In parkinson’ disease (PD), neurodegeneration is largely confined to one discrete group of nerve cells that produce the chemical dopamine (DA). Since the death of most DA neurons almost always precedes diagnosis, cell replacement remains especially attractive as a treatment strategy for PD. Towards this end, a variety of cell sources have been studied in animal models of PD, among which human embryonic stem cells (hES) is one of the most promising. Theoretically, hES cells can generate all cell types in the body, including midbrain DA neurons. And indeed a fraction of hES cells do develop into functional DA neurons both in the tissue culture dish and after transplantation into the rat brain. A major remaining obstacle to this approach however is the continued presence of other unwanted cell types in the graft.
Our lab has recently discovered genetic markers which identify, at an early stage, those hES cells which are destined to become DA neurons. Since these cells also express unique proteins on their cell surface, it should be possible to segregate these cells from other undesirable cell types. Therefore, with the support of the Michael J. Fox Foundation, we hope to select and enrich prospective DA neurons and study their functionality after transplantation into rats with a PD lesion.
Final Outcome
One of the ongoing difficulties in the stem cell field is the heterogeneity of cells present in hES grafts, including potential teratomaforming stem cells. Thus, a selection strategy that targets the desired cell population and simultaneously eliminates unwanted cells in hES grafts, represents a major step forward. In this project, Dr. Iacovitti examined a strategy that did not require the genetic manipulation of cells but instead took advantage of constitutively expressed cell surface proteins that are uniquely present on midbrain (Lmx1a+) dopamine-specified hES cells. Her preliminary studies indicated that Lmx1a and Aldh1a1 are early markers of prospective dopamine neurons, and as such, could serve as an invaluable experimental tool for the selection of these cells at specific stages in their development prior to their transplantation.