biostudies-literatureYang ASPEuropean Research CouncilDutch Research Council (NWO)The Netherlands Organisation for Health Research and Development Off-Road grantZonMw4631https://www.ebi.ac.uk/biostudies/studies/S-EPMC10397232biostudies-literatureUnknown14(1)Plasmodium falciparum (Pf) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf-infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf-development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf-infected HepOrg cells has identified 80 Pf-transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.Nature communicationsDevelopment of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures.PMC1039723204510012010050VI.Veni.212.134VI.Veni.192.171016.Veni.171.015016.166.140101042738Kretzschmar KBoonekamp KEYang ASPClevers HHendriks DSauerwein RWDutta Dvan Waardenburg YChuva de Sousa Lopes SMHu HPuschhof Jvan Gemert GJde Wilt JHWBousema TfalseDevelopment of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures.Plasmodium falciparum (Pf) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf-infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf-development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf-infected HepOrg cells has identified 80 Pf-transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.2023-01-01T00:00:00Z2023 Aug2025-04-18T17:01:13.57Z2025-04-07T04:31:15.244ZS-EPMC103972323753270410.1038/s41467-023-40298-7