CD47 and autism
April 23, 2021
By Christopher Vaughan
Researchers at the Institute for Stem Cell Biology and Regenerative Medicine have linked an immune molecule to brain growth aberrations associated with autism. Their research points the way to potential treatments for this kind of brain alteration.
“It’s very exciting to able to find underlying cellular mechanisms that may be at play in at least these forms of autism, and to start looking at ways we might be able to intervene therapeutically,” said assistant professor Sundari Chetty, PhD. Chetty did her research in association with professor Irv Weissman, MD, director of the Institute for Stem Cell Biology and Regenerative Medicine. The research was recently published in the Proceedings of the National Academy of Sciences (PNAS)
The most severe forms of autism spectrum disorder often occur in people with larger than average heads, and many of these people also have deletions in a region of chromosome 16 known as 16p11.2, Chetty said. To understand what might be happening on a cellular level in people with alterations of the 16p11.2 gene locus, Chetty and her colleagues studied cell samples from autism patients with this genetic alteration. The cells were turned into iPS cells—chemically reset so that they can grow into the brain cells they wanted to study.
Normally brain development is a process of rapid cell multiplication and growth, combined with a process of pruning away cells that are not serving a functional purpose. “We wanted to test the hypothesis that the pruning process is aberrant in people with this chromosomal change, leading to brain overgrowth as cells that should be pruned away are not,” Chetty said.
In the lab, the researchers grew brain progenitor cells from patient-derived iPS cells to see how they behaved and began to focus on the action of a protein called CD47. CD47 is well documented to act as a “don’t eat me” signal that impedes the activity of immune cells whose job it is to devour and destroy cells in the body that are defective or infected with pathogens. Nearly all cancers overexpress CD47 to protect themselves against the immune system, and a drug that blocks this “don’t eat me” signal is currently in clinical trials as an anti-cancer therapy.
“We found that brain progenitor cells with 16p11.2 deletion syndrome overexpressed CD47, leading us to believe that cells that should be eliminated during brain development are not,” Chetty said. They also found that cells with 16p11.2 deletion show increased cell surface levels of a protein called calreticulin, an “eat me” marker that signals the immune system that something is wrong with the cells and should be eliminated. “So we think these cells without the 16p11.2 locus are marked for elimination and would be pruned away if it weren’t for the increased presence of the CD47 “don’t eat me” signals that counteract that message,” Chetty said.
The researchers next tested that idea by growing the brain progenitor cells in the presence of macrophages, the immune cells that devour and destroy defective cells. They observed that the cells with 16p11.2 deletion syndrome were not only making more CD47, the cells were also much less likely to be eaten by macrophages than control cells, as they hypothesized.
“These results raised the possibility that the normal state of affairs could be restored if the CD47 “don’t eat me” signal was blocked,” Chetty said. “Luckily we have antibodies that can do this.” They performed the same experiments with the 16p11.2-deleted brain progenitor cells and macrophages, but this time also added an antibody that blocked the CD47 signal. “When we blocked the CD47 signal, it resulted in a more normal pattern of elimination of the 16p11.2-deleted cells,” she said.
Lastly, the researchers wondered if blocking the CD47 signal would also restore normal brain cell elimination outside of a laboratory dish. They implanted 16p11.2-deleted brain progenitor cells in young mice, and also administered cd47-blocking antibody to some of them. Chetty and her colleagues found that CD47-blocking antibodies did indeed result in increased elimination of the 16p11.2-deficient brain cells and a more normal pattern of brain growth.
“This raises the possibility that, at least for people with this particular syndrome, we might develop a way to intervene as the brain is developing so that proper pruning of brain cells takes place,” Chetty said.
Chetty and her colleagues note that improper pruning of the developing brain is also implicated in other psychiatric disorders like bipolar disorder, and it may be worth investigating whether CD47 or other immune regulating molecules are involved in those syndromes.
For Weissman, the research represents the fruits of scientific ideas he brought forth decades ago. “Nearly 20 years ago I suggested that the reprogramming of adult cells to bring them back to an embryonic-stage stem cells could be used to understand human genetic diseases,” Weissman said. “Specifically, this technique can be used to understand which variant genes lead to which kind of disease, and how variant genes cause the disease at a cellular and mechanistic level.” It was about ten years ago that Weissman and his colleagues discovered CD47, and intervening years they and others have documented how dangerous cells use it to protect themselves from the immune system, spawning a wide variety of diseases.
“Thanks to the brilliant work of Chetty and our collaborators, it is gratifying to me that this example provides evidence that combining these two scientific approaches can open the door to understanding diseases that cannot be studied in living humans,” Weissman said.