Treatment of surgically induced acute liver failure by transplantation of HNF4‐overexpressing embryonic stem cells

Kuai, Xiao Ling; Cong, Xiao Qian; Du, Zhong Wei; Bian, Yu; Xiao, Shu Dong

doi:10.1111/j.1443-9573.2006.00253.x

Cited by 10 publications

(5 citation statements)

References 29 publications

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“…Consistent with previous reports [Ishizaka et al, ; Kanda et al, ], when cells were cultured in induction media containing some inducing factors, Foxa2 expression significantly increased differentiation into hepatocyte‐like cells. Although the stable constitutive expression of Foxa2 and Hnf4a increased differentiation to a less significant level compared with that of Foxa2 alone, Hnf4a expression alone could not increase differentiation, a result that is inconsistent with a previous report [Kuai et al, ]. Our results were confirmed by quantitative PCR, immunofluorescence, FACS analysis and PAS staining.…”

Section: Discussionmentioning

confidence: 93%

Induction of hepatocyte-like cells from mouse embryonic stem cells by lentivirus-mediated constitutive expression of Foxa2/Hnf4a

et al. 2013

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Hepatocytes can be generated from embryonic stem cells (ESCs) using inducers such as chemical compounds and cytokines, but issues related to low differentiation efficiencies remain to be resolved. Recent work has shown that overexpression of lineage-specific transcription factors can directly cause cells phenotypic changes, including differentiation, trans-differentiation, and de-differentiation. We hypothesized that lentivirus-mediated constitutive expression of forkhead box A2 (Foxa2) and hepatocyte nuclear factor 4 alpha (Hnf4a) could promote inducing mouse ESCs to hepatocyte-likes cells. First, ESC lines that stably expressed Foxa2, Hnf4a, or Foxa2/Hnf4a were constructed via lentiviral expression vectors. Second, observations of cell morphology changes were made during the cell culture process, followed by experiments examining teratoma formation. Then, the effects of constitutive expression of Foxa2 and Hnf4a on hepatic differentiation and maturation were determined by measuring the marker gene expression levels of Albumin, α-fetoprotein, Cytokeratin18, and α1-antitrypsin. The results indicate that constitutive expression of Foxa2 and Hnf4a does not affect ESCs culture, teratoma formation, or the expression levels of the specific hepatocyte genes under autonomous differentiation. However, with some assistance from inducing factors, Foxa2 significantly increased the hepatic differentiation of ESCs, whereas the expression of Hnf4a alone or Foxa2/Hnf4a could not. Differentiated CCE-Foxa2 cells were more superior in expressing several liver-specific markers and protein, storing glycogen than differentiated CCE cells. Therefore, our method employing the transduction of Foxa2 would be a valuable tool for the efficient generation of functional hepatocytes derived from ESCs.

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Section: Discussionmentioning

confidence: 93%

Induction of hepatocyte-like cells from mouse embryonic stem cells by lentivirus-mediated constitutive expression of Foxa2/Hnf4a

et al. 2013

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“…Following transplantation, engrafted cells are exposed to various combinations of cytokine/growth factor signals in their own local microenvironment and experience direct cellular interactions with adjacent host tissue. Results from recent studies suggest that local microenvironmental cues from the host tissue encompassing the transplanted cells influence the ability of the grafted cells to differentiate(25; 34; 47). This has led to the concept that organ-specific cytokine/growth factors can direct ES cells into organ-specific cell-type differentiation.…”

Section: Introductionmentioning

confidence: 99%

“…This has led to the concept that organ-specific cytokine/growth factors can direct ES cells into organ-specific cell-type differentiation. For example, undifferentiated ES cells (1×10 5 cells) transplanted into the CCl4 treated mice will differentiate into hepatic cells when they are exposed to local liver-specific cytokines/growth factors with no evidence of teratoma formation(25; 34; 47). Based on this concept of tissue-specific microenvironments, many investigators have transplanted undifferentiated ES cells into different organs and observed tissue-specific differentiation without teratoma formation (25; 34; 47).…”

Section: Introductionmentioning

confidence: 99%

Embryonic Stem Cells in Cardiac Repair and Regeneration

Singla

2009

Antioxidants & Redox Signaling

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Cell transplantation is a fast growing research with a potential of therapeutic approach for the treatment of heart diseases. Clinical applications require preparation of large number of donor cells. Stem cell studies published todate demonstrate that scientist have not reached at the general consensus to use optimal cell type for better cardiac repair and regeneration. We use embryonic stem (ES) cells and their released factors for cardiac repair and regeneration. The major concern of cardiac regeneration using stem cells includes engraftment, differentiation and teratoma formation following ES cell transplantation. Our current knowledge of ES cell transplantation in the heart is very limited. This review will discuss the use of various growth factors to enhance ES cells engraftment and differentiation as well as the issue of teratoma formation.

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“…The basic role of Hnf4a in liver development has been previously demonstrated. In addition, it could induce a hepatic program in ES cells [30]. Therefore we choose Hnf4a factor for analysis of hepatic gene expression upon its overexpression in two differentiation methods.…”

Section: Discussionmentioning

confidence: 99%

Forced expression of Hnf4a induces hepatic gene activation through directed differentiation

Yahoo

Pournasr

Rostamzadeh

et al. 2016

Biochemical and Biophysical Research Communications

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Embryonic stem (ES) cells are capable of unlimited self-renewal and have a diverse differentiation potential. These unique features make ES cells as an attractive source for developmental biology studies. Having the mature hepatocyte in the lab with functional activities is valuable in drug discovery studies. Overexpression of hepatocyte lineage-specific transcription factors (TFs) becomes a promising approach in pluripotent cell differentiation toward liver cells. Many studies generate transgenic ES cell lines to examine the effects of specific TFs overexpression in cell differentiation. In the present report, we have addressed whether a suspension or adherent model of differentiation is an appropriate way to study the role of Hnf4a overexpression. We generated ES cells that carried a doxycycline (Dox)-inducible Hnf4a using lentiviral vectors. The transduced cells were subjected to induced Hnf4a overexpression through both spontaneous and directed differentiation methods. Gene expression analysis showed substantially increased expression of hepatic gene markers, particularly Ttr and endogenous Hnf4a, in transduced cells differentiated by the directed approach. These results demonstrated that forced expression of TFs during directed differentiation would be an appropriate way to study relevant gene activation and the effects of overexpression in the context of hepatic differentiation.

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Treatment of surgically induced acute liver failure by transplantation of HNF4‐overexpressing embryonic stem cells

Abstract: Transplantation of ES cells could be a potential treatment in supporting life during acute liver insufficiency and could be a bridge to orthotopic liver transplantation.

Cited by 10 publications

References 29 publications

Induction of hepatocyte-like cells from mouse embryonic stem cells by lentivirus-mediated constitutive expression of Foxa2/Hnf4a

Induction of hepatocyte-like cells from mouse embryonic stem cells by lentivirus-mediated constitutive expression of Foxa2/Hnf4a

Embryonic Stem Cells in Cardiac Repair and Regeneration

Forced expression of Hnf4a induces hepatic gene activation through directed differentiation

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