FEATURED ARTICLES Good News, Bad News Neuroscience Gateway (November 2006)

FEATURED ARTICLES Good news, bad news Neuroscience Gateway (November 2006) | doi:10.1038/aba1695

A new preparation of embryonic stem cells replaces dopamine neurons in a rat model of Parkinson disease, but may cause tumor formation.

According to the 80's rock band Poison, "every rose has its thorn." Similarly, many disease treatments have harmful side effects. Roy et al. report stem cell grafts alleviate Parkinson disease, but may be tumorigenic in a recent article in Nature Medicine.

Parkinson disease destroys Donor cells (red) on the border dopamine neurons in the of the graft incorporate with midbrain, resulting in motor host astrocytes (green). dysfunction, including tremor and rigidity. Proposed therapies replace neurons lost to disease with neurons derived from embryonic stem cells. However, current stem cell culturing conditions yield few dopaminergic neurons.

By coculturing embryonic stem cells with midbrain glia, the authors increased the yield of dopaminergic neurons from stem cells. They generated stable lines of human glia by infecting astrocytes from the embryonic midbrain and forebrain with telomerase reverse transcriptase protein, which helps cells avoid senescence by maintaining telomere length. When the embryonic stem cell line H9 was cocultured with forebrain or midbrain astrocytes, growth factor treatment produced more neurons relative to H9 cells cultured alone. Tyrosine hydroxylase is an enzyme important in dopamine production. H9 stem cells cocultured with midbrain astrocytes generated more tyrosine hydroxylase-positive neurons relative to stem cells cultured alone or with forebrain astrocytes. Nearly 70% of the neurons derived from stem cells cocultured with midbrain astrocytes expressed tyrosine hydroxylase.

One animal model of Parkinson disease is unilateral injection of 6- hydroxydopamine, which selectively kills dopamine neurons located in the same brain hemisphere as the injection. The dopamine agonist apomorphine can be used to determine the number of surviving dopamine neurons, by activating them and causing animals to rotate in the direction of the unlesioned hemisphere. The authors implanted cells derived from H9 embryonic stem cells cocultured with midbrain astrocytes into 6- hydroxydopamine-lesioned rats. Six weeks after implantation, rats with implants showed reduced numbers of apomorphine- induced rotations relative to unimplanted controls.

The authors examined the stem cell grafts four to ten weeks after implantation. The percentage of tyrosine hydroxylase-positive neurons declined following implantation. Approximately 65% of the tyrosine hydroxylase-positive neurons in the graft localized to the graft's outer edges and incorporated with host-derived reactive astrocytes.

What about the center of the graft? Here, only 10% of the cells expressed tyrosine hydroxylase. Many expressed the neural progenitor markers nestin and musashi, suggesting that these cells were not fully differentiated. Bromodeoxyuridine incorporates into the DNA of dividing cells. Approximately 7% of cells in the grafts were immunoreactive for bromodeoxyuridine after 48 hours of treatment, suggesting that unlike mature neurons, cells in the graft continued to divide.

Although the authors did not find any cancer cells in the stem cell grafts, the presence of slowly dividing cells suggested that the grafts might become tumorigenic over time. The authors believe that selection of differentiated cells before implantation will reduce the possibility for tumorogenesis while maintaining the therapeutic benefit of stem cell grafts in Parkinson disease patients.

Debra Speert

1. Roy, N. S. et al.Functional engraftment of human ES cell- derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nature Medicine 12, 1259–1268(2006). | Article |