One of the most difficult challenges in stem cell research is figuring out exactly what biological events cause stem cells to differentiate into specific, functioning cells in the body. For nerve cells this mystery may now be solved. For the first time, researchers have genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain.
Stroke, Alzheimer’s, Parkinson’s and Huntington’s disease destroy brain cells, causing speech and memory loss and other debilitating consequences. Transplanting neuronal brain cells could restore at least some brain function, just as heart transplants restore blood flow. But until now there has been no reliable method of coaxing stem cells to become nerve cells.
“We found that we could create new nerve cells from stem cells, transplant them effectively and make a positive difference in the behavior of the mice,” said Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Neuroscience, Aging, and Stem Cell Research Center at The Burnham Institute. “These findings could potentially lead to new treatments for stroke and neurodegenerative diseases such as Parkinson’s disease.”
Prior to this research, creating pure neuronal cells from ES cells had been problematic as the cells did not always differentiate into neurons. Sometimes they became glial cells, which lack many of the neurons’ desirable properties. Even when the neuronal cells were created successfully, they often died in the brain following transplant—a process called programmed cell death or apoptosis. In addition, the cells would sometimes become tumors.
Dr. Lipton solved these problems by inducing ES cells to express a protein discovered in his laboratory called myocyte enhancer factor 2C (MEF2C). MEF2C is a transcription factor that turns on specific genes which then drive stem cells to become nerve cells. Using MEF2C, the researchers created colonies of pure neuronal progenitor cells, a stage of development that occurs before becoming a nerve cell, with no tumors. These cells were then transplanted into the brain and later became adult nerve cells. MEF2C also protected the cells from apoptosis (programmed cell death) once inside the brain.
The next step was to determine whether the transplanted neural progenitor cells became nerve cells that integrated into the existing network of nerve cells in the brain. Dr. Lipton’s investigative team showed that the new nerve cells, derived from the stem cells, could send and receive proper electrical signals to the rest of the brain. They then determined if the new cells could provide cognitive benefits to the stroke-afflicted mice. The team executed a battery of neurobehavioral tests and found that the mice that received the transplants showed significant behavioral improvements, although their performance did not reach that of the non-stroke control mice. These results suggest that MEF2C expression in the transplanted cells was a significant factor in reducing the stroke-induced deficits.
Adapted from the Burnham Institute announcement.