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Parkinson’s disease: utility of the stem cell-derived neurons

Two studies have yielded evidence that could prove a boon for stem cell therapies aimed at patients with Parkinson's disease and those with compromised immune systems due to intensive cancer therapy or autoimmune disease.

Researchers at the Karolinska Institutet in Sweden discovered a "master determinant" that turns embryonic stem cells into bona fide dopamine neurons, brain cells that degenerate in those with Parkinson's disease.

The findings hold promise for the future of cell replacement therapy for the debilitating and incurable disease characterized by tremors, said study authors Thomas Perlmann and Johan Ericson. The results also underscore the general importance of a thorough understanding of development for producing authentic cells of a desired type from stem cells.

" The use of cell replacement therapy in the treatment of Parkinson's disease is fraught with many problems," Perlmann said. " However, clinical trials have provided important proof of principle that transplantation of dopamine neurons might work in patients."

" Ethical and practical issues associated with transplantation of fetal dopamine neurons to patients with Parkinson's disease has triggered intense interest in the possibility of the use of in vitro-engineered stem cells as an unlimited cellular source for transplantation," the researchers added.

To investigate whether the identification of determinants underlying the specification of dopamine neurons during development could be exploited for generating dopamine neurons from stem cells, the researchers first looked for genes expressed in the dopamine progenitor cells in the developing midbrains of embryonic mice.

The researchers uncovered two transcription factor proteins, Lmx1a and Msx1, that are selectively expressed in dopamine progenitor cells. Further study found that Lmx1, but not Msx1, is sufficient and required for the formation of dopamine neurons in the midbrains of chicks. Early activity of Lmx1a induces expression of Msx1, leading to other events important to the differentiation of these nerve cells, they show.

Moreover, the researchers report that expression of Lmx1a in embryonic stem cells results in a robust generation of dopamine neurons with a correct midbrain identity.

" In the use of stem cells for therapy, it is of utmost importance to make the correct cell type," added Perlmann. " In the brain, there are at least 1000 different types of neurons, only one of which is clinically relevant to Parkinson's disease. Our data establish Lmx1a and Msx1 as critical intrinsic dopamine-neuron determinants in vivo and suggest that they may be essential tools in cell replacement strategies in Parkinson's disease."

Further study will elucidate the utility of the stem cell-derived neurons for treating rats with Parkinson's disease, they said. The researchers will also conduct studies to examine whether the findings in animals will hold for humans.

A second group at Mount Sinai School of Medicine in New York found that the sympathetic of the nervous system plays a critical role in coaxing bone marrow stem cells into the bloodstream. So-called hematopoietic stem cells in the bone marrow are the source for blood and immune cells.

Hematopoietic stem cell transplants are now routinely used to restore the immune systems of patients after intensive cancer therapy and for treatment of other disorders of the blood and immune system, according to the National Institutes of Health. While physicians once retrieved the stem cells directly from bone marrow, doctors now prefer to harvest donor cells that have been mobilized into circulating blood.

In normal individuals, the continuous trafficking of the stem cells between the bone marrow and blood fills empty or damaged niches and contributes to the maintenance of normal blood cell formation, according to the researchers. Although it has been known for many years that the mobilization of hematopoietic stem cells can be enhanced by multiple chemicals, the mechanisms that regulate this critical process are largely unknown, they said.

One factor in particular, known as hematopoietic cytokine granulocyte-colony stimulating factor ( G-CSF ), is widely used clinically to elicit hematopoietic stem cell mobilization for life-saving bone marrow transplantation, said senior author of the study, Paul Frenette.

Several years ago, Frenette's group reported that a second compound, fucoidan, which is synthesized by certain seaweeds, could also spur the stem cells into action. The group speculated that the seaweed derivative might work by imitating a similar compound, called sulfatide, naturally present in mammalian tissues.