Opti-HSC: The first commercially available iPSC-derived Hepatic stellate cells

The global burden of liver disease continues to rise, and currently accounts for approximately two million deaths per year. Independent of etiology (e.g., viral infection, metabolic-dysfunction associated fatty liver disease etc.), chronic liver disease progresses to liver fibrosis, which is characterised by abnormal accumulation of extracellular cell matrix components and is associated with liver injury, inflammation and cell death. Despite the severity of the condition, there are currently no FDA-approved treatments, mainly due to the lack of effective pre-clinical models able to accurately recapitulate disease phenotype. Traditional methods that involve animal models, primary human cells, or immortalized cell lines, have distinct limitations, often leading to inconsistent results that hinder drug development. DefiniGEN’s Opti-HSC, based on induced pluripotent stem cell (iPSC) technology, offers a superior alternative that addresses these issues and can de-risk drug discovery pipelines significantly. Here, we’ll explore why Opti-HSC is an essential advancement and examine the drawbacks of conventional models.

Drawbacks of Animal Models in Drug Discovery

Animal models, commonly used in liver fibrosis research, present numerous limitations:

• Species-specific Differences: Animal biology can differ significantly from human physiology, leading to low predictive accuracy when translating findings to human applications.
• Cost and Time: Research using animal models is often costly and time-consuming, making these models inefficient for fast-paced research demands.
• Ethical Concerns: The ethical implications of animal testing create obstacles in drug research.
  
  

These limitations can lead to unreliable data and significant delays and are a primary reason for the high attrition rate in drug development.

Limitations of Primary Human Hepatic Stellate Cells

Primary human hepatic stellate cells (pHSCs) are considered the gold-standard model for the study of liver fibrosis pathogenesis in vitro, as they retain many of the stellate cell characteristics observed in human liver. However, they also present considerable challenges for researchers:

• Limited Availability: Since hepatic stellate cells only make up approximately 5% of the overall liver, pHSCs are scarce and difficult to source, rendering their isolation complex, expensive, and time consuming.
• Donor variation: Genetic variation between donors possess a serious drawback for researchers since the data obtained from each donor yields low reproducibility, making it difficult to compare data sets confidently.
• Heterogeneity: Being directly isolated from human livers, pHSCs demonstrate significant heterogeneity even within the same culture, and a mixture of both quiescent and activated cells is observed, downstream decreasing the accuracy of fibrosis modeling. This limitation alongside the additive variation caused by the different isolation methods applied in different laboratory environments hinders long term investigations.

These factors contribute to unpredictable results that make primary HSCs suboptimal for drug discovery.

Figure 1: ICC stained image of iPSC-derived Hepatic Stellate cells; Opti-HSC, which do not suffer from the same drawbacks as human primary hepatic stellate cells. 

Drawbacks of Immortalized Cell Lines

Immortalized hepatic stellate cell lines, while easier to obtain and maintain in culture, still pose additional concerns:

• Altered Genomic Profile: Prolonged culturing may result in genetic and phenotypic drift, reducing model accuracy.
• Limited Activation Response: These cells often display an altered activation profile, rendering the study of HSC activation at disease state difficult.
• Low Predictive Value: The in vitro behavior of immortalized lines frequently fails to mimic in vivo responses, leading to lower predictive power for human applications.

The limitations of these cell lines make them a less reliable tool for fibrosis research and drug testing.

How Opti-HSC can overcome the drawbacks of traditional models

Opti-HSC is the first commercially available iPSC-derived hepatic stellate cell line for research use. Opti-HSC mitigates the drawbacks of traditional models by providing a consistent, scalable, and human-relevant in vitro model for the study of liver fibrosis pathogenesis. Key advantages include:

• Human Relevance and Consistency: Derived from human iPSCs, Opti-HSC maintain human-like physiology, overcoming the species-specific limitations of animal models. Since they are sourced from a single donor, they remove the donor variation seen in primary cells.
• Scalability: Unlike primary cells, Opti-HSC can be scaled to meet your research needs, ensuring reliable results for extensive efficacy screening and toxicology investigations.
• Accurate Disease Modeling: Opti-HSC express crucial activation markers, enabling precise modeling of hepatic fibrosis that closely mirrors human disease states.

Our Opti-HSC platform provides a transformative approach to hepatic fibrosis research and drug discovery. By offering a more predictive, consistent, and human-relevant model, Opti-HSC helps de-risk drug discovery pipelines, reducing both costs and development timelines.

Ready to enhance your drug screening capabilities with iPSC-derived hepatic stellates? You can learn more about our Opti-HSC here, or you can contact one of our experts today.