Spinal Twine Organoids Assist Check Paralysis Remedy

Despite being the most common cause of permanent disability, there are few effective treatments for spinal cord injuries. A new organoid model now offers a platform to test regenerative therapies, potentially accelerating the development of new therapies.

Injuries in the central nervous system (CNS)—such as those in the spinal cord—trigger glial scar formation, which inhibits nerve regeneration from healthy neurons surrounding the damage. This results in impaired motor, sensory, or autonomic functions.

Despite such spinal cord injuries being the leading cause of death and permanent disability and affecting up to 500,000 people globally each year, effective therapies remain rare.¹

Now, scientists have generated organoids from human induced pluripotent stem cells (iPSCs) and found that these accurately capture the key features in spinal cord injuries.² The results, published in Nature Biomedical Engineering, indicate that human spinal cord organoids offer a promising in vitro platform to evaluate novel treatments for such fatal injuries.

“One of the most exciting aspects of organoids is that we can use them to test new therapies in human tissue,” said study coauthor Samuel Stupp, a researcher specializing in biomaterials at Northwestern University , in a statement. “Short of a clinical trial, it’s the only way you can achieve this objective.”

To generate spinal cord organoids, Stupp and his team differentiated iPSCs into spinal cord cell types using a cocktail of specific chemicals. The organoids grew and matured over the next 28 weeks. Immunohistochemical analyses and single-cell RNA sequencing revealed the presence of neurons, astrocytes, and other cell types typically found in the spinal cord.

Next, the researchers modeled spinal cord injury in these organoid models. They damaged the organoids either using a scalpel—to model injuries commonly introduced in vivo—or a blunt impactor—to mimic contusion injuries in people after suffering from compressive trauma. The damaged organoids exhibited key outcomes of spinal cord injury, including cell death and glial scarring.

Stupp and his team then used this model to test the effect of a liquid therapeutic peptide they had previously used to reverse paralysis in spinal cord injuries in mice.³ The liquid applied to the injury gelled into a scaffold that had intense supramolecular motion, a dynamic movement that allows targeted drug delivery by enabling the therapeutic molecules to engage with constantly moving cellular receptors. Treating mice with the therapeutic reduced glial scarring and promoted axonal regeneration, survival of motor neurons, and functional recovery.

Consistent with the in vivo observations, treating injured organoids with the bioactive scaffold reduced scar tissue formation after a month. Fluorescence microscopy and scanning electron microscopy revealed the growth of projections from healthy neurons surrounding the injured cells, signifying axonal extension.

To further improve upon their organoid model, Stupp and his team added microglia—CNS-resident immune cells—which mediate neuroinflammation that causes glial scarring. They then injured these cocultured organoids and observed effects consistent with spinal cord damage. Treating the organoids with the bioactive molecule improved axonal extension, diminished neuroinflammation, and reduced glial scarring.

“We were the first to introduce microglia into a human spinal cord organoid, so that was a huge accomplishment. It means that our organoid has all the chemicals that the resident immune system produces in response to an injury,” said Stupp. “That makes it a more realistic, accurate model of spinal cord injury.”

The authors hope that these models or their future versions will pave the way for testing therapies to treat CNS trauma, one of the most devastating injuries that people can endure.