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Human pluripotent stem cell-derived hepatic progenitors exhibit a partially hypoimmunogenic phenotype and actively inhibit immune responses

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Title: Human pluripotent stem cell-derived hepatic progenitors exhibit a partially hypoimmunogenic phenotype and actively inhibit immune responses
Authors: Gantier, Malika, Ménoret, Séverine, Fourrier, Angélique, Delbos, Frédéric, Nguyen, Tuan Huy, Anegon, Ignacio
Contributors: LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Team 2 : Cell and gene engineering in tolerance, fertility and regenerative medicine (Team 2 - U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Plateforme "Production de protéines recombinantes" (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GoLiver Therapeutics UNIV Nantes (Institut de Recherche en Santé), Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a fellowship CIFRE-ANRT (2019/0174) and the French Government’s “France Relance” program « Soutien à l’investissement et la modernisation de l’industrie » and Bpifrance (GOMILLENIUM project).
Source: ISSN: 1664-3224.
Publisher Information: CCSD
Frontiers
Publication Year: 2025
Collection: Université de Nantes: HAL-UNIV-NANTES
Subject Terms: hepatic progenitors, liver, pluripotent stem cells, tolerance, transplantation, MESH: Cell Differentiation / immunology, MESH: Cells, Cultured, MESH: Pluripotent Stem Cells / metabolism, MESH: T-Lymphocytes / immunology, MESH: Hepatocytes / immunology, MESH: Hepatocytes / metabolism, MESH: Humans, MESH: Killer Cells, Natural / immunology, Natural / metabolism, MESH: Liver / immunology, MESH: Phenotype, MESH: Pluripotent Stem Cells / immunology, [SDV]Life Sciences [q-bio]
Description: International audience ; Introduction : GStemHep cells are human cryopreserved hepatic progenitors derived from pluripotent of stem cells (GStem cells) using a cGMP-compliant protocol. They were highly effective in rescuing mice from acute liver failure. Methods : The objective of this study was to analyze the immunogenicity and immunoregulatory properties of GStemHep cells. Results : As compared to GStem cells, GStemHep cells showed complete loss of HLA-I (ABC) and they lacked of expression of HLA-II, HLA-G, HLA-E and PD-L1. GStemHep cells also showed increased expression of CD47, maintained high expression of indoleamine 2,3-dioxygenase (IDO) and heme oxygenase-1 (HO-1) and reduced expression of CD200. In comparison with GStem cells, GStemHep cultured in inflammatory conditions increased the expression of PD-L1, CD200, HO-1, HLA-E, CD47 and HLA-I (ABC) as well as maintained expression of IDO and were negative for HLA-II and HLA-G. GStemHep culture in basal or inflammatory conditions has a low or absent immunogenic activity on T cells, associated to a suppressive effect on proliferation partially mediated by IDO. We observed phagocytosis of GStemHep by macrophages that was partially inhibited by CD47 expression. NK cells were activated by resting GStemHep cells. Upon culture in inflammatory conditions that induced expression of HLA-I molecules in GStemHep cells NK cell activation was reduced. Thus, GStemHep cells are partially hypoimmune cells due to the expression of several immune checkpoint inhibitors and the absence of HLA-I molecules. In inflammatory conditions, the expression of several of these molecules was increased but also of HLA-I that could be immunogenic for T cells but it was inhibitory for NK cells. Discussion : GStemHep cells show a favorable immunological profile for their use as allogeneic off-the shelf treatment of liver diseases with loss of hepatocyte function.
Document Type: article in journal/newspaper
Language: English
Relation: info:eu-repo/semantics/altIdentifier/pmid/40070824; PUBMED: 40070824; PUBMEDCENTRAL: PMC11893836
DOI: 10.3389/fimmu.2025.1507317
Availability: https://inserm.hal.science/inserm-05039836
https://inserm.hal.science/inserm-05039836v1/document
https://inserm.hal.science/inserm-05039836v1/file/fimmu-1-1507317.pdf
https://doi.org/10.3389/fimmu.2025.1507317
Rights: https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess
Accession Number: edsbas.E28A69AF
Database: BASE
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  Data: Human pluripotent stem cell-derived hepatic progenitors exhibit a partially hypoimmunogenic phenotype and actively inhibit immune responses
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  Data: <searchLink fieldCode="AR" term="%22Gantier%2C+Malika%22">Gantier, Malika</searchLink><br /><searchLink fieldCode="AR" term="%22Ménoret%2C+Séverine%22">Ménoret, Séverine</searchLink><br /><searchLink fieldCode="AR" term="%22Fourrier%2C+Angélique%22">Fourrier, Angélique</searchLink><br /><searchLink fieldCode="AR" term="%22Delbos%2C+Frédéric%22">Delbos, Frédéric</searchLink><br /><searchLink fieldCode="AR" term="%22Nguyen%2C+Tuan+Huy%22">Nguyen, Tuan Huy</searchLink><br /><searchLink fieldCode="AR" term="%22Anegon%2C+Ignacio%22">Anegon, Ignacio</searchLink>
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  Data: LabEX IGO Immunothérapie Grand Ouest<br />Nantes Université (Nantes Univ)<br />Immunology and New Concepts in ImmunoTherapy (INCIT)<br />Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE)<br />Nantes Université - pôle Santé<br />Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé<br />Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)<br />Team 2 : Cell and gene engineering in tolerance, fertility and regenerative medicine (Team 2 - U1064 Inserm - CR2TI)<br />Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI)<br />Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE)<br />Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE)<br />Plateforme "Production de protéines recombinantes" (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203)<br />Structure fédérative de recherche François Bonamy (SFR François Bonamy)<br />Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)<br />GoLiver Therapeutics UNIV Nantes (Institut de Recherche en Santé)<br />Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)<br />The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a fellowship CIFRE-ANRT (2019/0174) and the French Government’s “France Relance” program « Soutien à l’investissement et la modernisation de l’industrie » and Bpifrance (GOMILLENIUM project).
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  Data: <searchLink fieldCode="DE" term="%22hepatic+progenitors%22">hepatic progenitors</searchLink><br /><searchLink fieldCode="DE" term="%22liver%22">liver</searchLink><br /><searchLink fieldCode="DE" term="%22pluripotent+stem+cells%22">pluripotent stem cells</searchLink><br /><searchLink fieldCode="DE" term="%22tolerance%22">tolerance</searchLink><br /><searchLink fieldCode="DE" term="%22transplantation%22">transplantation</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Cell+Differentiation+%2F+immunology%22">MESH: Cell Differentiation / immunology</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Cells%22">MESH: Cells</searchLink><br /><searchLink fieldCode="DE" term="%22Cultured%22">Cultured</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Pluripotent+Stem+Cells+%2F+metabolism%22">MESH: Pluripotent Stem Cells / metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+T-Lymphocytes+%2F+immunology%22">MESH: T-Lymphocytes / immunology</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Hepatocytes+%2F+immunology%22">MESH: Hepatocytes / immunology</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Hepatocytes+%2F+metabolism%22">MESH: Hepatocytes / metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Humans%22">MESH: Humans</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Killer+Cells%22">MESH: Killer Cells</searchLink><br /><searchLink fieldCode="DE" term="%22Natural+%2F+immunology%22">Natural / immunology</searchLink><br /><searchLink fieldCode="DE" term="%22Natural+%2F+metabolism%22">Natural / metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Liver+%2F+immunology%22">MESH: Liver / immunology</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Phenotype%22">MESH: Phenotype</searchLink><br /><searchLink fieldCode="DE" term="%22MESH%3A+Pluripotent+Stem+Cells+%2F+immunology%22">MESH: Pluripotent Stem Cells / immunology</searchLink><br /><searchLink fieldCode="DE" term="%22[SDV]Life+Sciences+[q-bio]%22">[SDV]Life Sciences [q-bio]</searchLink>
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  Data: International audience ; Introduction : GStemHep cells are human cryopreserved hepatic progenitors derived from pluripotent of stem cells (GStem cells) using a cGMP-compliant protocol. They were highly effective in rescuing mice from acute liver failure. Methods : The objective of this study was to analyze the immunogenicity and immunoregulatory properties of GStemHep cells. Results : As compared to GStem cells, GStemHep cells showed complete loss of HLA-I (ABC) and they lacked of expression of HLA-II, HLA-G, HLA-E and PD-L1. GStemHep cells also showed increased expression of CD47, maintained high expression of indoleamine 2,3-dioxygenase (IDO) and heme oxygenase-1 (HO-1) and reduced expression of CD200. In comparison with GStem cells, GStemHep cultured in inflammatory conditions increased the expression of PD-L1, CD200, HO-1, HLA-E, CD47 and HLA-I (ABC) as well as maintained expression of IDO and were negative for HLA-II and HLA-G. GStemHep culture in basal or inflammatory conditions has a low or absent immunogenic activity on T cells, associated to a suppressive effect on proliferation partially mediated by IDO. We observed phagocytosis of GStemHep by macrophages that was partially inhibited by CD47 expression. NK cells were activated by resting GStemHep cells. Upon culture in inflammatory conditions that induced expression of HLA-I molecules in GStemHep cells NK cell activation was reduced. Thus, GStemHep cells are partially hypoimmune cells due to the expression of several immune checkpoint inhibitors and the absence of HLA-I molecules. In inflammatory conditions, the expression of several of these molecules was increased but also of HLA-I that could be immunogenic for T cells but it was inhibitory for NK cells. Discussion : GStemHep cells show a favorable immunological profile for their use as allogeneic off-the shelf treatment of liver diseases with loss of hepatocyte function.
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