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Efficient targeted integration in proliferating patient hepatocytes for inherited liver diseases

ABSTRACT: Efficient targeted integration in proliferating patient hepatocytes for inherited liver diseases

PROVIDER: PRJNA976238 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24738848_1.fastq.gz	Fastqsanger.gz
	SRR24738848_2.fastq.gz	Fastqsanger.gz
	SRR24738849_1.fastq.gz	Fastqsanger.gz
	SRR24738849_2.fastq.gz	Fastqsanger.gz
	SRR24738850_1.fastq.gz	Fastqsanger.gz

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Efficient targeted integration in proliferating patient hepatocytes for inherited liver diseases

Project description:Hepatocyte transplantation has shown great potential for treating inherited liver diseases. However, its prolonged clinical therapeutic efficacy is still hindered by serious immune rejection from the host immunological responses to the allogeneic hepatocytes and there is still no an effective approach to generate clinically available autologous hepatocytes for transplantation therapy. Here, we report advanced medium conditions that allow 10,000-fold expansion of primary human hepatocytes from patients suffering inherited liver diseases, providing a new autologous hepatocytes source to this problem. Moreover, we developed a CRISPR–Cas9 genome-targeting system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homology-independent large donor (greater than three kilobase) to achieve efficient targeted integration at the AAVS1 safe harbor locus in patient-derived proliferating human hepatocytes (ProliHHs). We further applied this strategy to correct a pathogenic OTC and FAH mutation in ProliHHs and demonstrated improved gene expression, while preserving cell viability for the expansion and purification of edited ProliHHs. Importantly, these edited ProliHHs repopulate into injured mouse liver at a level near to primary human hepatocytes, and they undergo maturation to successfully treat the tyrosinemia mouse model following transplantation in vivo. Thus, this study provides a new autologous hepatocyte therapy techniques that enable large-scale expansion and ex vivo gene correction in patient-derived transplantable ProliHHs, which holds the potential for modeling and treating human liver disease.

2023-09-12 | GSE233425 | GEO

Genetics of human inherited retinal diseases

Project description:Genetics of human inherited retinal diseases

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Genetics of human inherited retinal diseases

Project description:Genetics of human inherited retinal diseases

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RNA-seq transcriptional profiling in primary human hepatocytes, short- and long-term cultured Proliferating human hepatocytes (in vitro/in vivo)

Project description:One of the major challenges of cell therapy is manufacturing of the effective seed cells, which inevitably requires the expansion of cells in vitro. Although considerable progresses have been achieved in expansion of primary human hepatocytes (PHH) in vitro, the transplantation efficiency of proliferating human hepatocytes was decreased with the extended culture. The mechanism of declined transplantation is not clear.Here, we found that long-term cultured proliferating human hepatocytes (lc-ProliHH) significantly upregulated chemokines and proinflammatory cytokines associated with innate immune response. Moreover, lc-ProliHH elicited robust recruitment of macrophages and neutrophils at early stage of transplantation, and being cleared by macrophages caused the engraftment efficiency reduction.Based on these findings, we designed to treat recipient with Dexamethasone (Dex), which decreased the response of innate immune cells and significantly increased the transplantation efficiency to a level approximate to PHH in the liver-injured mice. Furthermore, ProliHH organoid reduced the expression of cytokine genes and behaved close to mature hepatocyte, and as a result, ameliorated their transplantation efficiency as well.

2024-01-25 | GSE184448 | GEO

This is a data repository for cat genomes with inherited diseases

Project description:This is a data repository for cat genomes with inherited diseases

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RNA-seq transcriptional profiling in primary human hepatocytes, short- and long-term cultured Proliferating human hepatocytes (in vitro/in vivo)

Project description:RNA-seq transcriptional profiling in primary human hepatocytes, short- and long-term cultured Proliferating human hepatocytes (in vitro/in vivo)

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Generation of integration-free induced hepatocytes from mouse fibroblasts

Project description:Previous studies demonstrated that hepatocyte-specific transcription factors could directly convert fibroblasts into functional hepatocytes-like cells, namely induced hepatocytes (iHeps) using viral systems. However, viral integration into host genome causes insertional mutation and risk of tumorigenecity. we showed iHeps could be generated from MEFs using the integration-free system. They were expandable in vitro and showed hepatic features, similar to primary hepatocytes. iHeps_G4H1F3 transfected (Episomal vectors) and iHeps_G4H1F3 transduced (pMXs) were duplicate, respectively. MEFs and primary hepatocytes were used as negative and positive controls, respectively.

2015-03-27 | E-GEOD-67362 | biostudies-arrayexpress

Inherited diseases in cattle

Project description:Inherited disease mutations in cattle

2020-08-28 | PRJEB40043 | EVA

Generation of integration-free induced hepatocytes from mouse fibroblasts

2015-03-27 | GSE67362 | GEO

Hepatocytes :MH vs. ProliHH vs. PHH vs. HLC

Project description:Hepatocytes isolated from DILI patient's liver (#2064) were cultured for a long term using irrMEF and EMUKK-05, and comprehensive gene expression was compared between Puromycin-treated and non-treated groups. In addition, comprehensive gene expression analysis of human mature hepatocytes, primary cultured cells, and ips cell-derived hepatocyte-like cells were performed as controls. Two-condition experiment, Proliferating hepatocytes (ProilHH) vs. puromycin-treated ProliHH. Primary human hepatocytes (PHH) and isolated humen mature hepatocytes (MH) and human iPSC-derived hepatocyte-like cells (HLC) as controls.

2021-12-30 | GSE192653 | GEO

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