Generation of Hepatic Stellate Cells by direct differentiation of human pluripotent stem cells

Researchers have developed a protocol to direct the differentiation of human induced pluripotent stem cells (iPSC) to HSCs. The final HSC–like population is highly enriched in PDGFRß positive cells and express key HSC markers at similar levels than primary HSC. Whole genome transcriptomic analysis revealed that iPSC-derived population display a phenotype intermediate between activated and quiescent HSCs. Moreover, iPS-HSC can be expanded in culture while maintaining the phenotype. Functional analysis showed that iPSC-HSC respond to injury mediators and accumulate retinyl esters into lipid droplets. To further characterize iPSC-HSC functionality and responsive capacities, the cells were assembled into 3D co-culture organoids together with human HepaRG cells. Exposure of the organoids to Acetaminophen (APAP), demonstrates a concentration dependent loss in ATP levels in the organoids which is accompanied by an increase of activation of iPS-HSC and organoid fibrogenesis, as has been previously shown for primary HSC/HepaRG organoids. These results also show that the iPSC-HSCs can efficiently support hepatocyte metabolic capacities in long-term cultures, since APAP needs to be metabolized (CYP2E1 and CYP3A4) into NAPQI to be toxic. Overall, these findings show that we have efficiently generated functional HSC-like cells from iPSC, which may have potential for in vitro and biomedical applications. Moreover, these results suggest the potential of iPS-HSC for the generation of complex in vitro systems for toxicity assessment.

Opportunity

 iPS-HSC can be maintained in culture and expanded for further applications

 iPS-HSC are useful for screening of fibrogenic and anti-fibrogenic compounds

 iPS-HSC can maintain hepatocyte metabolic function when cultured in aggregate configuration

 iPS-HSC are useful for long-term toxicity assessment

Intellectual Property

A patent application was filed on December 2015

Commercial Opportunity

IDIBAPS and Ku Leuven are seeking an industrial partner for licensing out and further develop this technology.