Brain injury triggers unexpected hormone release in progenitor cells

Following a brain injury, specific progenitor cells produce a neuropeptide to prevent their neighboring cells from maturing too quickly, a process that aids in tissue repair. This regulatory mechanism also guides myelin formation in the developing and adult brain under healthy conditions. The findings were published in the journal Cell Reports.

The central nervous system relies on myelin, an insulating layer that forms around nerves. This protective sheath allows electrical impulses to transmit quickly and efficiently along nerve networks. Oligodendrocytes are the specialized cells responsible for producing this vital myelin.

When the brain is injured or developing, it needs to generate new oligodendrocytes. These mature cells arise from oligodendrocyte progenitor cells, which migrate to where they are needed and transform into their final, myelin-producing state. This maturation process requires strict regulation to ensure the cells survive and function properly.

Neuropeptides are small protein-like molecules that brain cells use to communicate. Unlike classical neurotransmitters that cross tiny gaps between two specific cells, neuropeptides are released in large amounts and wash over a broader area. This localized broadcasting process is known as volume transmission.

Corticotropin-releasing hormone is one of the most heavily studied neuropeptides in biology. It is primarily known for coordinating the body’s response to stress by interacting with its main cellular receptor, CRHR1. Researchers Clemens Ries, Jan M. Deussing, and their colleagues at the Max Planck Institute of Psychiatry sought to understand how this hormone might act outside of traditional stress pathways.

The research team used genetically modified mice that produce a fluorescent red marker whenever a cell expresses the corticotropin-releasing hormone. In a small study involving brain injuries like tiny stab wounds, the researchers tracked the cellular response. They observed that cells producing the hormone aggregated around the injury sites, with the first such cells detectable as early as twelve hours after injury.

By applying specific chemical stains to the brain tissue, they identified these glowing cells. The cells were not neurons, as one might normally expect for this specific hormone, but rather oligodendrocyte progenitor cells. This marked an early and unusual secretory response by these progenitor cells to physical brain trauma.

To understand the ultimate fate of these specific progenitor cells, the researchers tracked them for over four months. They found that these cells multiplied heavily in the days immediately following the initial injury. Over the following weeks, they reliably transformed into mature oligodendrocytes.

These newly formed oligodendrocytes successfully integrated into the healing brain tissue. They extended their physical processes to form myelin sheaths around local nerve fibers. Once established, the cells survived for the entire duration of the four-month observation period.

Because neuropeptides operate by binding to specific receptors, the team searched for cells in the injury area equipped with the CRHR1 receptor. Using a different strain of genetically modified mice, they highlighted the receptor’s exact location. They discovered a completely separate group of oligodendrocyte progenitor cells expressing this receptor.

This finding established a potential communication network in the damaged tissue. One group of progenitor cells was releasing the hormone in response to injury, while a distinct neighboring group was equipped to receive that signal. The researchers then designed experiments to see what information the signal carried.

The researchers tested what happens when this communication is disrupted. They bred mice lacking the ability to produce the hormone in progenitor cells, as well as mice completely lacking the CRHR1 receptor. After inducing brain injuries, they compared these altered mice to regular mice.

In the altered mice, the progenitor cells equipped with the receptor matured into myelin-producing cells much faster than normal. Under typical conditions, the hormone acts as a brake, forcing the cells to delay their maturation. Removing the signal removed the brake.

While maturing faster might sound beneficial for wound healing, it proved detrimental in cases of larger brain injuries. The rapid maturation led to a noticeable drop in the number of oligodendrocytes that survived long-term. The researchers suspect that the injured environment contains high levels of oxidative stress.

The hormone-induced delay likely helps the cells wait for these harsh conditions to subside before completing their vulnerable final transformation. Moving beyond injury models, the team investigated whether this signaling network operates in healthy, uninjured brains. They counted the receptor-equipped progenitor cells in mice at various ages.

The team noted that these specific progenitor cells naturally increase in number as the mice grow into adulthood. To test the network’s role in healthy development, they examined postnatal mice lacking the CRHR1 receptor. In these young mice, oligodendrocytes formed earlier than usual in the brain’s white matter.

This confirmed that the hormone system also prevents premature cellular maturation during normal brain development. The researchers then evaluated how this early developmental shift affected the adult brain’s physical structure. They analyzed the brains of adult mice lacking the receptor using magnetic resonance imaging.

The researchers utilized a specialized imaging technique that detects the density of myelin by measuring how protons interact with surrounding macromolecules. The imaging revealed that mice lacking the receptor possessed a higher overall myelin content across multiple brain regions, including the corpus callosum. To see the microscopic details, the team employed electron microscopy.

Using the electron microscope, they measured the mathematical relationship between the radius of the inner nerve axon and the radius of the entire myelinated fiber. A lower ratio indicates a thicker myelin sheath relative to the nerve size. The microscopic analysis showed a structural shift in how myelin was distributed across the nerve fibers.

Smaller nerve fibers received thicker myelin sheaths than usual. In contrast, the myelin sheaths on larger nerve fibers were unusually thin. This suggests the hormone network helps ensure myelin is distributed in the correct proportions based on nerve fiber size.

Readers should exercise caution when interpreting these results in the context of psychological stress. While corticotropin-releasing hormone is heavily involved in emotional stress responses, this study focuses strictly on localized tissue signaling after physical trauma or during baseline cellular development. The results do not imply that psychological stress directly alters myelin through this specific pathway.

The study features limitations regarding the genetic models used in the experiments. The primary mouse model lacking the receptor had it deleted globally, meaning the receptor was missing in neurons as well as progenitor cells. This systemic absence could indirectly influence the behavior of the brain’s glial cells.

Future investigations will need to use genetic models that delete the receptor exclusively in oligodendrocyte progenitor cells. Additional studies could also explore how this hormone network responds to diseases that actively destroy myelin.

The study, “Neuropeptide CRH prevents premature differentiation of OPCs following CNS injury and in early postnatal development,” was authored by Clemens Ries, Tibor Stark, Benoit Boulat, Torben Ruhwedel, Jan Philipp Delling, Antonio Miralles Infante, Julia T. von Poblotzki, Alessandro Ulivi, Iven-Alex von Mücke-Heim, Simon Chang, Kenji Sakimura, Keiichi Itoi, Dennis B. Nestvogel, Alessio Attardo, Michael Czisch, Klaus-Armin Nave, Wiebke Möbius, Leda Dimou, and Jan M. Deussing.