Microglia are the brain’s resident immune sentinels and account for around ten percent of all brain cells. These dynamic, highly specialized cells control a plethora of neurobiological functions, from scavenging pathogens and damaged brain cells to orchestrating inflammation and promoting repair.
Despite being the subject of intense research, much of microglia’s origin story remains shrouded in mystery. A*STAR researchers, in collaboration with an international team of scientists, have thus turned to a genomic technique called single-cell sequencing to chart the spectrum of microglia biology over 450 million evolutionary years.
The study was led by Ido Amit’s laboratory at the Weizmann Institute of Science in Israel, with contributions from the laboratory of Florent Ginhoux, a Senior Principal Investigator at the Singapore Immunology Network (SIgN).
The researchers’ deep dive into microglial biology spanned 18 species—including humans, whales, marmosets, snakes and macaques—and showed that these cells have been around for a long time. “We found that microglia exist in multiple species, including old ones! It is a macrophage population that has been conserved for millions of years,” said Ginhoux.
Take, for example, the differences between human and mouse microglia, which have an evolutionary distance of about 96 million years. The researchers found that humans have signature genetic patterns relating to Alzheimer’s and Parkinson’s disease susceptibility that mice lack. Longer-living species such as humans also have a higher degree of diversity and heterogeneity among their microglia.
By examining the genetic information of individual cells with next-generation sequencing, the researchers were able to amplify subtle differences between microglia subpopulations in the context of its microenvironment, revealing never-before-seen layers of complexity in the cellular and genetic makeup of the brain.
“Single-cell analysis allows us to map every cell, group them by their expression profile and appreciate the level of heterogeneity within a cell population like never before,” explained Ginhoux.
Such investigations are integral to advancing our understanding of brain aging and neuropathology—areas of research that have been limited due to the lack of robust experimental models. It will also support neurobiologists seeking novel targets for clinical interventions against Alzheimer's disease and other neurodegenerative conditions, Ginhoux said.
“We are trying to find new [microglia] sub-populations, better separate them and study them at single-cell resolution. When you know what molecules and proteins are involved in cellular pathways, you can then design better treatments,” he said.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).