Human iPSC-derived liver organoid model multicellular tissue responses and therapeutic rescue in Wolman disease

Abstract Wolman disease (WD), the severe infantile form of lysosomal acid lipase (LAL) deficiency, is a rare metabolic disorder caused by inactivating mutations in the LIPA gene. Although WD is characterized by profound hepatic dysfunction, experimental human systems capable of modeling multicellular liver pathology and supporting therapeutic testing remain limited. Here, we generated an isogenic human model of WD by introducing LIPA loss-of-function mutations into induced pluripotent stem cells and differentiating them into multicellular human liver organoids (HLOs). LIPA-deficient HLOs preserved hepatic lineage specification while recapitulating key biochemical and cellular features of WD, including loss of LAL activity, lysosomal expansion, lipid accumulation, and activation of inflammatory and fibrogenic programs. Single-cell RNA sequencing resolved cell-type-specific disease states across hepatocyte-, stromal-, and biliary-like populations, revealing the emergence of a reactive biliary program consistent with ductular reaction (DR), a complex tissue response associated with chronic liver injury. Importantly, this reactive biliary phenotype was supported by targeted gene-expression analysis in WD liver organoids and independently validated in liver tissue from mouse models and WD patients. Isolated LIPA-deficient cholangiocyte organoids failed to reproduce the DR-associated program, indicating that this response depends on multicellular interactions within the hepatic microenvironment rather than on biliary cell-autonomous dysfunction alone. Consistently, hepatocyte-directed AAV-mediated restoration of LIPA expression attenuated metabolic stress, inflammatory and fibrogenic programs and suppressed ductular reaction both in organoids and in vivo. Together, these findings establish multicellular human liver organoids as a physiologically relevant platform for modeling emergent tissue-level responses in WD and for evaluating therapeutic rescue strategies in a human context.

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Publication Details

Journal
Cell Death and Disease
Published
2026-10-16
DOI
https://doi.org/10.1038/s41419-026-09345-1
Primary Topic
Lysosomal Storage Disorders Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Human iPSC-derived liver organoid model multicellular tissue responses and therapeutic rescue in Wolman disease

Nicolò de Manzini, Beatrice Anfuso, Andrea Marfoglia, Deborah Bonazza et al.
Cell Death and Disease
Lysosomal Storage Disorders Research
article

Human iPSC-derived liver organoid model multicellular tissue responses and therapeutic rescue in Wolman disease

Nicolò de Manzini, Beatrice Anfuso, Andrea Marfoglia, Deborah Bonazza, Suresh Velnati, Fabrizio Zanconati, Marine Laurent, Rebecca Bertolio, Daniela Capello, Philippe Drabent, Annamaria Antona, Silvia Palmisano, Manuela Mastronardi, Luciano Conti, Davide Selvestrel, Alessia Mattivi, Giannino Del Sal, Mario Amendola, Luca L. Fava, Giovanni Sorrentino, Claudio Tiribelli, Natalia Rosso, Marcello Manfredi, Caterina Da Rodda, Karin Hofmann
article en

Abstract

Abstract Wolman disease (WD), the severe infantile form of lysosomal acid lipase (LAL) deficiency, is a rare metabolic disorder caused by inactivating mutations in the LIPA gene. Although WD is characterized by profound hepatic dysfunction, experimental human systems capable of modeling multicellular liver pathology and supporting therapeutic testing remain limited. Here, we generated an isogenic human model of WD by introducing LIPA loss-of-function mutations into induced pluripotent stem cells and differentiating them into multicellular human liver organoids (HLOs). LIPA-deficient HLOs preserved hepatic lineage specification while recapitulating key biochemical and cellular features of WD, including loss of LAL activity, lysosomal expansion, lipid accumulation, and activation of inflammatory and fibrogenic programs. Single-cell RNA sequencing resolved cell-type-specific disease states across hepatocyte-, stromal-, and biliary-like populations, revealing the emergence of a reactive biliary program consistent with ductular reaction (DR), a complex tissue response associated with chronic liver injury. Importantly, this reactive biliary phenotype was supported by targeted gene-expression analysis in WD liver organoids and independently validated in liver tissue from mouse models and WD patients. Isolated LIPA-deficient cholangiocyte organoids failed to reproduce the DR-associated program, indicating that this response depends on multicellular interactions within the hepatic microenvironment rather than on biliary cell-autonomous dysfunction alone. Consistently, hepatocyte-directed AAV-mediated restoration of LIPA expression attenuated metabolic stress, inflammatory and fibrogenic programs and suppressed ductular reaction both in organoids and in vivo. Together, these findings establish multicellular human liver organoids as a physiologically relevant platform for modeling emergent tissue-level responses in WD and for evaluating therapeutic rescue strategies in a human context.

Cell Death and Disease
University of Foggia (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Trieste (IT), Inserm (FR), University of Trento (IT), Université Paris Cité (FR), Université Paris-Saclay (FR), Fondazione Italiana Fegato (IT), Ospedale di Cattinara (IT), IFOM (IT), Genethon (France) (FR), Université d'Évry Val-d'Essonne (FR), International Centre for Genetic Engineering and Biotechnology (IT)
Dipartimenti di Eccellenza, European Commission, Agence Nationale de la Recherche, Associazione Italiana per la Ricerca sul Cancro, NextGenerationEU
Good health and well-being
Openalex Percentile: Top 13%
Lysosomal Storage Disorders Research
DOIOpen Access PDFOpenAlex
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