Researchers report that they have successfully transplanted human microglia cells into mouse retina to create a model that could be used to test new treatments for incurable eye diseases.
The findings are published in eLife in the article titled, “Human iPSC-derived Microglia Cells Integrated into Mouse Retina and Recapitulated Features of Endogenous Microglia Cells.”
“Microglia exhibit both maladaptive and adaptive roles in the pathogenesis of neurodegenerative diseases and have emerged as a therapeutic target for central nervous system (CNS) disorders, including those affecting the retina,” wrote the researchers. “Replacing maladaptive microglia, such as those impacted by aging or over-activation, with exogenous microglia that enable adaptive functions has been proposed as a potential therapeutic strategy for neurodegenerative diseases. To investigate the potential of microglial cell replacement as a strategy for retinal diseases, we first employed an efficient protocol to generate a significant quantity of human-induced pluripotent stem cells (hiPSC)-derived microglia.”
“Our understanding of microglia function comes predominantly from rodent studies due to the difficulty of sourcing human tissue and isolating the microglia from these tissues. But there are genetic and functional differences between microglia in mice and humans, so these studies may not accurately represent many human conditions,” explained lead author Wenxin Ma, a PhD, biologist at the Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health.
“To address this concern, researchers have been growing human microglia from human stem cells. We wanted to take this a step further and see if we could transplant human microglia into the mouse retina, to serve as a platform for screening therapeutic drugs as well as explore the potential of microglia transplantation as a therapy itself,” added senior author Wai Wong, vice president of retinal disease, Janssen Research and Development.
To test their approach, the researchers grew microglia from hiPSCs. They conducted a series of tests and at four and eight months after transplantation, the human microglial cells had migrated into the retina and were well distributed. The introduction of hiPSC-microglia cells had no negative effects on the surrounding cells of the retina.
The team then tested whether the transplanted cells had a normal immune reaction to retinal cell injury. They found that the cells behaved exactly as the resident mouse microglia. Not only did the transplanted microglia move into the damaged regions, but they also hoovered up the damaged light-receiving cells. This further suggests that the transplanted cells mirrored normal functions of resident microglia in the eye.
One limitation of the study is uncertainty around its claim that the microglia generated from hiPSCs are mature, and therefore comparable to human-derived mature microglia cells. Further work is needed to claim they are mature human microglia.
“Understanding microglial cell function is essential for investigating disease mechanisms and identifying accurate targets for treating degenerative retinal diseases,” said senior author Wei Li, a senior investigator in the retinal neurophysiology section, National Eye Institute, National Institutes of Health. “Our model provides a new way of studying the functions of human microglia within disease mechanisms and a platform for evaluating the potential therapeutic effects of microglia cell transplants from diverse patient backgrounds.”