Abstract
Successful cell therapy for Parkinson’s disease (PD) requires large numbers of homogeneous ventral mesencephalic dopaminergic (vmDA) precursors. Enrichment of vmDA precursors via cell sorting is required to ensure high safety and efficacy of the cell therapy. Here, using LMX1A-eGFP knock-in reporter human embryonic stem cells, we discovered a novel surface antigen, trophoblast glycoprotein (TPBG), which was preferentially expressed in vmDA precursors. TPBG-targeted cell sorting enriched FOXA2+LMX1A+ vmDA precursors and helped attain efficient behavioral recovery of rodent PD models with increased numbers of TH+, NURR1+, and PITX3+ vmDA neurons in the grafts. Additionally, fewer proliferating cells were detected in TPBG+ cell-derived grafts than in TPBG− cell-derived grafts. Our approach is an efficient way to obtain enriched bona fide vmDA precursors, which could open a new avenue for effective PD treatment.
Highlights
Parkinson’s disease (PD) is one of the most suitable neurodegenerative disorders for cell-based therapy due to the focal degeneration of ventral mesencephalic dopaminergic neurons
We sought to uncover novel cell surface markers that could be used for sorting ventral mesencephalic dopaminergic (vmDA) precursors
We generated a reporter human embryonic stem cells (hESCs) line in which an eGFP reporter gene is inserted into the LMX1A locus via TALENmediated genome editing (Fig. 1a and Supplementary Fig. 1): Among the three clones obtained (i.e., LMX1A-R2, LMX1A-R6, and LMX1A-R7), the LMX1A-R2 cell line was used for most analyses
Summary
Parkinson’s disease (PD) is one of the most suitable neurodegenerative disorders for cell-based therapy due to the focal degeneration of ventral mesencephalic dopaminergic (vmDA) neurons. Since the 1980s, efforts have been made to restore striatal dopamine release by engrafting fetal ventral mesencephalon tissue[1,2,3]. To further expand cell sources and avoid the pitfalls of using fetal tissue, including limited availability and batch-to-batch inconsistencies, increasing attention has been paid to using human pluripotent stem cells (hPSCs) due to their abundance and ability to differentiate into all cell types in the body[8,9]. Obtaining more homogeneous populations of hPSC-derived vmDA cells is needed for standardization of cell sources and successful translational research
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