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Unlocking immune cell origins
Dr. Miriam Merad, associate professor of gene and cell medicine at Mount Sinai School of Medicine and principal investigator of the study, calls it is a "startling discovery."
"We've shown that the precursor cells develop into microglia only during a short period after conception," she says. "Now that we know that microglia originate in early embryos, theoretically we should be able to generate microglia from embryonic stem cells to treat brain diseases caused by defective microglia. This is a very good example of why scientists need to be able to conduct research with embryonic stem cells."
According to Merad, it was previously thought that microglia originated at the same time as macrophages, which are other immune cells that are thought to develop at birth. She points out that the discovery has the potential to lead to future treatments of degenerative brain diseases such as Alzheimer's and autoimmune diseases such as multiple sclerosis. The study is published online last month in Science Express.
Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. Microglia are thought to play an important role in the development of many brain diseases, and that defective microglia could lead to the release of inflammatory molecules, which could participate in the development of degenerative brain diseases.
For the first part of the study, researchers transplanted blood cell precursors, which are precursors for all macrophages, from one newborn mouse to another.
Merad points out that the transplanted cells could not be differentiated in the recipient animal. These results suggest that microglia originated prior to birth during embryonic life.
The research team then used a mouse model that expresses fluorescent biosensors in blood precursors to determine when, during embryonic age, precursors develop into microglia.
"We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain," Merad says.
In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor–deficient mice.
"In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic Day 8," she says. "These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders."
Merad notes that once activated, the fluorescence does not go away and all cells that develop from the fluorescent precursors should remain fluorescent.
The team then activated the fluorescence as early as seven days after conception. When they examined adult mice they found fluorescent microglia but no fluorescent macrophages. These results established that microglia are unique in that they originate from precursors that arise around seven days after conception.
The discovery was a first step, and many challenges lay ahead for the research team.
"Moving forward we need to further study the normal development of precursor blood cells into microglia, which should help identify the role of microglia in various brain diseases and ultimately lead to advances in treatments," Merad says.