University of San Diego neuroscientists have used an animal model of spinal cord injury to test the ability of engrafted stem cells to regenerate damaged nerves. Mark Tuszynski and his team built on earlier work with implanted neural stem cells and embryonic stem cell-derived neural stem cells in rodents that had suffered spinal cord injuries.
In this study, Tuszynski and others used induced pluripotent stem cells that were made from a 86-year-old male. This shows that skin cells, even from human patients who are rather elderly, have the ability to be reprogrammed into embryonic stem cell-like cells. These cells were differentiated into neural stem cells and then implanted into the spinal cords of spinal cord-injured rodents.
The injured spinal cord is a very hostile place for implanted cells. Inflammation in the spinal cord summons white blood cells to devour cell debris. White blood cells are rather messy eaters and they release enzymes and toxic molecules that can kill off nearby cells. Also, regenerating cells run into a barrier made by support cells called glial cells that inhibit regenerating neurons from regenerating. Thus, the injured spinal cord is quite the toxic waste dump.
To get over this, Tuszynski and his coworkers treated their induced pluripotent stem cell-derived neural stem cells with growth factors. In fact, when the cells were implanted into the animal spinal cords, they were embedded in a matrix that contained growth factors. After three months, Tuszynski and his colleagues observed extensive axonal growth projecting from grafted neurons that reached long distances in both directions along the spinal cord from the brain to the tail end of the spinal cord. These sprouted axons appeared to make connections with the existing rat neurons. Importantly, these axons extended from the site of the injury, which is astounding given that the injured area of the spinal cord has characteristics that are inimical to neuronal and axon growth.
Even though Tuszynski and others showed that neural stem cells made from embryonic stem cells can populate the damaged spinal cord, using induced pluripotent stem cell-derived neural stem cells has an inherent advantage since these cells are less likely to be rejected by the patient’s immune system. Furthermore, the induced pluripotent stem cell-derived neural stem cells showed dramatic growth in the damaged spinal cord, but the implanted animals did not regain the use of their forelimbs. The implanted human cells were fairly young when the implanted animals were tested. Therefore, they might need to mature before they could restore function to the implanted animals.
“There are several important considerations that future studies will address,” Tuszynski said. “These include whether the extensive number of human axons make correct or incorrect connections; whether the new connections contain the appropriate chemical neurotransmitters to form functional connections; whether connections once formed are permanent or transient; and exactly how long it takes human cells to become mature. These considerations will determine how viable a candidate these cells might before use in humans.”
Tuszynski and his group hope to identify the most promising neural stem cell type for repairing spinal cord injuries. Tuszynski emphasized their commitment to a careful, methodical approach:
“Ultimately, we can only translate our animal studies into reliable human treatments by testing different neural stem cell types, carefully analyzing the results, and improving the procedure. We are encouraged, but we continue to work hard to rationally to identify the optimal cell type and procedural methods that can be safely and effectively used for human clinical trials.”