Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model
Human hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether cotransplantation of hepatocytes with hepatic stellate cells (HSCs) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were t...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2015-12-01
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| Series: | Cell Transplantation |
| Online Access: | https://doi.org/10.3727/096368915X686788 |
| _version_ | 1818605716463681536 |
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| author | Ange-Clarisse Dusabineza Mustapha Najimi Noémi Van Hul Vanessa Legry Dung Ngoc Khuu Leo A. Van Grunsven Etienne Sokal Isabelle A. Leclercq M.D., Ph.D. |
| author_facet | Ange-Clarisse Dusabineza Mustapha Najimi Noémi Van Hul Vanessa Legry Dung Ngoc Khuu Leo A. Van Grunsven Etienne Sokal Isabelle A. Leclercq M.D., Ph.D. |
| author_sort | Ange-Clarisse Dusabineza |
| collection | DOAJ |
| description | Human hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether cotransplantation of hepatocytes with hepatic stellate cells (HSCs) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were transplanted into SCID mice either alone or in a mixture with HSCs (quiescent or after culture activation) or LX-2 cells (ratio 20:1). Four weeks after transplantation into mouse livers, human albumin-positive (huAlb + ) hepatocytes were found scattered. When cotransplanted in a mixture with HSCs or LX-2 cells, huAlb + hepatocytes formed clusters and were more numerous occupying 2- to 5.9-fold more surface on the tissue section than in livers transplanted with hepatocytes alone. Increased huAlb mRNA expression in livers transplanted with the cell mixtures confirmed those results. The presence of HSCs increased the number of hepatocytes entrapped in the host liver at an early time point posttransplantation but not their proliferation in situ as assessed by cumulative incorporation of BrdU. Importantly, 4 weeks posttransplantation, we found no accumulation of αSMA + -activated HSCs or collagen deposition. To follow the fate of transplanted HSCs, HSCs derived from GFP + mice were injected into GFP - littermates: 17 h posttransplant, GFP + HSCs were found in the sinusoids, without proliferating or actively producing ECM; they were undetectable at later time points. Coculture with HSCs improved the number of adherent hepatocytes, with best attachment obtained when hepatocytes were seeded in contact with activated HSCs. In vivo, cotransplantation of hepatocytes with HSCs into a healthy liver recipient does not generate fibrosis, but significantly improves the engraftment of hepatocytes, probably by ameliorating cell homing. |
| first_indexed | 2024-12-16T13:59:23Z |
| format | Article |
| id | doaj.art-186d61e04c1d425c8efcfb1d3bb70ea8 |
| institution | Directory Open Access Journal |
| issn | 0963-6897 1555-3892 |
| language | English |
| last_indexed | 2024-12-16T13:59:23Z |
| publishDate | 2015-12-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cell Transplantation |
| spelling | doaj.art-186d61e04c1d425c8efcfb1d3bb70ea82022-12-21T22:29:08ZengSAGE PublishingCell Transplantation0963-68971555-38922015-12-012410.3727/096368915X686788Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal ModelAnge-Clarisse Dusabineza0Mustapha Najimi1Noémi Van Hul2Vanessa Legry3Dung Ngoc Khuu4Leo A. Van Grunsven5Etienne Sokal6Isabelle A. Leclercq M.D., Ph.D.7Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumLaboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumLaboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumLaboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumLaboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumLiver Cell Biology Lab, Vrije Universiteit Brussel, VUB, Brussels, BelgiumLaboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumLaboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, UCL, Brussels, BelgiumHuman hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether cotransplantation of hepatocytes with hepatic stellate cells (HSCs) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were transplanted into SCID mice either alone or in a mixture with HSCs (quiescent or after culture activation) or LX-2 cells (ratio 20:1). Four weeks after transplantation into mouse livers, human albumin-positive (huAlb + ) hepatocytes were found scattered. When cotransplanted in a mixture with HSCs or LX-2 cells, huAlb + hepatocytes formed clusters and were more numerous occupying 2- to 5.9-fold more surface on the tissue section than in livers transplanted with hepatocytes alone. Increased huAlb mRNA expression in livers transplanted with the cell mixtures confirmed those results. The presence of HSCs increased the number of hepatocytes entrapped in the host liver at an early time point posttransplantation but not their proliferation in situ as assessed by cumulative incorporation of BrdU. Importantly, 4 weeks posttransplantation, we found no accumulation of αSMA + -activated HSCs or collagen deposition. To follow the fate of transplanted HSCs, HSCs derived from GFP + mice were injected into GFP - littermates: 17 h posttransplant, GFP + HSCs were found in the sinusoids, without proliferating or actively producing ECM; they were undetectable at later time points. Coculture with HSCs improved the number of adherent hepatocytes, with best attachment obtained when hepatocytes were seeded in contact with activated HSCs. In vivo, cotransplantation of hepatocytes with HSCs into a healthy liver recipient does not generate fibrosis, but significantly improves the engraftment of hepatocytes, probably by ameliorating cell homing.https://doi.org/10.3727/096368915X686788 |
| spellingShingle | Ange-Clarisse Dusabineza Mustapha Najimi Noémi Van Hul Vanessa Legry Dung Ngoc Khuu Leo A. Van Grunsven Etienne Sokal Isabelle A. Leclercq M.D., Ph.D. Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model Cell Transplantation |
| title | Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model |
| title_full | Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model |
| title_fullStr | Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model |
| title_full_unstemmed | Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model |
| title_short | Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model |
| title_sort | hepatic stellate cells improve engraftment of human primary hepatocytes a preclinical transplantation study in an animal model |
| url | https://doi.org/10.3727/096368915X686788 |
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