A specific type of white blood cell, considered the sentinel of the immune system, can now be made in almost limitless volumes in the laboratory.
A two-step protocol, developed by A*STAR researchers, for turning reprogrammed stem cells into various types of tissue-specific white blood cells, known as macrophages, could help scientists design new medicines for inflammatory diseases of the lungs, brain and other organs.
The first step in the process involves converting induced pluripotent stem cells into a kind of primordial macrophage. Florent Ginhoux and his colleagues at the A*STAR Singapore Immunology Network devised a recipe for doing this with either mouse or human cells, creating what they called iPSC-derived primitive macrophages — or simply iMacs.
These iMacs were genetically and functionally similar to early macrophages found in the developing embryo. And by making iMacs from the iPSCs of someone with Familial Mediterranean Fever, they showed that these cells provide a tractable system for studying the ways in which a genetic disease can cause immune signaling to go awry.
Ginhoux’s team next coaxed the iMacs to form the kinds of mature macrophages found in different tissues of the adult body. In one experiment, the researchers mixed the iMacs in a lab dish with neurons that had also been made from the same batch of iPSCs. After about a week of co-culturing, the iMacs started to develop tentacle-like projections called dendrites, suggesting they had morphed into a type of immune cells, known as microglia, involved in brain defense.
The researchers could also form these lab-made microglia — or iMicro cells, as they called them — by implanting iMacs directly into the brains of newborn mice. Putting iMacs into the lungs of mice also resulted in lung-specific macrophages.
With the protocols all worked out, these kinds of tissue-resident immune cells now provide a valuable tool for studying diseases characterized by macrophage dysregulation in different organ systems. For example, the iMicros could help scientists shed light on the immune contributions to neurodevelopmental disorders such as autism and neurodegenerative disorders such as Alzheimer's disease.
"[These cells] will provide insights into the mechanism of primitive macrophage maturation into microglia,” says Ginhoux. “Furthermore, the co-culture model has the potential to serve as an in vitro drug screening system for the development of novel therapies against brain diseases.”
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network, the Translational Laboratory in Genetic Medicine and the Genome Institute of Singapore. For more information about the team’s research, please visit the Ginhoux lab webpage.
Takata, K., Kozaki, T., Lee, C. Z. W., Thion, M. S., Otsuka, M. et al. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 47, 183–198.e6 (2017). | Article