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Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

ABSTRACT: Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

PROVIDER: PRJNA345194 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4340560.fastq.gz	Fastqsanger.gz
	SRR4340570.fastq.gz	Fastqsanger.gz
	SRR4340580_1.fastq.gz	Fastqsanger.gz
	SRR4340580_2.fastq.gz	Fastqsanger.gz
	SRR4340561.fastq.gz	Fastqsanger.gz

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Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

Project description:Transplantation of genetically corrected hepatocytes is an attractive alternative to liver transplantation but is hampered by the low amplification potential of these cells in vitro. Here, we describe a method for generating proliferative hepatic progenitor cells (iHPC) from human hepatocytes as an expandable cell source for liver therapy. Dedifferentiation of primary hepatocytes to iHPC was achieved in less than 7 days by culturing the cells in medium with a cocktail of growth factors and small molecules. In culture, iHPC expressed a combination of endoderm hepatic progenitor and mesenchymal stem cell markers and proliferated vigorously, allowing for their expansion by at least 104 times. RNA sequencing of iHPC demonstrated that they displayed far more subtle changes in both transcriptome and transposcriptome, compared to hepatocyte-derived iPSC. Finally, transplantation of iHPC into the liver of immuno-deficient mice showed iHPC differentiation potential in vivo, without triggering detectable tumor development.

2019-09-25 | GSE87559 | GEO

Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

2019-09-25 | GSE87558 | GEO

Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes.

Project description:The liver is an organ with strong regenerative capacity, yet primary hepatocytes have a low amplification potential in vitro, a major limitation for the cell-based therapy of liver disorders and for ex vivo biological screens. Induced pluripotent stem cells (iPSCs) may help to circumvent this obstacle but often harbor genetic and epigenetic abnormalities, limiting their potential. Here, we describe the pharmacological induction of proliferative human hepatic progenitor cells (HPCs) through a cocktail of growth factors and small molecules mimicking the signaling events involved in liver regeneration. Human HPCs from healthy donors and pediatric patients proliferated vigorously while maintaining their genomic stability and could be redifferentiated in vitro into metabolically competent cells that supported the replication of hepatitis B and delta viruses. Redifferentiation efficiency was boosted by three-dimensional culture. Finally, transcriptome analysis showed that HPCs were more closely related to mature hepatocytes than iPSC-derived hepatocyte-like cells were. Conclusion: HPC induction holds promise for a variety of applications such as ex vivo disease modeling, personalized drug testing or metabolic studies, and development of a bioartificial liver.

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Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-09-25 | GSE87560 | GEO

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.

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A two-step de-differentiation and maturation of primary human hepatocytes in vitro with efficient metabolic and regenerative capacities

Project description:Hepatocytes hold significant promise for applications in drug screening, disease modeling, and clinical cell transplantation. Generating large amouts of hepatocyte in vitro for those application is still challenging. We have previously established a 5C medium for long-term culture and functional maintanace human primary hepatocytes (PHHs) in vitro. However, 5C condtion could not support hepatocyte expansion, which limited its application. In this study, we established a new hepatocyte expansion medium (NHEM) for efficient hepatocyte expansion, which turned the PHHs into hepatic progenitor-like cells (HPLCs). We also generated an optimized 6C condtion for HPLCs maturation. Overall, this study provide a new strategy to generate large amounts of hepatocytes in vitro.

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