Astrocyte replacement shows promise in a rat model of ALS

Stem cell approaches for the treatment of neurodegenerative diseases has become a very attractive option. In amyotrophic lateral sclerosis (ALS), the cells affected in the disease, the motor neurons, have extremely long processes that need to be appropriately connected with the muscles they innervate, making motor neuron transplantation a daunting task. Over the past years, however, increasing evidence supports the notion that not only are motor neurons affected in the disease, but their surrounding cells including astrocytes, important cells regulating glutamate concentrations (required for normal function but if abnormally increased become toxic to the cells). In a study published this week in Nature Neuroscience and led by The ALS Association-funded Nicholas Maragakis, M.D., investigators demonstrate in a rat model that a feasible approach to increase survival in these animals is to transplant astrocytes. Although a great deal still needs to be done to apply this approach in the clinic, these studies do provide compelling evidence that this may one day be feasible.
 

Investigators isolated astrocyte precursors from developing spinal cord and transplanted these into the cervical spinal cord of 90 day old rats carrying the G93A SOD1 mutation. Investigators chose the cervical region with the hope that these transplants would have benefit for motor neurons which project to the diaphragm muscle. Loss of these neurons ultimately effects the survival of people with ALS. These transplanted cells survived, differentiated into mature astrocytes, and interacted with motor neurons in the spinal cord. Interestingly, these transplanted astrocytes did not show any overt signs of damage related to their close proximity with neurons producing mutant SOD1 motor neurons. This is an interesting finding as one may have expected that toxic factors released from the mutant expressing cells may damage the transplanted cells. Transplanted astrocytes delayed disease onset as well as progression of disease by about two weeks.

Several contributors may have led to the increased survival. Increased levels of the glutamate transporter GLT1 (found exclusively on astrocytes) which have been previously shown to be decreased in people with ALS and is replicated in the animal models may account for the increased survival. Astrocytes also produce trophic factors which support the survival of motor neurons.  However in these transplants, investigators could not find increased levels for a variety of tropic factors they measured in the spinal cord including IGF1, BDNF and VEGF. Instead the investigators identified that there was a reduction in microglia, the inflammatory cells in the brain which may have contributed to the increased survival.

“In this study, we have been trying to design a paradigm which could be eventually translated to ALS patients.  That is why we focused on a region, the cervical spinal cord, where respiratory function is centered.  Our findings suggest that targeted cell replacement of cells other than motor neurons may be promising, and targeting astrocyte-relevant pathways in other ways may be important in ALS therapeutics as well,” commented Nicholas Maragakis, M.D.

To view the abstract, please click here.

Posted on October 22, 2008