Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
Hepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and a short half-life. Recent advances in in vitro differentiation of hepatocyte-like cells (HLCs) facilitated studies of hepatocyte–pathogen interactions. Here, we ai...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/11/3831 |
| _version_ | 1797566852223729664 |
|---|---|
| author | Lena Fischer Baltasar Lucendo-Villarin David C. Hay Cliona O’Farrelly |
| author_facet | Lena Fischer Baltasar Lucendo-Villarin David C. Hay Cliona O’Farrelly |
| author_sort | Lena Fischer |
| collection | DOAJ |
| description | Hepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and a short half-life. Recent advances in in vitro differentiation of hepatocyte-like cells (HLCs) facilitated studies of hepatocyte–pathogen interactions. Here, we aimed to define the anti-viral innate immune potential of human HLCs with a focus on pattern recognition receptor (PRR)-expression and the presence of a metabolic switch. We analysed cytoplasmic PRR and endosomal toll-like receptor (TLR)-expression, as well as activity and adaptation of HLCs to an inflammatory environment. We found that transcript levels of retinoic acid inducible gene I (RIG-I), melanoma differentiation antigen 5 (MDA5), and TLR3 became downregulated during differentiation, indicating the acquisition of a more tolerogenic phenotype, as expected in healthy hepatocytes. HLCs responded to activation of RIG-I by producing interferons (IFNs) and IFN-stimulated genes. Despite low-level levels of TLR3, receptor expression was upregulated in an inflammatory environment. TLR3 signalling induced expression of proinflammatory cytokines at the gene level, indicating that several PRRs need to interact for successful innate immune activation. The inflammatory responsiveness of HLCs was accompanied by the downregulation of cytochrome P450 3A and 1A2 activity and decreased serum protein production, showing that the metabolic switch seen in primary hepatocytes during anti-viral responses is also present in HLCs. |
| first_indexed | 2024-03-10T19:33:14Z |
| format | Article |
| id | doaj.art-f36b84bb7ec147ceaa8425ea622673dd |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:33:14Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f36b84bb7ec147ceaa8425ea622673dd2023-11-20T02:01:24ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-012111383110.3390/ijms21113831Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune ResponseLena Fischer0Baltasar Lucendo-Villarin1David C. Hay2Cliona O’Farrelly3School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, IrelandCentre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UKCentre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UKSchool of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, IrelandHepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and a short half-life. Recent advances in in vitro differentiation of hepatocyte-like cells (HLCs) facilitated studies of hepatocyte–pathogen interactions. Here, we aimed to define the anti-viral innate immune potential of human HLCs with a focus on pattern recognition receptor (PRR)-expression and the presence of a metabolic switch. We analysed cytoplasmic PRR and endosomal toll-like receptor (TLR)-expression, as well as activity and adaptation of HLCs to an inflammatory environment. We found that transcript levels of retinoic acid inducible gene I (RIG-I), melanoma differentiation antigen 5 (MDA5), and TLR3 became downregulated during differentiation, indicating the acquisition of a more tolerogenic phenotype, as expected in healthy hepatocytes. HLCs responded to activation of RIG-I by producing interferons (IFNs) and IFN-stimulated genes. Despite low-level levels of TLR3, receptor expression was upregulated in an inflammatory environment. TLR3 signalling induced expression of proinflammatory cytokines at the gene level, indicating that several PRRs need to interact for successful innate immune activation. The inflammatory responsiveness of HLCs was accompanied by the downregulation of cytochrome P450 3A and 1A2 activity and decreased serum protein production, showing that the metabolic switch seen in primary hepatocytes during anti-viral responses is also present in HLCs.https://www.mdpi.com/1422-0067/21/11/3831stem cellshepatocyte-like cellsinnate anti-viral immunitypattern recognition receptors (PRRs)metabolic switch |
| spellingShingle | Lena Fischer Baltasar Lucendo-Villarin David C. Hay Cliona O’Farrelly Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response International Journal of Molecular Sciences stem cells hepatocyte-like cells innate anti-viral immunity pattern recognition receptors (PRRs) metabolic switch |
| title | Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response |
| title_full | Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response |
| title_fullStr | Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response |
| title_full_unstemmed | Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response |
| title_short | Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response |
| title_sort | human psc derived hepatocytes express low levels of viral pathogen recognition receptors but are capable of mounting an effective innate immune response |
| topic | stem cells hepatocyte-like cells innate anti-viral immunity pattern recognition receptors (PRRs) metabolic switch |
| url | https://www.mdpi.com/1422-0067/21/11/3831 |
| work_keys_str_mv | AT lenafischer humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse AT baltasarlucendovillarin humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse AT davidchay humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse AT clionaofarrelly humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse |