Improvement of the Survival Rate by Fetal Liver Cell Transplantation in a Mice Lethal Liver Failure Model

Machimoto, Takafumi; Yasuchika, Kentaro; Komori, Junji; Ishii, Takamichi; Kamo, Naoko; Shimoda, Masayuki; Konishi, Sayuri; Saito, Michiko; Kohno, Kenji; Üemoto, Shinji; Ikai, Iwao

doi:10.1097/01.tp.0000287967.54222.4d

Cited by 12 publications

(17 citation statements)

References 36 publications

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“…The DT receptor has been identified as a membrane‐anchored form of the HB‐EGF precursor . Recently, it was shown that transplanted hepatic progenitor cells derived from the fetal liver were efficiently engrafted and repopulated in the liver of recipient HB‐EGF‐expressing mice with DT stimulation . Using this model, efficient engraftment of the transplanted cells in recipient mice with HB‐EGF expression in the liver enabled us to examine the fate of transplanted hepatic progenitor cells with constitutive AID expression.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the actively transcribed genes in the liver‐lineage cells preferentially accumulated SNVs and might contribute to the development of tumor cells. However, based on the model used in our study, we could not fully determine whether the developed tumors derived directly from the fetal hepatic progenitor cells or via mature hepatocytes, because the transplanted fetal progenitor cells differentiated into mature hepatocytes in the recipient liver . Moreover, the truly significant driver mutations responsible for hepatocarcinogenesis remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…To achieve efficient engraftment of transplanted hepatic progenitor cells to livers of the recipient mice, we used TRECK mice as a liver‐specific regeneration model . TRECK mice express DT receptor under control of the albumin promoter, and treatment with DT selectively and efficiently ablates the hepatocytes, resulting in enhanced liver regeneration and efficient colonization of transplanted hepatic progenitor cells . The enriched hepatic progenitor cells were transplanted into 7‐ to 9‐week old TRECK mice using an intrasplenic approach .…”

Section: Methodsmentioning

confidence: 99%

“…Hepatic progenitor cells were obtained from the fetal liver of pregnant wild-type, AID Tg and green fluorescent protein (GFP) Tg mice on gestational day 13.5 and were enriched through sphere formation as previously described. 27 Briefly, after the digestion of fetal liver tissues using a 0.5% collagenase solution (Invitrogen, Carlsbad, CA), fetal liver cells were subjected to floating culture to form spheres in RPMI 1640 (Invitrogen) supplemented with 10% fetal calf serum. After 16 h incubation, the formed spheres were selected by gravity sedimentation and inoculated on Type-I collagen-coated culture plates (Asahi Glass, Chiba, Japan).…”

Section: Isolation Of Enriched Hepatic Progenitor Cells Cell Transplmentioning

confidence: 99%

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A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations

Kim

Nasu

Komori

et al. 2013

Intl Journal of Cancer

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Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient "toxin-receptor mediated conditional cell knockout" (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Isolation Of Enriched Hepatic Progenitor Cells Cell Transplmentioning

confidence: 99%

See 2 more Smart Citations

A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations

Kim

Nasu

Komori

et al. 2013

Intl Journal of Cancer

Self Cite

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“…The adult primary hepatocytes were used commonly in experimental and pre-clinical studies(26). These cells include allogeneic, xenogeneic or autologus primary isolated hepatocytes.…”

Section: Types Of Cells For Transplantation In Liver Diseasesmentioning

confidence: 99%

Cellular Transplantation for Liver Diseases

Jameson¹

2008

Gastroen Res

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Presently, the orthotropic liver transplantation (OLT) is still the most effective therapeutic for patients with acute or chronic hepatic failure. However, due to the shortage of donor livers, the number of patients benefited from this approach is limited. Therefore, some alternative modalities have been paid attention for restoring the liver function. The cell transplantation is one of the promising modalities to realize this purpose. The types of cells used in the cell transplantation include syngeneic hepatocytes, allogeneic hepatocytes, immortalized hepatocytes, and stem cells derived heptocytes. The stem cells, especially the adult stem cells from bone marrow, are shown as a promising cell source for liver repopulation. The mesenchymal bone marrow stem cells and embryonic stem cells can be induced to differentiate into the hepatic lineage and might be used in the cell transplantation for liver diseases. Compared to OLT, the advantages of cell-based therapy for liver disease are, but not limited to, less invasive, less expensive, easy manipulated, easy expansion of cells in vitro. Cells can be stored in a cell bank for future use. Though most of the current studies are experimental and animal based, the cellular therapy for liver disease is expected to be an effective alternative in clinical settings in near future.

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Liver progenitor cell interactions with the extracellular matrix

Zhu

Coombe

Zheng

et al. 2012

J Tissue Eng Regen Med

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Liver progenitor cells (LPCs) are a promising source of cells to treat liver disease by cell therapy, due to their capability for self‐replication and bipotentiality. In order to establish useful culture systems of LPCs and apply them to future clinical therapies, it is necessary to understand their interactions with their microenvironment and especially with the extracellular matrix (ECM). There is considerable evidence from in vivo studies that matrix proteins affect the activation, expansion, migration and differentiation of LPCs, but the information on the role that specific ECMs play in regulating LPCs in vitro is more limited. Nevertheless, current studies suggest that laminin, collagen type III, collagen type IV and hyaluronic acid help to maintain the undifferentiated phenotype of LPCs and promote their proliferation when cultured in media supplemented with growth factors chosen for LPC expansion, whereas collagen type I and fibronectin are generally associated with a differentiated phenotype under the same conditions. Experimental evidence suggests that α6β1 and α5β1 integrins as well as CD44 on the surface of LPCs, and their related downstream signals, are important mediators of interactions between LPCs and the ECM. The interactions of LPCs with the ECM form the focus of this review and the contribution of ECM molecules to strategies for optimizing in vitro LPC cultures for therapeutic applications is discussed. Copyright © 2012 John Wiley & Sons, Ltd.

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Improvement of the Survival Rate by Fetal Liver Cell Transplantation in a Mice Lethal Liver Failure Model

Abstract: The transplanted cells were engrafted and repopulated the liver of recipient mice, resulting in the improvement of the survival rate of the liver injury model mice. We therefore propose that HPCs are a desirable cell source for cell transplantation.

Cited by 12 publications

References 36 publications

A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations

A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations

Cellular Transplantation for Liver Diseases

Liver progenitor cell interactions with the extracellular matrix

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