Using a new approach, researchers have identified novel signaling molecules that regulate the activation of specific subsets of astrocytes thought to cause inflammation. multiple sclerosis (MS).
A new methodology called FIND-seq allows the selection of single cells from a sample based on the expression of specific genes and the analysis of their complete gene expression profile.
Using cells from a mouse model of MS, the researchers found that the NR3C2 and NCOR2 proteins could inhibit the disease-promoting astrocyte activity by suppressing the activity of the XBP1 protein. Researchers point out that modulating these molecules may reduce inflammation and neurodegeneration in the brain.
“These findings identify new targets for therapeutic intervention in neurological disorders such as MS,” said Francisco Quintana, professor of neurology at Harvard Medical School and scientist at Brigham and Women’s Hospital (BWH) in Boston. says Dr. university press release.
the study, “Identification of astrocyte regulators by nucleic acid cytometry,was published in Nature.
Astrocytes are a family of nerve-supporting cells located in the central nervous system (CNS), or brain and spinal cord. These tiny, star-shaped cells work to keep nerve cells healthy by regulating blood flow, supporting energy needs, and helping nerve cells repair after injury.
Astrocytes are normally activated in response to brain injury. This process involves structural and functional changes that mediate an inflammatory response to help repair damage.no control Astrocyte reactivity However, it has been implicated in many chronic neuroinflammatory conditions, including MS.
researcher previously identified a subset of astrocytes Promoted neuroinflammation in animal models of MS. These cells were differentiated by the activation of XBP1, a transcription factor that controls cellular activity by regulating gene activity. However, distinguishing and isolating them in the laboratory for research is notoriously difficult.
In fact, according to researchers at BWH who have developed new methods to isolate and study astrocyte subsets that classify cells based on RNA, the available approaches to study astrocyte subsets are specifically those Due to the rarity of cell types, it is often expensive, inefficient, or impractical. or a DNA marker specific to that cell type. RNA is an intermediate molecule used in converting DNA into protein products.
This approach, called FIND-seq, “uses a multistep process that takes millions of cells as input and can analyze rare cell populations. [less than 1%] Abundant in a cost-effective manner,” the researchers wrote.
Using a newly developed approach, they isolated and studied a subset of XBP1-positive astrocytes to identify potential targets that might attenuate their proinflammatory activity.
Approximately 18 days after inducing MS-like disease in mice, these cells were found at approximately 10-fold higher levels than before induction. They also showed increased proinflammatory signaling molecule activity.
“Together, these findings underscore the ability of FIND-seq to dissect astrocyte subsets of interest relevant to promoting CNS pathology,” the researchers wrote.
Analysis of these isolated astrocytes also identified signaling molecules that may regulate disease-driving properties of the cells. One such molecule, NR3C2, has known immunomodulatory effects.
Experimental blocking of the gene encoding that protein in astrocytes exacerbated symptoms of MS in a mouse model. A potential role for was supported.
The results showed that NR3C2 may cooperate with another protein called NCOR2 to suppress inflammation.
To validate their findings, the researchers examined brain tissue from MS patients. Analysis showed signs of reduced NR3C2 levels and reduced NR3C2-NCOR2 signaling in astrocytes compared to healthy tissues.
“Together, these findings suggest that the balance between XBP1 and NR3C2-NCOR2 signaling controls disease-promoting astrocyte activity that contributes to CNS pathology,” the researchers said. wrote, adding that targeting NR3C2 and/or NCOR2 may provide new strategies to treat MS. Other diseases characterized by neuroinflammation and neurodegeneration.
