Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue
Presently, orthotopic liver transplant is the major therapeutic option for patients affected by primary liver diseases. This procedure is characterized by major invasive surgery, scarcity of donor organs, high costs, and lifelong immunosuppressive treatment. Transplant of hepatic precursor cells rep...
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doaj-e60e149d8dfb45f596b33b3e8b1de6f12020-11-25T03:52:03ZengSAGE PublishingCell Transplantation0963-68971555-38922012-09-012110.3727/096368911X637452Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose TissueGiuliana Di Rocco0Antonietta Gentile1Annalisa Antonini2Silvia Truffa3Giulia Piaggio4Maurizio C. Capogrossi5Gabriele Toietta Ph.D.6Experimental Oncology Department, Istituto Regina Elena IRCCS, Rome, ItalyVascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, ItalyVascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, ItalyVascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, ItalyExperimental Oncology Department, Istituto Regina Elena IRCCS, Rome, ItalyVascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, ItalyVascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, ItalyPresently, orthotopic liver transplant is the major therapeutic option for patients affected by primary liver diseases. This procedure is characterized by major invasive surgery, scarcity of donor organs, high costs, and lifelong immunosuppressive treatment. Transplant of hepatic precursor cells represents an attractive alternative. These cells could be used either for allogeneic transplantation or for autologous transplant after ex vivo genetic modification. We used stromal cells isolated from adipose tissue (AT-SCs) as platforms for autologous cell-mediated gene therapy. AT-SCs were transduced with lentiviral vectors expressing firefly luciferase, allowing for transplanted cell tracking by bioluminescent imaging (BLI). As a complementary approach, we followed circulating human α1-antitrypsin (hAAT) levels after infusion of AT-SCs overexpressing hAAT. Cells were transplanted into syngeneic mice after CCl 4 -induced hepatic injury. Luciferase bioluminescence signals and serum hAAT levels were measured at different time points after transplantation and demonstrate persistence of transplanted cells for up to 2 months after administration. These data, along with immunohistochemical analysis, suggest engraftment and repopulation of injured livers by transplanted AT-SCs. Moreover, by transcriptional targeting using cellular tissue-specific regulatory sequences, we confirmed that AT-SCs differentiate towards a hepatogenic-like phenotype in vitro and in vivo. Additionally, in transplanted cells reisolated from recipient animals' livers, we detected activation of the α-fetoprotein (AFP) promoter. This promoter is normally transcriptionally silenced in adult tissues but can be reactivated during liver regeneration, suggesting commitment towards hepatogenic-like differentiation of engrafted cells in vivo. Our data support AT-SC-mediated gene therapy as an innovative therapeutic option for disorders of liver metabolism.https://doi.org/10.3727/096368911X637452 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giuliana Di Rocco Antonietta Gentile Annalisa Antonini Silvia Truffa Giulia Piaggio Maurizio C. Capogrossi Gabriele Toietta Ph.D. |
spellingShingle |
Giuliana Di Rocco Antonietta Gentile Annalisa Antonini Silvia Truffa Giulia Piaggio Maurizio C. Capogrossi Gabriele Toietta Ph.D. Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue Cell Transplantation |
author_facet |
Giuliana Di Rocco Antonietta Gentile Annalisa Antonini Silvia Truffa Giulia Piaggio Maurizio C. Capogrossi Gabriele Toietta Ph.D. |
author_sort |
Giuliana Di Rocco |
title |
Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue |
title_short |
Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue |
title_full |
Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue |
title_fullStr |
Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue |
title_full_unstemmed |
Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue |
title_sort |
analysis of biodistribution and engraftment into the liver of genetically modified mesenchymal stromal cells derived from adipose tissue |
publisher |
SAGE Publishing |
series |
Cell Transplantation |
issn |
0963-6897 1555-3892 |
publishDate |
2012-09-01 |
description |
Presently, orthotopic liver transplant is the major therapeutic option for patients affected by primary liver diseases. This procedure is characterized by major invasive surgery, scarcity of donor organs, high costs, and lifelong immunosuppressive treatment. Transplant of hepatic precursor cells represents an attractive alternative. These cells could be used either for allogeneic transplantation or for autologous transplant after ex vivo genetic modification. We used stromal cells isolated from adipose tissue (AT-SCs) as platforms for autologous cell-mediated gene therapy. AT-SCs were transduced with lentiviral vectors expressing firefly luciferase, allowing for transplanted cell tracking by bioluminescent imaging (BLI). As a complementary approach, we followed circulating human α1-antitrypsin (hAAT) levels after infusion of AT-SCs overexpressing hAAT. Cells were transplanted into syngeneic mice after CCl 4 -induced hepatic injury. Luciferase bioluminescence signals and serum hAAT levels were measured at different time points after transplantation and demonstrate persistence of transplanted cells for up to 2 months after administration. These data, along with immunohistochemical analysis, suggest engraftment and repopulation of injured livers by transplanted AT-SCs. Moreover, by transcriptional targeting using cellular tissue-specific regulatory sequences, we confirmed that AT-SCs differentiate towards a hepatogenic-like phenotype in vitro and in vivo. Additionally, in transplanted cells reisolated from recipient animals' livers, we detected activation of the α-fetoprotein (AFP) promoter. This promoter is normally transcriptionally silenced in adult tissues but can be reactivated during liver regeneration, suggesting commitment towards hepatogenic-like differentiation of engrafted cells in vivo. Our data support AT-SC-mediated gene therapy as an innovative therapeutic option for disorders of liver metabolism. |
url |
https://doi.org/10.3727/096368911X637452 |
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