A collection of human pluripotent stem cells that reflects the genetic makeup of the Brazilian population has been developed by researchers from the University of São Paulo (USP) affiliated with the National Embryonic Stem Cell Laboratory (LaNCE).
“In addition to their therapeutic uses, stem cells can make an important contribution to new drug development by supplementing or even replacing animal trials and enhancing the safety of human trials. They can also help us study diseases that are frequently found in our population,” said Lygia da Veiga Pereira, head of LaNCE, in an interview with Agência FAPESP.
For several years, Pereira’s team cultured stem cell lines derived from embryos that had been frozen during in vitro fertilization procedures. According to Pereira, however, genomic analysis showed that these lines were not representative of the Brazilian population, as their ancestry was more than 90% European.
“These embryos came from private clinics, which only a small proportion of the population can afford,” Pereira said. “Public health services don’t freeze surplus embryos for cost reasons. So, we decided to partner with researchers involved in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)”.
Funded by the Health Ministry and the Science, Technology, Innovation & Communications Ministry, ELSA is a multicenter study that has been in progress since 2008 at six universities in multiple Brazilian states. It tracks 15,105 men and women aged 35-74. Five thousand of these volunteers are monitored at Hospital Universitário (HU), USP’s teaching hospital, under the supervision of Paulo Lotufo, who is a Full Professor at USP’s Medical School.
The volunteers are given regular tests to evaluate the risk of cardiovascular diseases and diabetes. According to Lotufo, biological samples taken during the first examination were kept and used to create the new stem cell library.
The LaNCE team used the induced pluripotent stem cell (iPSC) technique for which Shinya Yamanaka of Kyoto University in Japan was awarded the 2012 Nobel Prize in Medicine. Using the technique described in 2006 by Yamanaka, the LaNCE team inserted certain genomic reprogramming proteins into peripheral blood cells from ELSA volunteers.
These proteins, called transcription factors, activate genes associated with embryonic-stage cells and switch off other genes that should be active after maturation, creating induced pluripotent stem cells that, in response to appropriate stimuli, can potentially differentiate into all tissues types in the human body.
“We created an initial library of 23 cell lines merely as a proof of concept,” Pereira said. “But we have samples from 1,872 individuals and can create new lines according to demand from the scientific community or pharmaceutical companies.”
According to the findings described in the paper published in Scientific Reports, the European genomic contribution to the cells in the new collection ranged from 14.2% to 95%, while the contribution of African ancestry ranged from 1.6% to 55.1% and that of Native American ancestry ranged from 7% to 56%. This admixture is considered representative of the Brazilian population’s ethnic diversity.
Another major advantage of the researchers’ partnership with ELSA, Pereira added, is that the biological samples are accompanied by a huge clinical database, which enables the researchers to use the material in various kinds of analysis.
“I can select from the ELSA database only samples from volunteers with high blood pressure, or diabetes, or depression, or asthma, and create a suitable collection of cell lines for each study,” Pereira explained. “For example, ELSA shows us that the incidence of hypertension in Brazil is 30% and that 10% of people with hypertension don’t respond to treatment. But what’s the molecular mechanism behind this resistance to treatment? With these stem cells, we can design experiments to try to answer this sort of question.”
Another important topic, in her view, is the variable responses of individuals to different drugs, which, once approved, may not always work or may cause adverse side effects in some patients.
“Adverse reactions to drugs account for one in 15 hospital admissions in the UK, while 2 million patients per year in the US suffer severe adverse drug reactions and 100,000 die. We know our genes are the most important factor in how we respond to a drug, so trials conducted in Europe may not show the same responses to drugs as trials held in Asia, for example.”
Given that the cost of testing new drugs before they are approved and marketed is unaffordably high in several countries, she continued, it would be possible to use stem cells with the genetic characteristics of the populations of interest in order to reduce costs, enhance safety and speed up the drug development process.
“For the time being, we have samples for only some of the ELSA volunteers monitored in São Paulo, but we’d like to expand that to include all the more than 15,000 participants,” Pereira said. “This library of the Brazilian population significantly enriches the genetic diversity of the pluripotent stem cells available in the world, the vast majority of which are of European and Asian origin. The reason we published this paper was to make more people aware of the availability of this collection of cells and the associated clinical data, so that researchers all over the world can use these resources in their work.”
LaNCE is a nonprofit organization and can develop cell lines via partnerships, charging only enough to cover operating costs, Pereira explained. Anyone interested can contact Pereira by email at email@example.com.
LaNCE is part of the Center for Cell-Based Therapy (CTC), one of the Research, Innovation & Dissemination Centers (RIDCs) funded by FAPESP. The research also received funding from the National Scientific & Technological Development Council (CNPq) and the National Development Bank (BNDES).