Organoid transplant approaches for the liver

Reza, Hasan Al; Okabe, Ryo; Takebe, Takanori

doi:10.1111/tri.14128

Cited by 24 publications

(11 citation statements)

References 103 publications

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“…However, the shortage of liver donors is a major limitation of their therapeutic modalities. Human liver organoids (HLOs) consisting of hepatocyte-like cells (HLCs) and cholangiocyte like-cells (CLCs), which are differentiated from human-induced pluripotent stem cells (hiPSCs), may become a good source for personalized regenerative therapy for liver diseases [1][2][3] . Generally, 2 × 10 8 liver cells per kg body weight are required to regenerate and restore the physiological function of liver failure or liver cirrhosis to ensure therapeutic efficacy 4 .…”

mentioning

confidence: 99%

Dialysis based-culture medium conditioning improved the generation of human induced pluripotent stem cell derived-liver organoid in a high cell density

Torizal

Utami

Lau

et al. 2022

Sci Rep

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Human pluripotent stem cell-derived liver organoids (HLOs) have recently become a promising alternative for liver regenerative therapy. To realize this application, a large amount of human-induced pluripotent stem cells (hiPSCs) derived-liver cells are required for partial liver replacement during transplantation. This method requires stepwise induction using costly growth factors to direct the hiPSCs into the hepatic lineage. Therefore, we developed a simple dialysis-based medium conditioning that fully utilized growth factors accumulation to improve hepatic differentiation of hiPSCs at a high cell density. The results demonstrated that the dialysis culture system could accumulate the four essential growth factors required in each differentiation stage: activin A, bone morphogenetic protein 4 (BMP4), hepatocyte growth factor (HGF), and oncostatin M (OSM). As a result, this low lactate culture environment allowed high-density bipotential hepatic differentiation of up to 4.5 × 107 cells/mL of human liver organoids (HLOs), consisting of hiPSC derived-hepatocyte like cells (HLCs) and cholangiocyte like-cells (CLCs). The differentiated HLOs presented a better or comparable hepatic marker and hepatobiliary physiology to the one that differentiated in suspension culture with routine daily medium replacement at a lower cell density. This simple miniaturized dialysis culture system demonstrated the feasibility of cost-effective high-density hepatic differentiation with minimum growth factor usage.

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mentioning

confidence: 99%

Dialysis based-culture medium conditioning improved the generation of human induced pluripotent stem cell derived-liver organoid in a high cell density

Torizal

Utami

Lau

et al. 2022

Sci Rep

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“…We suppose one possible reason why plasma FIX antigen could not be detected was an insufficient number of transplanted cells derived from the iPSCs in mice and incomplete differentiation. A highly efficient method for differentiating iPSCs into mature hepatocytes for therapeutic application remains to be established 51 . The advancement of novel technologies, including three-dimensional culture and organoid formation 52 , 53 , may also lead to iPSC-based cell therapy for inherited liver diseases.…”

Section: Discussionmentioning

confidence: 99%

PAM-flexible Cas9-mediated base editing of a hemophilia B mutation in induced pluripotent stem cells

et al. 2023

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Background Base editing via CRISPR-Cas9 has garnered attention as a method for correcting disease-specific mutations without causing double-strand breaks, thereby avoiding large deletions and translocations in the host chromosome. However, its reliance on the protospacer adjacent motif (PAM) can limit its use. We aimed to restore a disease mutation in a patient with severe hemophilia B using base editing with SpCas9-NG, a modified Cas9 with the board PAM flexibility. Methods We generated induced pluripotent stem cells (iPSCs) from a patient with hemophilia B (c.947T>C; I316T) and established HEK293 cells and knock-in mice expressing the patient’s F9 cDNA. We transduced the cytidine base editor (C>T), including the nickase version of Cas9 (wild-type SpCas9 or SpCas9-NG), into the HEK293 cells and knock-in mice through plasmid transfection and an adeno-associated virus vector, respectively. Results Here we demonstrate the broad PAM flexibility of SpCas9-NG near the mutation site. The base-editing approach using SpCas9-NG but not wild-type SpCas9 successfully converts C to T at the mutation in the iPSCs. Gene-corrected iPSCs differentiate into hepatocyte-like cells in vitro and express substantial levels of F9 mRNA after subrenal capsule transplantation into immunodeficient mice. Additionally, SpCas9-NG–mediated base editing corrects the mutation in both HEK293 cells and knock-in mice, thereby restoring the production of the coagulation factor. Conclusion A base-editing approach utilizing the broad PAM flexibility of SpCas9-NG can provide a solution for the treatment of genetic diseases, including hemophilia B.

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“…Organoids can be differentiated from human PSCs or progenitor cells, which reserve certain functions and have similar cell types and tissue structures as internal organs ( Reza et al, 2021 ). PSCs, including embryonic stem cells (ESCs) and induced PSCs (iPSCs), have been widely used in biomedical and biological sciences due to their potential to differentiate into all types of cells in the body ( Yamanaka, 2020 ).…”

Section: Gi Tumor Organoid Derivation and Culturementioning

confidence: 99%

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research

Yan,

He,

Zhu

et al. 2024

Front. Cell Dev. Biol.

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Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality with a poor prognosis. It is one of the leading causes of cancer-related deaths worldwide. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. As a novel preclinical model, tumor patient-derived organoids (PDOs), can be established from patients’ tumor tissue and cultured in the laboratory in 3D architectures. This 3D model can not only highly simulate and preserve key biological characteristics of the source tumor tissue in vitro but also reproduce the in vivo tumor microenvironment through co-culture. Our review provided an overview of the different in vitro models in current tumor research, the derivation of cells in PDO models, and the application of PDO model technology in gastrointestinal cancers, particularly the applications in combination with CRISPR/Cas9 gene editing technology, tumor microenvironment simulation, drug screening, drug development, and personalized medicine. It also elucidates the ethical status quo of organoid research and the current challenges encountered in clinical research, and offers a forward-looking assessment of the potential paths for clinical organoid research advancement.

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Organoid transplant approaches for the liver

Cited by 24 publications

References 103 publications

Dialysis based-culture medium conditioning improved the generation of human induced pluripotent stem cell derived-liver organoid in a high cell density

Dialysis based-culture medium conditioning improved the generation of human induced pluripotent stem cell derived-liver organoid in a high cell density

PAM-flexible Cas9-mediated base editing of a hemophilia B mutation in induced pluripotent stem cells

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research

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