Turning Back the Clock to Regenerate Nerves

Treating spinal cord injury and vision loss by restoring cells’ regenerative ability

 

Neurons can regenerate while the body develops, but rapidly lose that capability after birth. To tackle conditions where neurons are damaged, such as spinal cord injury and vision loss, Harvard Stem Cell Institute Principal Faculty member Zhigang He, Ph.D., B.M., is turning back the clock and helping neurons to regain their youthful regenerative state.

Healing spinal cord injuries without scars

 
In adult mammals, axons — the long projections of neurons that transmit signals — do not regrow after spinal cord injury. Moreover, many types of harmful cells accumulate around the injury site, further interfering with the axons’ ability to reconnect. To find a solution, HSCI researchers studied spinal cord injury and repair responses in two-day-old mice.
 
“Unexpectedly, we found that the injury in these young pups lead to scar-free healing that permitted the growth of axons through the site of the lesion,” said He.
 
The researchers identified that microglial cells, a type of immune cell found in the brain and spinal cord, play an essential protective role in scar-free wound repair. First, they help re-form bridges between the severed axon ends. Second, microglia from newborn mice — but not adult mice — produce molecules that interfere with the action of certain harmful proteins.
 
“These protein inhibitors are involved in quickly tamping down the inflammatory response after spinal cord injury,” said He. “The microglia essentially orchestrated swift removal of harmful cell debris after injury and stopped inflammation.”
Microscopy image of mouse spinal cord.
A spinal cord injury is repaired in the newborn mouse with the help of a specialized cell type, the microglia. Credit: He Lab
 
The researchers next tested whether axons could be regenerated in adult mice with spinal cord injuries. They found that transplanting microglia from newborn mice into adult mice with spinal cord lesions significantly improved healing and axon growth. They also saw similar results when transplanting adult microglia that were pre-treated with the helpful protein inhibitors.
 
The researchers are now testing several types of protein inhibitors to see which may be most effective in boosting the scar-free healing potential of microglial cells. Their discovery may also help advance treatments for neurodegenerative conditions such as Alzheimer’s disease, ALS, and Parkinson’s disease.
 
“One of the key players in these diseases is microglia,” said He. “Perhaps we can find a gene that might convert those chronically active microglia to treat neurodegeneration.”
 

Reversing aging in the eye

 
Vision loss occurs when the optic nerve is damaged, either due to injury or the aging process. HSCI researchers were part of a team that developed a gene therapy to reprogram neurons to an earlier age and restore vision. 
 
In addition to He, the project’s leaders were David Sinclair of Harvard Medical School, HSCI Affiliate Faculty member Bruce Ksander, and Meredith Gregory-Ksander of the Schepens Eye Research Institute.
 
The researchers’ approach focused on the epigenome, the collection of chemical modifications to DNA that control which genes are turned on and off. The pattern of epigenomic markers changes as cells age, so the researchers designed a therapy to deliver three genes that restore the youthful pattern from embryonic development.
 
The researchers first tested the gene therapy in adult mice with optic nerve injury, and the treatment led to improved cell survival and nerve regrowth. Next, the team tested the therapy in a mouse model of glaucoma, a condition that is associated with aging and a leading cause of blindness. The treatment led to increased neuron electrical activity and a notable increase in visual acuity, as measured by the animals’ ability to see moving vertical lines on a screen. Remarkably, this improvement happened after the glaucoma-induced vision loss had already occurred.
Microscopy image of nerves.
When aged mice were given the gene therapy, optic nerve axons regenerated after injury. Credit: Yuancheng Lu
 
The treatment worked similarly well in elderly, 12-month-old mice with diminishing vision due to normal aging. Following treatment of the elderly mice, the gene expression patterns and electrical signals of the optic nerve cells were similar to young mice, and vision was restored.
 
“Regaining visual function after the injury occurred has rarely been demonstrated by scientists,” Ksander said. “This new approach, which successfully reverses multiple causes of vision loss in mice without the need for a retinal transplant, represents a new treatment modality in regenerative medicine.”