NFIA Protein Essential to Astrocytes, Brain Cells Active in Spinal Cord Repair and Remyelination, Study Suggests

A protein known as nuclear factor I-A (NFIA) is key for spinal cord repair and timely remyelination by astrocytes — the most abundant cells in the brain and first responders to sites of injury, findings in a mouse model of multiple sclerosis (MS) suggest.

In brain lesions, NFIA is also essential to generating reactive astrocytes, the state these cells assume when responding either to acute injury or to neurodegeneration due to chronic disease. But whether their role in disease is beneficial or harmful is still not clear.

Partly, that’s because scientists don’t yet understand how astrocytes are regulated by factors specific to a given disease, like MS. Data simply is scarce.

The study, “Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury,” was published in The Journal of Clinical Investigation.

A team with Baylor College of Medicine focused on NFIA, a transcription factor — tiny proteins involved in gene expression — with a key role in astrocyte development, and implicated in neurological diseases such as glioma and white matter injury (WMI). NFIA has also been found in precursors of oligodendrocytes, the cells that form myelin — the protective coating of nerve fibers, whose degeneration is a MS hallmark.

Using human brain tissue, the researchers found high levels of NFIA in reactive astrocytes in MS and neonatal ischemic stroke lesions.

In mice with WMI — an MS model — and ischemic stroke, the scientists also saw that NFIA had specific roles depending on the type of injury.

When they eliminated NFIA in mice astrocytes, they observed that, in the spinal cord, reactive astrocytes were generated and migrated toward the injury, but did not repair the damaged blood-brain barrier — a barrier shielding the brain from peripheral blood circulation. This repair failure was also associated with delayed remyelination.

Likewise, mice with ischemic stroke in the cerebral cortex — the outer layer of the brain — were unable to repair the injury if lacking NFIA. In contrast to animals with this protein, reactive astrocytes were not generated from the subventricular zone (SVZ), a small stem-cell niche and a source of reactive astrocytes.

In both cases, in the spinal cord and in the cerebral cortex, the injury was not properly repaired, but the underlying reasons were different.

“The results were surprising,” Benjamin Deneen, PhD, the study’s senior author and a professor of neurosurgery, said in a Baylor news release written by Ana María Rodríguez, PhD.  “Until now, it was thought that, regardless of the type of injury or where it occurred in the central nervous system, reactive astrocytes would respond in the same way.”

“These findings suggest that NFIA’s function in reactive astrocytes is dependent upon the type of injury and brain region in which the injury occurs. In the cerebral cortex, NFIA is crucial for making reactive astrocytes, while in the spinal cord NFIA is important for sealing off leaking blood vessels. These results hint at an extensive reservoir of reactive astrocyte responses that vary according to form and location of injury,” Deneen added.

Results also showed no thrombospondin 4 (THBS4), key for the generation of reactive astrocytes, in the SVZ and other brain regions of mice lacking NFIA. In vitro (lab dish) experiments revealed the binding site of NFIA in the THBS4 gene, indicating the key role of NFIA in THBS4 production. Analysis in human samples further supported this link, as both proteins were produced by the same cells.

“Together, these studies uncover critical roles for NFIA in reactive astrocytes, and illustrate how region- and injury-specific factors dictate the spectrum of reactive astrocyte responses,” the investigators wrote.

“Although our study was conducted in mice and more research is needed, we think our findings may reflect what occurs in people, as NFIA also is abundantly present in reactive astrocytes in both pediatric and adult neurological injuries,” Deneen said.

The research team, Deneen added, is also interested in studying NFIA’s role in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. “It’s possible it has a completely different set of functions in these conditions,” the researcher said.