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Researchers Create New Map of Brain’s Immune System

Summary: Researchers have successfully created a new map of the brain’s immune system in both mice and humans. The findings suggest microglia all have the same core signatures, but can act differently, depending on their function. The map also details how the brain’s immune system changes as multiple sclerosis progresses.

Source: University of Freiburg.

A team of researchers under the direction of the Medical Center – University of Freiburg has created an entirely new map of the brain’s own immune system in humans and mice.

The scientists succeeded in demonstrating for the first time ever that the phagocytes in the brain, the so-called microglia, all have the same core signature but adopt in different ways depending on their function. It was previously assumed that these are different types of microglia.

The discovery, made by means of a new, high-resolution method for analyzing single cells, is important for the understanding of brain diseases. Furthermore, the researchers from Freiburg, Göttingen, Berlin, Bochum, Essen, and Ghent (Belgium) demonstrated in detail how the human immune system in the brain changes in the course of multiple sclerosis (MS), which is significant for future therapeutic approaches.

The study was published on 14. February 2019 in the journal Nature.

“We were able to show that there is only a single type of microglia in the brain that exist in multiple flavours,” says project head Prof. Dr. Marco Prinz, medical director of the Institute of Neuropathology at the Medical Center – University of Freiburg. “These immune cells are very versatile all-rounders, not specialists, as has been the textbook opinion up to now,” sums up Prof. Prinz.

Versatile All-Rounders, Not Specialists

Since the immune cells located in the blood cannot reach the brain and spinal cord on account of the blood-brain barrier, the brain needs its own immune defense: the microglia. These phagocytes of the brain develop very early on in the process of embryonic development and later remove invading germs and dead nerve cells. They contribute to the maturation and lifelong malleability of the brain. It was previously unclear whether there are subtypes of microglia for the various functions they serve in the healthy and diseased brain.

Researchers led by Prof. Prinz and the co-first authors of the study, Dr. Takahiro Masuda, Dr. Roman Sankowski, and Dr. Ori Staszewski from the Institute of Neuropathology at the Medical Center – University of Freiburg, conducted detailed studies on microgliain the brain, both on a mouse model and on human brain tissue removed from patients.

With the help of a new method for conducting single-cell analysis, the researchers were able to demonstrate the features of microglia in great detail. To do so, they used a microscope to study microglia in different brain regions and at different stages of development. They also analyzed the RNA-levels of these cells using single-cell analysis. The analyses revealed that microglia all have the same core signatures but adapt differently at different stages of development, in different brain regions, and depending on the function they are meant to serve.

Hope for Patients with Multiple Sclerosis

Dysregulated microglia are also involved in several brain diseases. In particular, they play a key role in the development of Alzheimer’s, multiple sclerosis (MS), and a few psychiatric diseases like autism. In the healthy brain, microglia form a uniform network around the nerve cells that can change in just a few minutes in the case of disease and form numerous new phagocytes to limit the damage.

map

Single-cell analysis of microglia: each point shows a cell, and the color signals how strongly particular immunologically significant genes are activated in the various cells. NeuroscienceNews.com image is credited to Takahiro Masuda / Medical Center – University of Freiburg.

“We now possess the first high-resolution immune cell atlas of the human brain. This also enables us to understand how these cells change during course of diseases like MS,” says Prof. Prinz, who is also involved in the Signalling Research Excellence Clusters BIOSS and CIBSS of the University of Freiburg. “In MS patients, we managed to characterize microglia in a state that is specific for multiple sclerosis. We hope that it will be possible in the future to target microglia subsets in harmful state.”

“It is extremely exciting to see how flexible the microglia can be,” says Prof. Prinz. The studies on the mouse model put the researchers on the right track. However, co-first author Dr. Masuda also succeeded in showing that human microglia are much more complex than those of laboratory animals. “The individual changes in the human brain also leave traces in the microglia in the course of life,” says Dr. Masuda.

About this neuroscience research article

Source: Marco Prinz – University of Freiburg
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Rob Jenkins, University of Freiburg.
Original Research: Abstract for “Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution” by Takahiro Masuda, Roman Sankowski, Ori Staszewski, Chotima Böttcher, Lukas Amann, Christian Scheiwe, Stefan Nessler, Patrik Kunz, Geert van Loo, Volker Arnd Coenen, Peter Christoph Reinacher, Anna Michel, Ulrich Sure, Ralf Gold, Josef Priller, Christine Stadelmann & Marco Prinz in Nature. Published February 13 2019.
doi:10.1038/s41586-019-0924-x

Cite This NeuroscienceNews.com Article

University of Freiburg”Researchers Create New Map of Brain’s Immune System.” NeuroscienceNews. NeuroscienceNews, 19 February 2019.
<http://neurosciencenews.com/brain-immune-system-map-10769/>.
University of Freiburg(2019, February 19). Researchers Create New Map of Brain’s Immune System. NeuroscienceNews. Retrieved February 19, 2019 from http://neurosciencenews.com/brain-immune-system-map-10769/
University of Freiburg”Researchers Create New Map of Brain’s Immune System.” http://neurosciencenews.com/brain-immune-system-map-10769/ (accessed February 19, 2019).

Abstract

Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1,2,3,4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.

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