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Modelado del Codesarrollo de Linajes Inmunitarios en Organoides Hepáticos Derivados de Células Madre Pluripotentes

Milad Rezvani1, Susanna Quach2, Kyle Lewis3

  • 1Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT)Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health, BIH Charité Clinician Scientist Program, 10178 Berlin, Germany; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Der Simulierte Mensch (Si-M), Joint research center of Technische Universität Berlin and Charité - Universitätsmedizin Berlin, Amrumer Str. 33, 13353 Berlin.

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PubMed
Resumen

Los organoides de hígado fetal humano (FLO) modelan con éxito el desarrollo hepático y el codesarrollo de células inmunitarias. Este innovador sistema de organoides permite el estudio de las lesiones hepáticas y las posibles terapias regenerativas.

Palabras clave:
Hígado FetalHematopoyesisCélulas Madre Pluripotentes HumanasInmunidadOrganoides HepáticosMielopoyesisiPSC

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Área de la Ciencia:

  • Biología de células madre
  • Biología del desarrollo
  • Inmunología

Sus antecedentes:

  • El desarrollo hepático implica interacciones complejas entre células hepáticas e inmunitarias.
  • Los modelos in vitro actuales carecen de nichos endógenos para el codesarrollo sanguíneo, lo que limita la producción de células inmunitarias.
  • Se necesita un modelo que replique un nicho de desarrollo para estudiar estas interacciones.

Objetivo del estudio:

  • Desarrollar organoides de hígado fetal humano (FLO) que alberguen un sistema hematopoyético multipotente.
  • Modelar interacciones complejas multilineales en el desarrollo y la lesión hepática.
  • Investigar el codesarrollo de linajes hepáticos e inmunitarios dentro de un nicho endógeno.

Principales métodos:

  • Generación de FLO a partir de células madre pluripotentes humanas (hPSC).
  • Codesarrollo de mesodermo hemogénico y endodermo hepático dentro de los FLO.
  • Evaluación del potencial de las células progenitoras hematopoyéticas y los linajes epiteliales mediante transcriptómica, inmunofenotipado y ensayos funcionales.

Principales resultados:

  • Los FLO apoyaron con éxito la aparición de linajes hepatobiliares, endoteliales y mesenquimales, así como de células progenitoras hematopoyéticas multipotentes.
  • Los linajes hematopoyéticos y hepáticos maduraron dentro del microambiente de los FLO sin factores externos.
  • Los FLO revelaron una respuesta de lesión impulsada por neutrófilos mediada por IL-8 en la lesión esteatótica-lipotóxica, lo que elucidó los mecanismos inmunitarios intrínsecos del hígado.

Conclusiones:

  • Los FLO proporcionan un modelo fisiológicamente relevante para la hemato-hepatogénesis y la inmunidad innata del hígado.
  • Este sistema recapitula funciones críticas del hígado fetal, ofreciendo una plataforma para estudiar el desarrollo hepático y las lesiones mediadas por el sistema inmunitario.
  • Los FLO sirven como una herramienta traslacional para investigar enfermedades hepáticas pediátricas y terapias regenerativas.