Are these underappreciated cells, which may be found in the spleen, heart, and lungs, star players?
|Glial cells may take on significant roles in the body in unexpected places.
However, evidence has accumulated in recent decades indicating glia are more than just background characters who keep the show running. They are involved in many of the brain's most important functions, including remembering, learning, and thinking.
Glia's story now has a surprising new setting: beyond the brain, according to a recent study. Glia populations in the heart, spleen, lungs and other organs are mysterious. However, no one is sure how they'll fit into the story. Early indications suggest that the story will be gripping.
Already, tantalizing hints about what these cells are up to are pouring in. For example, glia appears to aid in the regulation of the heartbeat. Glia in the spleen is located between nerve cells and immunological cells, making them an ideal location to affect the link between health and stress. It's unclear what glia do in the lungs, but whatever it is, it appears to be vital, as early trials reveal - mice without lung glia perish.
"The discovery of these new glial cell types in unique organs should hopefully set off a lot of lightbulbs," says Sarah Ackerman, a neurobiologist at Washington University in St. Louis. Ackerman, like most glia researchers, focuses on glia inside the brain.
The handful of new studies that look at far-flung glia has a lot of promise for her. "It's going to be a revelation that specialized glia exist in all of these organs, supporting not only the function of the neurons but also the overall health of the organ."
Some scientists believe that a better understanding of the roles of glia outside the brain could lead to better treatments for heart disease, immune system difficulties, and potentially lung cancer.
Tawaun Lucas, a neuroimmunologist at Genentech in San Francisco, says, "If we continue to disregard these cells, it will only slow us down." He just discovered new information regarding glia in the spleens of mice.
A family affair
Several forms of glia in the brain keep things going smoothly. Microglia are immunological cells that help prune nerve cell connections, patrol for pathogens, and more. Oligodendrocytes cover nerve fibers in myelin, which acts as insulation and speeds up communication. Astrocytes impact nerve cell growth, regulate blood flow and guide nerve cell growth.
It's too early to say how crucial glia outside the brain will prove to be. Perhaps these glia studies are the start of a new field of study. Perhaps the secret will never be solved. "It remains to be seen what connection it will have to the traditional world of glia as we know it," says Bruce Ransom, a neurologist and neuroscientist at the City University of Hong Kong and editor in chief of the scholarly journal Glia.
Nonetheless, the possible plotlines of these newly characterized glia groupings are intriguing. "We're always on the lookout for that tiny aperture where you can widen and see something extremely essential," Ransom adds. "That's a possibility in this situation."
The immune system meets the nervous system
It's too early to tell how important glia outside of the brain will be. Maybe these glia studies are the beginning of a new field of research. It's possible that the mystery will never be solved. "What link it will have to the traditional world of glia as we know it remains to be seen," says Bruce Ransom, a neurologist and neuroscientist at the City University of Hong Kong and editor in chief of the scientific journal Glia.
The potential plotlines of these newly identified glia clusters, however, are intriguing. "We're always looking for that tiny hole where you can enlarge and see something incredibly important," adds Ransom. "In this case, that's a possibility."
Outside of the brain, scientists have a decent understanding of the functions of various glia. For example, enteric glia helps the gut digest food, while Schwann cells, which are sisters to the brain's oligodendrocytes, distribute myelin on peripheral nerves to assist in speeding up communications. According to a study published in Science in 2019, specific Schwann cells in the skin trigger painful feelings.
Glia in other organs, such as the spleen glia that fascinate Lucas, is less well understood. The cells sometimes share similarities with various types of glia, making naming this glia difficult. For the time being, these outsider glia are classified as either non myelinating Schwann cells or satellite glia.
Lucas began his career as a brain researcher at Stanford University. Then a mouse under a microscope drew his focus away from him. The glia of the mouse was genetically modified to glow green. Lucas noticed green cells throughout the body, including in the spleen, lymph nodes, kidney, liver, and lungs.
The spleen glia rapidly fascinated his Stanford mentor, neurologist Marion Buckwalter. "When I first started reading about the spleen, I thought to myself, 'This is incredibly fascinating,'" she said. Immune cells abound in the spleen.
The spleen, like many other organs, has nerves that are part of the body's sympathetic nervous system. This control system has the ability to dilate pupils, increase heart rates, and cause the body to sweat. The sympathetic nervous system, often known as the "fight-or-flight system," kicks up when you're kicked in the head, chased by a tiger, or have stressful things going on at work, according to Lucas.
In the spleen, the sympathetic nervous system and the immune system merge, and glia may play a key role in this link. Experiments on mice revealed large, sophisticated glia alongside message-sending nerve cell axons in the spleen. Buckwalter adds that immune cells are "just microns away." The glia in the spleen is optimally positioned to interact between the neurological system and the immune system, according to researchers who published their findings in Glia in 2021.
Lucas and colleagues discovered that the spleen's glia has the cellular equipment to speak the language of both immune cells and nerve cells by looking at the genetic instructions inside the glia found in the spleen.
They can sense chemical signals made by immune cells and chemical signals sent by nerve cells. It's unclear how these cells use this machinery, but the findings suggest that spleen glia are crucial communicators. No one knew anything about the glia's behavior until Lucas' experiments, according to Buckwalter.
Buckwalter believes that the prospect of communication between glia, nerve cells, and immune cells in the spleen has "enormous ramifications." The immune system can be harmed by stress and brain traumas such as strokes.
The sympathetic nervous system, for example, causes the death of immune cells termed B lymphocytes in the spleen after a stroke, which can lead to serious infections. Immune cells are also involved in autoimmune diseases like multiple sclerosis and rheumatoid arthritis, which can flare up in stressed persons. If glia has an effect on immune cells, their activity could be changed to prevent flare-ups.
So yet, the research has only been preliminary. It's still unclear if these spleen glia is actually transmitting messages between the neurological and immune systems, and if so, what the outcomes are. Buckwalter believes it's too early to say whether glia in people's spleens has a role in autoimmune illnesses. However, the concept has sparked her interest.
She describes studying these mystery cells in organs as a "new kind of science." It's more difficult than looking for a lost puzzle piece. "It's like we just got a puzzle with no labels on the pieces and no picture on the box."
The throbbing heart
In the heart, there is a comparable problem.
Cody Smith, a neural biology student at the University of Notre Dame in Indiana, knew the heart was densely packed with nerve cells. Glia is known to be present in most nerve cells, and Smith was keen to identify the heart's glia. Smith went looking for them with graduate student Nina Kikel-Coury. He explains, "We had no idea what to expect."
A colony of glia has been discovered in the hearts of zebrafish. These cells, known as cardiac nexus glia, arise early in zebrafish development and spread out to form a gossamer-thin web around the heart, Smith, and Kikel-Coury reported in PLOS Biology last year.
This glia plays a vital role in the formation of the heart and the regulation of heartbeat in zebrafish. The heart rates of the fish increased when the researchers interfered with the cells. Smith describes the effect as "strange." Cardiac rates usually slow when heart cells are disrupted.
The researchers discovered cells with similar collections of active genes to the heart glia in the zebrafish by looking at other datasets that list the genes active in mouse and human heart cells. This glia may be found in the hearts of numerous species, based on their shared DNA. According to Smith, the statistics "support the assumption that they're in humans."
Defects in the outflow tract of the heart, where blood exits to an artery, are found in some congenital cardiac problems. This is also where this glia first arises in the early stages of zebrafish development. According to Smith, this glia could be involved in human heart problems. "We're still in the early stages of this project," he warns. "I wish we had more information."
The mystery deepens.
Glia's research on the spleen and brain is just the beginning. Glia may be used by organs all over the body, according to recent research. Glia have been detected in the lungs of mice by Buckwalter and Gabriela Suarez-Mier, a Ph.D. student at the time the experiment was completed.
According to Lucas, lung glia may be involved in breathing and oxygen exchange in capillaries, but more information is needed. Lucas' preliminary investigations imply that certain glia is crucial: "All of the animals die" when researchers employ poison to kill the glia in the lungs.
Lucas' current research focuses on the role of glia in cancer. Nerves attach to tumors in the lungs (as well as the liver and pancreas), and glia wrap themselves around those nerves, according to Lucas. Other researchers have discovered that Schwann cells will develop into cancer cells in a lab dish. According to Lucas, the behavior of glia that persists near a tumor is now an essential subject.
Getting some fresh air
Glia (green) wrap around thick nerve bundles (a) running down the lung and meshlike nerves that surround large and tiny bronchi in a mouse lung (b and c). Glia also wraps around the nerves of blood vessels (d) and tiny airways (e). This diverse morphology suggests that lung glia may assist with oxygen exchange in a variety of ways.
Understanding the glia in the body and maybe mobilizing them to combat the disease will take more than a cursory glance. Glia throughout the body will be better-understood thanks to techniques that demonstrate how individual cells use different sets of genes.
Other genetic labeling techniques can be used to track these perplexing glia in living animals. "The technologies will allow us to get from 'OK, they're there,' to 'What are they doing?'" says Ackerman, a Washington University neurobiologist.
Glia scientists looking beyond the brain are still in the early stages of their research. "What cells are present, and how do they interact?" Lucas inquires. "We're starting from the beginning."
Because they are located outside of the brain, this glia is a suitable candidate for therapy, according to Ackerman. Because of its protective blood-brain barrier, medicines have a difficult time reaching the brain. Brain cells are also less capable of self-repair than peripheral nervous system cells. "We may be able to effect beneficial change in a more effective manner than trying to direct repair in the brain or spinal cord," she says.
It's too early to tell if glia outside the brain is part of the same tale as glia inside the brain. According to Ransom of the City University of Hong Kong, "the multiplicity of glia existing outside the brain may all wind up being isolated fragments of disparate biology, never merging into a narrative that is significant for the overall nervous system." "I think it's exciting and engaging work," he says, "and I believe it's perfectly justified to explore it extensively." For the time being, we have no idea where glia's story will lead us.
N.L. Kikel-Coury et al. Identification of astroglia-like cardiac nexus glia that are critical regulators of cardiac development and function. PLoS Biology. Vol. 19. Published November 18, 2021. DOI: 1371/journal.bio.3001444.
T. Lucas, L. Zhu and M. S. Buckwalter. Spleen glia is a transcriptionally unique glial subtype interposed between immune cells and sympathetic axons. Glia. March 12, 2021. DOI: 10.1002/glia.23993.
G. B. Suarez-Mier and M. S. Buckwalter. Glial Fibrillary Acidic Protein-expressing glia in the mouse lung. ASN Neuro. October 6, 2015. DOI: 10.1177/1759091415601636.
H. Abdo et al. Specialized cutaneous Schwann cells initiate pain sensation. Science. Vol. 365, August 16, 2019, p. 695. DOI: 10.1126/science.aax6452.