(2023/10/17)

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Converting brain immune cells into neurons helps mice recover after stroke goals
New research offers a tantalizing avenue for treating stroke by reprogramming microglia, themain immune cells in the brain, to replace damaged neurons.
Fukuoka, Japan – Researchers at Kyushu University have discovered that turning brainimmune cells into neurons successfully restores brain function after stroke-like injury in mice.
These findings, published on October 10 in PNAS, suggest that replenishing neurons fromimmune cells could be a promising avenue for treating stroke in humans.
Stroke, and other cerebrovascular diseases, occur when blood flow to the brain is affected,
causing damage to neurons. Recovery is often poor, with patients suffering from severe
physical disabilities and cognitive problems. Worldwide, it’s one of the most common causes
for needing long-term care.
“When we get a cut or break a bone, our skin and bone cells can replicate to heal our body.
But the neurons in our brain cannot easily regenerate, so the damage is often permanent,”
says Professor Kinichi Nakashima, from Kyushu University’s Graduate School of MedicalSciences. “We therefore need to find new ways to replace lost neurons.”
One possible strategy is to convert other cells in the brain into neurons. Here, the researchers
focused on microglia, the main immune cells in the central nervous system. Microglia aretasked with removing damaged or dead cells in the brain, so after a stroke, they movetowards the site of injury and replicate quickly.
“Microglia are abundant and exactly in the place we need them, so they are an ideal target
for conversion,” says first author, Dr. Takashi Irie from Kyushu University Hospital.
In prior research, the team demonstrated that they could induce microglia to develop into
neurons in the brains of healthy mice. Now, Dr. Irie and Professor Nakashima, along with
Lecturer Taito Matsuda and Professor Noriko Isobe from Kyushu University Graduate Schoolof Medical Sciences, showed that this strategy of replacing neurons also works in injured
brains and contributes to brain recovery.
To conduct the study, the researchers caused a stroke-like injury in mice by temporarily
blocking the right middle cerebral artery – a major blood vessel in the brain that is commonly
associated with stroke in humans. A week later, the researchers examined the mice andfound that they had difficulties in motor function and had a marked loss of neurons in a brain
region known as the striatum. This part of the brain is involved in decision making, action
planning and motor coordination.
The researchers then used a lentivirus to insert DNA into microglial cells at the site of theinjury. The DNA held instructions for producing NeuroD1, a protein that induces neuronalconversion. Over the subsequent weeks, the infected cells began developing into neurons
and the areas of the brain with neuron loss decreased. By eight weeks, the new induced

neurons had successfully integrated into the brain’s circuits.
At only three weeks post-infection, the mice showed improved motor function in behavioraltests. These improvements were lost when the researchers removed the new inducedneurons, providing strong evidence that the newly converted neurons directly contributed torecovery.
“These results are very promising. The next step is to test whether NeuroD1 is also effectiveat converting human microglia into neurons and confirm that our method of inserting genes
into the microglial cells is safe,” says Professor Nakashima.
Furthermore, the treatment was conducted in mice in the acute phase after stroke, whenmicroglia were migrating to and replicating at the site of injury. Therefore, the researchers
also plan to see if recovery is also possible in mice at a later, chronic phase.

###For more information about this research, see "Direct neuronal conversion ofmicroglia/macrophages reinstates neurological function after stroke" Takashi Irie,
Taito Matsuda, Yoshinori Hayashi, Kanae Matsuda-Ito, Akihide Kamiya, Takahiro Masuda,
Marco Prinz, Noriko Isobe, Jun-ichi Kira, and Kinichi Nakashima, PNAS,
https://www.pnas.org/doi/10.1073/pnas.2307972120

Fig. 1. Production of NeuroD1 in microglial cells induces
their development into neurons, therefore decreasing thearea of the brain with neuron loss. In scans of the micebrains, neurons are stained in red, while the dark patches
represent areas with neuron loss.

Fig. 2. After stroke-like injury, the conversion of
microglia into induced neurons restored motor
function in mice.

[Contact]
Kinichi Nakashima, Professor
Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences.
Tel: +81-92-642-6195
E-mail: nakashima.kinichi.718@m.kyushu-u.ac.jp