjavtseva E.I. Morozova O.V. Fleishman D.I. Engelhardt N.V. Duncan S.A. Hepatology. 2004; 39: 1038-1047Crossref PubMed Scopus (166) Google Scholar). However, it remains unclear why overexpression of Hnf4α impaired proliferation in the hands of Huang et al., but not Sekiya et al. The fact that Huang et al. used adult fibroblasts, whereas Sekiya et al. used embryonic fibroblasts, is not likely the reason because Sekiya et al. confirmed their findings in adult cells. A possible explanation could be that Hnf4α levels were higher in iHep cells of Huang et al. because of the lentiviral vector system they used and because they overexpressed Hnf4α together with Hnf1α, which activates the endogenous Hnf4α promoter (Kyrmizi et al., 2006Kyrmizi I. Hatzis P. Katrakili N. Tronche F. Gonzalez F.J. Talianidis I. Genes Dev. 2006; 20: 2293-2305Crossref PubMed Scopus (187) Google Scholar). Along these lines, it would be interesting to know whether the spontaneous proliferation of iHep cells observed by Sekiya et al. was also facilitated by p19Arf suppression. p19Arf is suppressed by Tbx3 in embryonic liver progenitors (Suzuki et al., 2008Suzuki A. Sekiya S. Büscher D. Izpisúa Belmonte J.C. Taniguchi H. Development. 2008; 135: 1589-1595Crossref PubMed Scopus (89) Google Scholar), and although Sekiya et al. found that Tbx3 overexpression was not essential for iHep cell generation, it is possible that their reprogramming strategy activated endogenous Tbx3. Importantly, iHep cells were also capable of proliferating in vivo: iHep cells engrafted and expanded in livers of fumarylacetoacetate hydrolase (Fah)-deficient mice, a model of the human liver disease tyrosinemia that develops liver failure unless treated with the drug NTBC (Dorrell et al., 2011Dorrell C. Erker L. Schug J. Kopp J.L. Canaday P.S. Fox A.J. Smirnova O. Duncan A.W. Finegold M.J. Sander M. et al.Genes Dev. 2011; 25: 1193-1203Crossref PubMed Scopus (180) Google Scholar). However, in contrast to primary hepatocytes, which repopulate virtually the entire Fah-deficient liver within 8 weeks, iHep cells showed variable repopulation efficiency and failed to rescue all mice from death. Moreover, liver function was not completely normal in the survivors, and it is currently unclear whether this was due to insufficient liver repopulation, potentially reflecting limited proliferation of iHep cells in vivo, or due to impaired functional output per iHep cell. However, the findings that (1) up to 80% liver repopulation with iHep cells was possible and (2) iHep cells ceased to express liver progenitor markers in vivo suggest that current limitations can be overcome in the future. An obvious next step is to generate iHep cells from human fibroblasts, which appears feasible, considering that signals identified in mouse liver development can direct the differentiation of human pluripotent stem cells into hepatocytes. Provided that human iHep cells function and proliferate similarly to the mouse cells, they would be promising therapeutic candidates: correction of most human liver diseases requires replacing billions of hepatocytes. iHep cells may allow this demand to be met because of their ability to proliferate in vitro and in vivo, which would facilitate producing and transplanting a large cell mass that could further expand in response to disease-intrinsic or artificial stimuli, such as those elicited by Fah deficiency or localized liver irradiation (Yamanouchi et al., 2009Yamanouchi K. Zhou H. Roy-Chowdhury N. Macaluso F. Liu L. Yamamoto T. Yannam G.R. Enke C. Solberg T.D. Adelson A.B. et al.Hepatology. 2009; 49: 258-267Crossref PubMed Scopus (89) Google Scholar). In addition, iHep cell transplantation would not carry the risk of teratoma formation from contaminating pluripotent stem cells, which has hampered the clinical application of pluripotent stem cell-derived hepatocytes. Importantly, the finding by both Huang et al. and Sekiya et al. that continued transgene expression was not needed to maintain iHep cell identity in vitro suggests that these cells can be generated without viruses and, thus, in a clinically acceptable fashion. Clearly, iHep cells have great potential for liver research and liver cell therapy." @default.
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• W2061765327 date "2011-08-01" @default.
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• W2061765327 title "A Simple Code for Installing Hepatocyte Function" @default.
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