Authors:
L. Iacovitti, A. Donaldson, & J. Cai
Summary:
Symptoms of the neurodegenerative disorder, Parkinson’s Disease (PD), are caused by the degeneration of dopamine neurons in the midbrain (mDA), the majority of which are lost prior to diagnosis. Cell replacement remains an important potential therapy, particularly at later stages of PD. While mature DA neurons do not survive harvest and transplantation, DA progenitor cells derived from pluripotent human embryonic stem (hES) cells represent a practical and promising source of renewable cells for transplantation in PD. Current challenges in this field are identification of the optimal stage of differentiating DA lineage and the development of methods to produce a large enough number of progenitors for transplantation. We have identified distinct stages in mDA differentiation of hES cells based on the sequential expression of Lmx1a, Aldh1a1, and TH. We believe Lmx1a+ neural progenitor cells (NP), which are committed to the mDA lineage yet retain proliferative capacity, may be at an ideal stage for transplantation. However, cells cannot be selected by this transcription factor. Interestingly, we have discovered that the cell surface protein TrkB is expressed in 47% of Lmx1a+ cells but is not expressed in Aldh1a1+ DA precursor cells or in any other cell type in culture. Using this cell surface marker, DA progenitor cells derived from hES cells can be selected from a heterogeneous population by MACS or FACS. In addition, we have also largely amplified the number of neural progenitors by including VEGF at the embryoid body stage, which provides a greater progenitor pool for further purification of DA progenitors. These findings demonstrate progress towards both enrichment and selection of the DA progenitor population for cell replacement therapy in PD.
Source:
Neuroscience 2008, the 38th Annual Meeting of the Society for Neuroscience; 720.15/B18, Washington Convention Center: Hall A-C, 10:00AM-11:00AM (11/19/08)