summary: Researchers have developed human brain organoids containing microglia, the brain’s immune cells. These organoids allow researchers to study how microglia develop and function in a more realistic environment than previous models.
Researchers have found that microglia are influenced by the environment in which they develop, and that microglia are involved in both development and disease. Their findings could lead to new treatments for neurological disorders.
Important facts:
- Microglia are responsible for removing cellular debris and pathogens and also play a role in neuroprotection.
- Researchers found that microglia in people with autism spectrum disorders were more responsive to injury and intruders.
- Researchers hope their findings will lead to new treatments for neurological disorders such as autism spectrum disorders and Alzheimer’s disease.
sauce: Salk Institute
At the intersection of the human immune system and the brain are microglia, specialized brain immune cells that play an important role in development and disease. Although the importance of microglia is undisputed, modeling and studying microglia remains a challenging task.
Unlike some human cells that can be studied in vitro or in non-human models, human microglia become difficult to study when removed from a human brain-like environment.
To overcome this barrier, Salk scientists developed organoid models, three-dimensional aggregates of cells that mimic the characteristics of human tissue. This model allows researchers to study human microglia development and function for the first time in living human-derived tissue.
In addition, scientists studied large-headed autism spectrum disorder (infants with a head circumference greater than 97 percent of other infants) to determine whether the brain environment influences the development of more reactive microglia. We examined microglia from pediatric patients with the large condition).
The survey results are cell On May 11, 2023, we will highlight the importance of immune cell-brain interactions and advance our understanding of neurodegenerative and developmental disorders such as autism spectrum disorders and Alzheimer’s disease.
“Outside the brain environment, microglia lose nearly all function and meaning,” says Rusty, senior author and holder of the Vi & John Alder Commission Chair of Age-Related Neurodegenerative Disease Research. Professor Gage says
“If we find a way to recreate the human brain environment in organoids to study human microglia, we will be able to understand how healthy and diseased brains affect microglia, and vice versa. We knew we would eventually have a tool to look at how the brain affects us: microglia affect the brain.”
Emerging nearly a decade ago, organoids have become a popular tool for bridging the gap between cellular and human research. Organoids can mimic human development and organogenesis better than other experimental systems, allowing researchers to study how drugs and disease affect human cells in a more realistic setting. can do.
Cerebral organoids are typically cultured in culture dishes, but are structurally and functionally limited by lack of blood vessels, short survival times, and inability to maintain diverse cell types (such as microglia).
“To create a brain organoid model that contains mature microglia and allows us to study them, we used a novel transplantation technique that creates an environment that resembles the human brain,” said co-first author Abed. Mr Mansoor says He is currently an assistant professor at the Hebrew University of Jerusalem.
“This allowed us to finally create human brain organoids with all the necessary features to coordinate human microglia growth, behavior and function.”
Unlike previous models, the researchers created human brain organoids with microglia. and An environment that mimics the human brain has finally made it possible to examine the effects of the environment on microglia throughout brain development.
They found that a distinctive protein, called SALL1, appears as early as 11 weeks into development and helps confirm microglial identity and promote mature function. Furthermore, we found that brain-environment-specific factors such as the proteins TMEM119 and P2RY12 are required for microglial function.
“Creating a human brain model that can effectively replicate the human brain environment is of great interest,” said Associate Professor Axel Nimmayan, another author of the study.
“With this model, we can finally examine how human microglia function within the human brain environment.”
As the research team learned more about microglia, the importance of the relationship between the brain environment and microglia became clear, especially in disease scenarios.
The lab previously examined neurons from people with autism spectrum disorders and found that they grew faster and had more complex branching than neurotypical neurons.
Using the new organoid model, the researchers will be able to ask whether these neuronal differences alter the brain environment and affect microglia development.
To do so, they compared microglia derived from skin samples of three individuals with autism spectrum disorders with macrocephaly and three neurotypical individuals with macrocephaly.
Researchers found that individuals with autism spectrum disorders exhibited neuronal differences that the research team had previously noted, and that microglia were influenced by those differences in their environment. bottom.
This neuron-dependent environmental change made microglia more responsive to injury and intruders. This finding may explain the brain inflammation observed in some patients with autism spectrum disorder.
Since this was a preliminary study with a small sample size, the researchers plan to examine microglia from more people in the future to validate their findings. They also aim to extend their research to other developmental and neurodegenerative disease studies to examine how microglia contribute to disease development.
“Instead of dismantling the brain, we decided to build it ourselves,” says co-lead author Simon Schaefer. He is a former postdoctoral fellow in Gage’s lab and is now an assistant professor at the Technical University of Munich.
“By building our own brain model, we are able to work bottom-up and find solutions that are not possible top-down. I would like to continue.”
Other authors include Monique Pena, Saeed Ghassemzadeh, Lisa Mitchell, Amanda Mar, Daphne Quang, Sarah Stumpf, and Clara Baek of the Salk Institute. Johannes C.M. Schrachecki, Addison J. Lana, and Christopher K. Glass of the University of California, San Diego. Irene Santistevan of the Technical University of Munich. Raggad Zagar of the Hebrew University of Jerusalem.
Funding: This study was supported by the National Institutes of Health (R01 AG056306, R01 AG057706, R01 AG056511, R01 AG061060, R01 NS108034, U19 NS123719, NCI CCSG: P30 014195, NCI CCSG: P30 014195), the American Heart Association, and Paul G. Ren Frontiers Group (Grant 19PABHI34610000), Brain and Behavior Research Foundation (27685 and 30421), German Research Foundation (500300695), Milky Way Research Foundation, Annette C. Merl Smith and Robert and Mary Jane Engman Foundation, European Molecular Biology Agency (ALTF 1214-2014), Human Frontier Science Program (LT001074/2015), European Research Council, Chapman Foundation, JBP Foundation, and Helmsley Charitable Trust.
About this neuroscience research news
author: Salk Communications
sauce: Salk Institute
contact: Salk Communication – Salk Institute
image: Image credited to Neuroscience News
Original research: open access.
“An In Vivo Neuroimmune Organoid Model to Study Human Microglial PhenotypesBy Rusty Gage et al. cell
overview
An In Vivo Neuroimmune Organoid Model to Study Human Microglial Phenotypes
highlight
- As xenograft brain organoids in vivo A platform for studying human microglia (hMG)
- hMG acquires a unique human transcriptome signature, in vivo– Identity like
- hMG engages in monitoring the human brain environment and responds to perturbations.
- Patient-derived model reveals brain environment-induced immune responses in autism
summary
Microglia are specialized brain-resident macrophages that play an important role in brain development, homeostasis, and disease. However, until now, our ability to model the interaction between the human brain environment and microglia has been severely limited.
To overcome these limitations, we in vivo The xenograft approach allows us to study functionally mature human microglia (hMG) functioning within a physiologically relevant angiogenic and immunocompetent human brain organoid (iHBO) model.
Our data show that hMG present within organoids acquires a human-specific transcriptomic signature that closely resembles that organoid. in vivo Corresponding person. in vivo Two-photon imaging has revealed that hMG is actively involved in monitoring the human brain environment, responding to local injury and to systemic inflammatory cues.
Finally, the transplanted iHBO developed here provides an unprecedented opportunity to study functional human microglial phenotypes in health and disease, and cerebral environment-induced phenotypes in a patient-specific model of autism with macrocephaly. We demonstrate that it provides experimental evidence of an immune response.
