CU Anschutz pharmaceutical researchers use stem cells to mimic infant liver cells in testing drug safety and efficacy
A new tool developed in a CU Anschutz lab may help clinicians make data-driven prescribing decisions for infants.
Currently, prescribing decisions for babies are based on safety and efficacy studies done on adults. Dosages are typically calculated based on weight - and the assumption is that the drug will behave exactly the same in the baby as it does in an adult.
"We don't do clinical trials on babies, for obvious ethical reasons, so clinicians have no choice but to use drugs off-label in neonates. Sometimes, this can have pretty deleterious effects," said Jed Lampe, PhD, associate professor at CU Anschutz Skaggs School of Pharmacy and Pharmaceutical Sciences.
Lampe wants to help clinicians make safer prescribing and dosing decisions. So he and his team asked the question: Can we create a stem-cell based model that looks, acts and behaves like the liver cells of an infant?
The answer is yes.
"We have demonstrated that, in the lab, we can recapitulate almost identically the drug metabolic and toxicity profile that we observe in the neonatal hepatocytes," Lampe said.
Creating a new model for testing
The liver is the primary organ for drug metabolism. Drugs can be tested in healthy adults or by using adult liver cells (hepatocytes). Drug dosing is determined by pharmacokinetics, a process that helps us understand how the drug is absorbed, distributed, metabolized and excreted by the body.
Currently, there isn't an appropriate model to test the toxicity profile of drugs - or how they are metabolized - in infants. This includes xenobiotic toxicants, the environmental toxins and synthetic chemicals developed by industry that can impact air, soil, water and human health.
In adults, we can understand toxicity levels and metabolism by incubating a toxin or drug with adult liver cells. Lampe said adult liver cells are "fairly easy to come by." But infant liver cells aren't as readily available due to the low infant mortality rates in the U.S.
So, Lampe and his fourth year PhD student, Emily Gracey, created a sustainable, ethically sourced line of cells using adult induced pluripotent stem cells that can provide useful data about toxicity and metabolism in the neonate and developing infant. Using adult stem cells - specifically, adult fibroblasts - they reprogrammed the cells to behave as if they were a fetal or neonatal liver cell. The cell line represents the continuum of development from the third trimester to three months post birth.
Validating the tool
When creating the models, Lampe insisted that the science go beyond "surface-level validation." The cells had to have the same gene expression profile as a neonatal hepatocyte. But they also needed to ensure the cells behaved metabolically the same as a neonatal cell.
"We didn't just compare gene expression and call it a day. We went a step further," Lampe said.
The team was able to do a side-by-side comparison of the model cells with actual neonatal hepatocytes to ensure they responded the same in terms of drug metabolism and toxicity.
"The results were exciting," Lampe said. "The profiles lined up well - not just at the mRNA level but in terms of the phenotype and how they responded. Our model behaves much like real neonatal hepatocytes when it comes to metabolism and toxicity."
Lampe said it's important to note that stem cell-derived cells, when programmed, are not identical to the primary cell. But the approximation can still be incredibly valuable as a tool.
Applications of the model
The researchers are working with CU Innovations to patent the technology, which in addition to pharmaceutical applications has chemical industry applications as well.
"When a company develops a new pesticide, they test it on adult liver cells. And they may find it to be nontoxic to adults. But this line of cells can actually help them test to be sure the same is true for neonates and developing infants," Lampe said.
The cell line they developed is reproducible, and Lampe hopes it can be offered to researchers to get consistent, meaningful results that mirror what they'd see if they were working with actual neonatal hepatocytes. The line of liver stem cells also offers the opportunity to reduce reliance on animal models.
"This is a profound, paradigm-shifting model that we're able to offer where people can now look at something that's a lot more relevant to humans in order to understand the toxicity profile of a drug, whether it's a pharmaceutical discovery or an industrial toxin such as a pesticide or herbicide," Lampe said.
