In vitro platform for antimalarial testing developed from stem cells
Lab-grown liver cells derived from induced pluripotent stem cells may allow for personalized testing on antimalarial drugs and vaccines, according to recent data.
“Our platform can be used for testing candidate drugs that act against the parasite in the early liver stages, before it causes disease in the blood and spreads back to the mosquito vector,” Sangeeta Bhatia, MD, PhD, of Massachusetts Institute of Technology and Brigham and Women’s Hospital, said in a press release. “This is especially important given the increasing occurrence of drug-resistant strains of malaria in the field.”
Bhatia and colleagues reprogrammed human skin cells to generate induced pluripotent stem cells (iPSC), which were then adapted to model cells from the liver using a 20-day in vitro differentiation protocol. These were then infected with malaria parasites including Plasmodium berghei, Plasmodium yoelii, Plasmodium falciparum and Plasmodium vivax, and subsequently introduced to the prototypical antimalarial agents atovaquone and primaquine
“Primary human hepatocytes are a preferable cell type to model liver-stage malaria in vitro for the purposes of antimalarial drug development,” the researchers wrote. “However, primary human hepatocytes are sourced from a small pool of donors and thus may not represent the genetic diversity of the human population.
“Compared to primary human hepatocytes, stem cell-derived hepatocytes can represent more diverse genotypes, can be personalized to exhibit rare genotypes and are renewable in culture.”
In vitro liver-stage malaria infections of the studied bacterium were established, with differentiated iPSC phenotypically stable and ready to be infected up to 55 days after initiation of differentiation. These cells were initially found to be sensitive to atovaquone but not primaquine; however, when the cells were chemically matured through exposure to small molecules, primaquine sensitivity was conferred.
“The establishment of Plasmodium liver-stage infections in induced pluripotent stem cell-derived hepatocyte-like cells lays the foundation for their use in antimalarial drug discovery as well as paves the way to study the genetic basis of host-Plasmodium interactions,” the researchers concluded. – by Dave Muoio
Disclosure: The researchers report no relevant financial disclosures.