Scar Blocking Nerve Regeneration Converted into Neurons... Paralyzed Mice Regain Hind Limb Movement [Reading Science]

IBS and Yonsei University Directly Convert Reactive Astrocytes into Motor Neurons with 87% Efficiency

Reconstructing Neural Circuits by Utilizing Injured Site Cells Without Stem Cell Transplantation

A technology has been developed that utilizes a 'scar'—previously regarded as an obstacle to nerve regeneration after spinal cord injury—as material to generate new neurons. The research team succeeded in directly converting astrocytes at the injury site into motor neurons, reestablishing neural circuits, and restoring hind limb motor function in paralyzed mice with spinal cord injuries.

On September 16, the Institute for Basic Science (IBS) announced that the research team led by Chang Joong Lee, Director of the Cognitive & Glia Science Group at the Center for Cognition and Sociality, and the team of Professor Ha Yoon from Yonsei University College of Medicine, have jointly developed a selective gene expression technology called 'TRANsCre-DIONE'.

Schematic diagram of research outcomes. Provided by the research team.

When the spinal cord is injured, astrocytes—a star-shaped, non-neuronal cell that maintains the environment around nerve cells—change and proliferate, forming what is known as a 'glial scar' that surrounds the injury site. While this scar prevents the spread of damage to surrounding areas, it also acts as a barrier to neuronal regrowth and neural circuit repair.

Instead of removing this scar, the research team chose to convert 'reactive astrocytes' that comprise the scar into new neurons. Using TRANsCre-DIONE, the protein 'Neurogenin2 (Ng2)', which induces cells to become neurons, was selectively expressed in reactive astrocytes at the injury site.

As a result, astrocytes were directly converted into neurons with motor neuron characteristics, without passing through a stem cell stage. The newly formed cells generated electrical signals and established synapses with surrounding neurons, exhibiting the functional traits of actual neurons.

Conversion into GABAergic Neurons in the Brain, Motor Neurons in the Spinal Cord

Interestingly, even when the same Ng2 was used, the type of neuron generated differed depending on the surrounding environment. In the striatum of the mouse cerebrum, astrocytes were primarily converted into GABAergic neurons, which relay inhibitory signals, whereas in the spinal cord, they were converted into motor neurons. This implies that the microenvironment of surrounding tissue influences the type of neuron newly produced.

In the mouse striatum injury model, 62% of astrocytes were converted into neurons. The research team further confirmed that, in the crab-eating monkey striatum, they could target reactive astrocytes with a high precision rate of 93.13%, and achieve cell conversion as well.

Using 'TRANsCre-DIONE', reactive astrocytes at the injury site were directly converted into neurons and their functions were verified. After selectively targeting only reactive astrocytes and transforming them into neurons, immunostaining and electrophysiological analyses confirmed neuronal conversion, action potential generation, and connections with surrounding neurons. In the spinal cord, the number of cells converted into motor neurons increased, nerve fibers were interconnected, and tissue loss and cyst formation at the injury site decreased, demonstrating the potential for neural circuit reconstruction. Provided by the research team.

The most crucial findings come from the spinal cord injury mouse experiments. When TRANsCre-DIONE was applied, the conversion efficiency of reactive astrocytes into neurons reached 87%. The newly converted neurons reconstructed local neural circuits around the injury site, and the paralyzed hind limb motor function in mice was restored.

This technique leverages astrocytes already present at the injury site, with no need for transplantation of stem cells or other cell types from outside sources. Furthermore, it is designed so that gene expression is selectively activated only in astrocytes that have responded to injury, not in normal astrocytes. However, to apply this technology for human patients, further preclinical and clinical validation regarding long-term safety and therapeutic efficacy is necessary.

Professor Ha Yoon of Yonsei University stated, "TRANsCre-DIONE presents the possibility of fundamentally reconstructing neural circuits. We expect that, upon clinical application, this approach will shift the paradigm of spinal cord injury treatment from mere preservation of function to a focus on neural regeneration."

Lee Changjoon, research director at IBS, added, "This technology has potential applications not only for spinal cord injuries, but also for a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and stroke."

The findings were published online in the international journal 'Experimental & Molecular Medicine' on September 11.

This content was produced with the assistance of AI translation services.