Turning brain immune cells into neurons

New research offers a tantalizing avenue for treating stroke by reprogramming microglia.

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While the adult mammalian brain retains little neurogenic capability, it would be ideal for regenerating lost neurons in the ischemia-wounded brain to repair the damage. There is little evidence of functional recovery following brain injury employing in vivo neuronal conversion technology, and it is unknown if induced neuronal cells directly aid in healing.

After stroke-like damage in rats, researchers at Kyushu University have found that turning brain immune cells into neurons effectively recovers brain function. Researchers have demonstrated the significant potential of directly converting macroglia/macrophages into neurons in the brain as a therapeutic approach for ischemic brain injury.

Microglia are the primary immune cells in the central nervous system. They remove damaged or dead cells in the brain, so after a stroke, they move toward the injury site and replicate quickly. Due to their abundance and exact placement, they are an ideal target for conversion.

Previously, scientists demonstrated that microglia can be induced to develop into neurons in the brains of healthy mice. In this study, scientists showed that replacing neurons works in injured brains and contributes to brain recovery.

To carry out the study, researchers momentarily blocked the right middle cerebral artery, a significant blood vessel in the brain frequently linked to stroke in people, to injure mice like a stroke. When the mice were analyzed a week later, the researchers discovered that in addition to having significant neuronal loss in the striatum, a part of the brain, the mice also exhibited problems with motor function. This brain area involves motor coordination, action planning, and decision-making.

Next, researchers inserted DNA into microglial cells at the injury site using a lentivirus. Instructions for making the protein NeuroD1, which triggers neuronal conversion, were encoded in the DNA. The areas of the brain lacking neurons diminished during the following weeks as the infected cells developed into neurons. The newly generated neurons had successfully merged into the brain’s circuits by eight weeks.

The mice demonstrated enhanced motor function in behavioral tests three weeks after infection. Vital proof that the newly converted neurons contributed to recovery is that these gains were reversed when the researchers deleted the newly generated neurons.

Kinichi Nakashima, from Kyushu University’s Graduate School of Medical Sciences Nakashima said“These results are auspicious. The next step is to test whether NeuroD1 is also effective at converting human microglia into neurons and confirm that our method of inserting genes into the microglial cells is safe.”

Additionally, the treatment was applied to mice after a stroke during the acute phase, when microglia were migrating to and multiplying at the injury site. Hence, researchers plan to see if recovery is also possible in mice at a later, chronic phase.

Journal Reference:

  1. Takashi Irie, Taito Matsuda, et al. Direct neuronal conversion of microglia/macrophages reinstates neurological function after stroke. PNAS, DOI: 10.1073/pnas.2307972120
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