Differentiation of a hepatic phenotype after heterotropic transplantation of heart, kidney, brain, and skin tissues into liver in F344 rats

Watanabe, Haruo; Ochiya, Takahiro; Ueda, Shigetomo; Kominami, Yoko; Gon, Rina; Nishiki, Masayo; Hayashi, Masaomi; Sasaki, Atsushi; Shiraishi, Miho; Kashimoto, Naoki; Myojin, Yuki; Kamiya, Kenji

doi:10.1016/j.bbrc.2006.12.236

Cited by 14 publications

(14 citation statements)

References 45 publications

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“…22 These findings indicate that MSCs possess the potential to differentiate into hepatic lineage, but the mechanism remains unclear. MSC differentiation is known to be mediated by a local niche environment in vivo.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Bone-Marrow-Derived Mesenchymal Stem Cells Differentiated with Growth-Factor-Free Coculture Method in Liver-Injured Rats

Kim²,

Cho³

et al. 2010

Tissue Engineering Part A

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Mesenchymal stem cell (MSC) differentiation by growth factors may be improper due to possibility of clinical risk. We have previously developed a growth-factor-free coculture method and observed rat MSCs differentiated into hepatic progenitor cells. This study was aimed to validate hepatic differentiation potential in vivo. MSCs from bone marrow of green fluorescent protein-transgenic Sprague-Dawley rats were cocultured with hepatocytes from normal Sprague-Dawley rats, sharing growth-factor-free media. After 14 days, cells were implanted into the spleen of carbon tetrachloride (CCl 4 )-injured rats and kept for 4 weeks. Fibrosis remarkably decreased in CCl 4 / cocultured MSC at weeks 1, 3, and 4. Immunohistochemistry revealed that albumin, a-fetoprotein, and cytokeratin 19 (CK19) expression was high in CCl 4 /cocultured MSC only at week 1. Reverse transcription-polymerase chain reaction and Western blot revealed that CCl 4 /cocultured MSC had reduced a-fetoprotein expression at week 4, whereas CK18 and CK19 exhibited stronger expression. Albumin in CCl 4 /cocultured MSC increased at week 4 only in protein level. We assume that cocultured MSCs had stayed at hepatic progenitor stage until week 3, and differentiated into hepatocytes or bile-ductal epithelial cells afterward. Hepatic progenitor cells from MSC differentiation in the growth-factor-free coculture system may contribute to the therapeutic effect for liver disease in vivo.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Bone-Marrow-Derived Mesenchymal Stem Cells Differentiated with Growth-Factor-Free Coculture Method in Liver-Injured Rats

Kim²,

Cho³

et al. 2010

Tissue Engineering Part A

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show abstract

“…In recent studies, bone marrow cells developed into hepatocytes when transplanted in vivo [15]. These findings indicate that bone marrow cells possess the potential to differentiate into hepatic lineage, but the mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 96%

Growth factor-free cultured rat bone marrow derived mesenchymal stem cells towards hepatic progenitor cell differentiation

Shin

Cho

et al. 2008

Biotechnol Bioproc E

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Induction of mesenchymal stem cells (MSCs) differentiation by growth factors is not likely to be acceptable for clinical application. In this study, MSCs and hepatocytes isolated from male Sprague-Dawley rats were indirectly co-cultured by sharing media, without any growth factor, for 14 days. Differentiation was investigated by detection of hepatic markers, albumin, α-fetoprotein (AFP), cytokeratin-18 (CK18), and bile ductal epithelial cell marker cytokeratin-19 (CK19) on reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and Western blot. Periodic acid-schiff (PAS) staining, low density lipoproteins (LDL) uptake analysis, and urea assay were performed to detect metabolic activities of differentiated cells. MSCs in co-culture group showed positive expression for albumin, AFP, and CK19, but little for CK18. Data indicates that co-cultured MSCs were differentiated into oval cell stage, the hepatic progenitor, but not directly toward complete hepatocytes. Our finding suggests that indirect co-culture system has potential to generate regenerative hepatocytes by hepatic progenitor cells differentiated from MSCs. © KSBB

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“…They demonstrated continuous GFP expression, driven by the liver-specific albumin enhancer/promoter, in transplanted hepatocytes up to four months after transplantation. Other studies showed repopulation of injured liver tissue by transplanted syngeneic stem/progenitor cells expressing GFP [8], [9]. Therefore, we expected to see long-term survival of GFP-positive hepatocytes after transplantation into a wild-type Lewis rat liver.…”

Section: Introductionmentioning

confidence: 92%

Disappearance of GFP-Positive Hepatocytes Transplanted into the Liver of Syngeneic Wild-Type Rats Pretreated with Retrorsine

et al. 2014

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Background and AimGreen fluorescent protein (GFP) is a widely used molecular tag to trace transplanted cells in rodent liver injury models. The differing results from various previously reported studies using GFP could be attributed to the immunogenicity of GFP.MethodsHepatocytes were obtained from GFP-expressing transgenic (Tg) Lewis rats and were transplanted into the livers of wild-type Lewis rats after they had undergone a partial hepatectomy. The proliferation of endogenous hepatocytes in recipient rats was inhibited by pretreatment with retrorsine to enhance the proliferation of the transplanted hepatocytes. Transplantation of wild-type hepatocytes into GFP-Tg rat liver was also performed for comparison.ResultsAll biopsy specimens taken seven days after transplantation showed engraftment of transplanted hepatocytes, with the numbers of transplanted hepatocytes increasing until day 14. GFP-positive hepatocytes in wild-type rat livers were decreased by day 28 and could not be detected on day 42, whereas the number of wild-type hepatocytes steadily increased in GFP-Tg rat liver. Histological examination showed degenerative change of GFP-positive hepatocytes and the accumulation of infiltrating cells on day 28. PCR analysis for the GFP transgene suggested that transplanted hepatocytes were eliminated rather than being retained along with the loss of GFP expression. Both modification of the immunological response using tacrolimus and bone marrow transplantation prolonged the survival of GFP-positive hepatocytes. In contrast, host immunization with GFP-positive hepatocytes led to complete loss of GFP-positive hepatocytes by day 14.ConclusionGFP-positive hepatocytes isolated from GFP-Tg Lewis rats did not survive long term in the livers of retrorsine-pretreated wild-type Lewis rats. The mechanism underlying this phenomenon most likely involves an immunological reaction against GFP. The influence of GFP immunogenicity on cell transplantation models should be considered in planning in vivo experiments using GFP and in interpreting their results.

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Differentiation of a hepatic phenotype after heterotropic transplantation of heart, kidney, brain, and skin tissues into liver in F344 rats

Cited by 14 publications

References 45 publications

Therapeutic Potential of Bone-Marrow-Derived Mesenchymal Stem Cells Differentiated with Growth-Factor-Free Coculture Method in Liver-Injured Rats

Therapeutic Potential of Bone-Marrow-Derived Mesenchymal Stem Cells Differentiated with Growth-Factor-Free Coculture Method in Liver-Injured Rats

Growth factor-free cultured rat bone marrow derived mesenchymal stem cells towards hepatic progenitor cell differentiation

Disappearance of GFP-Positive Hepatocytes Transplanted into the Liver of Syngeneic Wild-Type Rats Pretreated with Retrorsine

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