When neurons that make a chemical called dopamine are slowly destroyed, nerve cells in that part of the brain cannot properly send the messages that would normally control muscle function. As the damage gets worse with time, a person experiences tremors and movement becomes difficult. This is Parkinson’s disease.
In short, Parkinson’s patients need more dopamine. Or, better yet, new neurons that produce dopamine on their own. In a paper published August 25 in the journal PLoS ONE, a team led by Dr. Stuart Lipton, director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, demonstrates how this therapeutic approach might be possible.
Here’s how it works. First, the team converted human embryonic stem cells to neural progenitor cells (precursors to brain cells). Then they applied a specific transcription factor protein called myocyte enhancer factor 2C (MEF2C for short) to coax the progenitor cells into becoming dopamine-producing neurons. Not only did MEF2C drive the generation of new neurons, but it also protected the new cells from dying prematurely and prevented the cells from proliferating into tumors.
Dr. Lipton’s group first discovered MEF2C in the 1990s. More recently, they showed that it regulates neural progenitor cell differentiation and maturation into neurons during embryonic development. The team has also found that mice engineered to lack MEF2C show signs of autism.
In this new study, the addition of a chronically active form of MEF2C forced neural progenitor cells to become neurons—neurons that produced dopamine. Buoyed by this finding in the lab, the researchers took their creation to a rat model of Parkinson’s disease.
In their attempts to use stem cells to replace diseased or damaged tissue in animal models, scientists often run into one of two hurdles: either the transplanted cells don’t survive to proliferate or they proliferate too much, leading to tumors. Even if the cells do survive, they don’t always migrate to the host brain and differentiate appropriately. But here, when Dr. Lipton’s team transferred MEF2C-programmed neural progenitor cells into Parkinsonian rats, the transplanted cells survived well, differentiated into neurons, and improved motor function. What’s more, the cells were safe. Since neural progenitor cells programmed with MEF2C are destined to become neurons—cells that do not divide and proliferate—they didn’t overgrow or form tumors in this model.
At the moment, treatments for Parkinson’s disease help manage the symptoms, but don’t restore dopaminergic neurons. There is no cure. However, as Dr. Lipton and the authors of this study concluded in their paper, “This approach could potentially provide a limitless supply of stem cells for therapeutic application in Parkinson’s disease. Our technique represents a unique approach for the production of cells for regenerative medicine, while at the same time avoiding [cell death]and tumorigenesis.”
These same MEF2C-programmed human stem cells are now being used in pre-clinical trials to test their efficacy in treating Parkinson’s disease in other animal models. If successful, these studies will likely lead to a human clinical trial within the next several years. To prepare, Dr. Lipton’s group was recently awarded a Disease Team Planning Award by the California Institute for Regenerative Medicine.
Cho EG, Zaremba JD, McKercher SR, Talantova M, Tu S, Masliah E, Chan SF, Nakanishi N, Terskikh A, & Lipton SA (2011). MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model. PloS one, 6 (8) PMID