The human brain is terrible at healing itself from injury or disease. But some animals can harness their own cellular abilities to not only repair injuries but also to regrow their brains entirely. Researchers from the University of Georgia have now pinpointed several of the genes that make brain regeneration possible in planarians, a type of flatworm that exhibits what the team describes in their newly published report in Nature Communications, as “extraordinary capacity for brain regeneration.”
Both flatworm and human brains are made up of networks of neurons that communicate with each other by sending electrical or chemical signals. Some neurons react to stimuli, such as light or touch, while others control movement. Flatworms can use stem cells to replace neurons after injury. But while humans also have stem cells, they are unable to transform into new neurons effectively enough to heal injury.
The new study sheds light on how shared genes work in flatworms and lays the groundwork for researchers to investigate similar pathways that might be activated in humans to design better therapies for traumatic brain injuries or diseases.
Rachel Roberts-Galbraith, PhD, associate professor in UGA’s Franklin College of Arts and Sciences, said, “Big picture: We would like to come up with ideas for how to better empower the human brain to regenerate itself. The understanding of brain regeneration that we can develop using simple animals gives us a reason to be optimistic. It’s not an inherent property of brains that makes them bad at regeneration. It’s something specific to humans.”
Roberts-Galbraith is senior and corresponding author, and Kendall Clay, PhD, and Taylor Medlock-Lanier, PhD, are co-first authors of the team’s study, titled “Combinatorial mechanisms specify cellular location and neurotransmitter identity during planarian neurogenesis.” In their paper the team concluded “Our work suggests that combinatorial instruction of cell type and spatial identity could improve exogenous stem cell therapies aimed at precisely replacing neurons after localized injuries.”
Planarians can be found in freshwater, salt water, and even on land. They don’t have circulatory or respiratory systems. But they do have stem cells that can differentiate into whatever their body needs at a given time. Using stem cells, planarians can regrow their entire body from just a sliver of a body fragment. They can rebuild tissues, muscles, and even their brain. Planarian flatworms are known for their regenerative abilities, including de novo brain regrowth after nearly any injury,” the authors wrote. “Critically, neurons are produced in the correct numbers, diversity, pattern, and connectivity to restore function … In addition to regenerative capacity, the planarian nervous system has spatial and cell type complexity, making it suitable for study.”
But how do these tiny creatures know what type of cell to make and where to send it? “… the full pathway from pluripotent stem cell to mature neuron has not been determined for any cell type in the planarian nervous system,” the authors stated. “To better understand how regenerative neurogenesis proceeds in planarians, we focused on a single, conserved cell type: dopaminergic neurons.”
Known as the “feel good” chemical, dopamine is more than just the brain’s reward and pleasure chemical. It also acts as a signal to help neurons communicate with one another and plays a key role in controlling movement. People with Parkinson’s disease, for example, experience tremors and stiffness due to low levels of dopamine.
Through their study the researchers identified almost a dozen genes responsible for instructing stem cells to turn into dopamine-producing neurons and directing those new neurons to the right locations in the worm’s body. “Altogether, we identified ten genes and characterized six genes critical for specifying mature dopaminergic neurons throughout the planarian nervous system, identifying factors that regulate both neurotransmitter identity and cellular location,” they wrote. “Our results demonstrate that planarian neurogenesis requires coordination of factors that initiate neurotransmitter choice and regional location.”
When the researchers knocked out some of the genes discovered in this study, they found the planarians struggled to make new dopamine-producing neurons and also experienced slow movement, similar to the effects of low dopamine in people and other mammals.
Currently, healthcare providers don’t have many options to treat conditions like Parkinson’s, Alzheimer’s or traumatic brain injuries. Harnessing the body’s own cells in the same way planarians do to heal wounds would be a game changer. “The ability to create new neurons in predictable types, numbers, and locations for a given injury or disease would revolutionize treatments of neurodegenerative diseases and other brain injuries,” the researchers noted in their paper. “Our work aims to leverage highly regenerative animals to understand principles of successful neuron replacement.”
Roberts-Galbraith added, “We figured out the genetic recipe for making these cell types in planarians. We’re hoping this work helps others figure out how to create dopamine-producing neurons from stem cells that can be more effectively transplanted into patients.”
The Roberts-Galbraith lab in the department of cellular biology is part of UGA’s Regenerative Bioscience Center, an interdisciplinary research hub focused on the potential of regenerative medicine.
