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Regenerative cell therapy for the treatment of hyperbilirubinemic Gunn rats with fresh and frozen human induced pluripotent stem cells-derived hepatic stem cells.
Fourrier, Angélique; Delbos, Frédéric; Menoret, Séverine; Collet, Camille; Thi Thuy, Linh Trinh; Myara, Anne; Petit, François; Tolosa, Laia; Laplanche, Sophie; Gómez-Lechón, María José; Labrune, Philippe; Anegon, Ignacio; Vallier, Ludovic; Garnier, Delphine; Nguyen, Tuan Huy.
Afiliación
  • Fourrier A; INSERM, UMRS 1064-Center for Research in Transplantation and Immunology, Nantes, France.
  • Delbos F; CHU Hôtel Dieu, Institut de Transplantation Urologie Néphrologie, Nantes, France.
  • Menoret S; Université de Nantes, Faculté de Médecine, Nantes, France.
  • Collet C; GoLiver Therapeutics, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
  • Thi Thuy LT; INSERM, UMRS 1064-Center for Research in Transplantation and Immunology, Nantes, France.
  • Myara A; CHU Hôtel Dieu, Institut de Transplantation Urologie Néphrologie, Nantes, France.
  • Petit F; Université de Nantes, Faculté de Médecine, Nantes, France.
  • Tolosa L; INSERM, UMRS 1064-Center for Research in Transplantation and Immunology, Nantes, France.
  • Laplanche S; CHU Hôtel Dieu, Institut de Transplantation Urologie Néphrologie, Nantes, France.
  • Gómez-Lechón MJ; Université de Nantes, Faculté de Médecine, Nantes, France.
  • Labrune P; Transgenesis Rat ImmunoPhenomic platform, INSERM 1064, SFR Francois Bonamy, CNRS UMS3556, Nantes, France.
  • Anegon I; INSERM, UMRS 1064-Center for Research in Transplantation and Immunology, Nantes, France.
  • Vallier L; CHU Hôtel Dieu, Institut de Transplantation Urologie Néphrologie, Nantes, France.
  • Garnier D; Université de Nantes, Faculté de Médecine, Nantes, France.
  • Nguyen TH; INSERM, UMRS 1064-Center for Research in Transplantation and Immunology, Nantes, France.
Xenotransplantation ; 27(1): e12544, 2020 01.
Article en En | MEDLINE | ID: mdl-31342573
Pluripotent stem cells have been investigated as a renewable source of therapeutic hepatic cells, in order to overcome the lack of transplantable donor hepatocytes. Whereas different studies were able to correct hepatic defects in animal models, they focused on the most mature phenotype of hepatocyte-like cells (HLCs) derived from pluripotent stem cells and needed freshly prepared cells, which limits clinical applications of HLCs. Here, we report the production of hepatic stem cells (pHSCs) from human-induced pluripotent stem cells (hiPSCs) in xeno-free, feeder-free, and chemically defined conditions using as extracellular matrix a recombinant laminin instead of Matrigel, an undefined animal-derived matrix. Freshly prepared and frozen pHSCs were transplanted via splenic injection in Gunn rats, the animal model for Crigler-Najjar syndrome. Following cell transplantation and daily immunosuppression treatment, bilirubinemia was significantly decreased (around 30% decrease, P < .05) and remained stable throughout the 6-month study. The transplanted pHSCs underwent maturation in vivo to restore the deficient metabolic hepatic function (bilirubin glucuronidation by UGT1A1). In conclusion, we demonstrate for the first time the differentiation of hiPSCs into pHSCs that (a) are produced using a differentiation protocol compatible with Good Manufacturing Practices, (b) can be frozen, and (c) are sufficient to demonstrate in vivo therapeutic efficacy to significantly lower hyperbilirubinemia in a model of inherited liver disease, despite their immature phenotype. Thus, our approach provides major advances toward future clinical applications and would facilitate cell therapy manufacturing from human pluripotent stem cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Crigler-Najjar / Hepatocitos / Trasplante de Células Madre / Células Madre Pluripotentes Inducidas / Tratamiento Basado en Trasplante de Células y Tejidos / Hiperbilirrubinemia / Hígado Tipo de estudio: Guideline Límite: Animals / Humans Idioma: En Revista: Xenotransplantation Asunto de la revista: TRANSPLANTE Año: 2020 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Dinamarca
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Crigler-Najjar / Hepatocitos / Trasplante de Células Madre / Células Madre Pluripotentes Inducidas / Tratamiento Basado en Trasplante de Células y Tejidos / Hiperbilirrubinemia / Hígado Tipo de estudio: Guideline Límite: Animals / Humans Idioma: En Revista: Xenotransplantation Asunto de la revista: TRANSPLANTE Año: 2020 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Dinamarca