Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson's disease

Abstract

The identity and functional potential of dopamine neurons derived in vitro from embryonic stem cells are critical for the development of a stem cell-based replacement therapy for Parkinson's disease. Using a parthenogenetic primate embryonic stem cell line, we have generated dopamine neurons that display persistent expression of midbrain regional and cell-specific transcription factors, which establish their proper identity and allow for their survival. We show here that transplantation of parthenogenetic dopamine neurons restores motor function in hemi-parkinsonian, 6-hydroxy-dopamine-lesioned rats. Exposure to Wnt5a and fibroblast growth factors (FGF) 20 and 2 at the final stage of in vitro differentiation enhanced the survival of dopamine neurons and, correspondingly, the extent of motor recovery of transplanted animals. Importantly for future development of clinical applications, dopamine neurons were post-mitotic at the time of transplantation and there was no tumour formation. These data provide proof for the concept that parthenogenetic stem cells are a suitable source of functional neurons for therapeutic applications.

Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats

“…We therefore transplanted differentiated PDiPS cells into the striatum of 6-OHDA-lesioned rats as a functional and behavioral model for PD. In all animals, viable grafts with a high number of DA neurons without signs of neurodegeneration were found 16 wk after transplantation, and the survival rate of these DA neurons-an indirect measure for cell vulnerability-was comparable to those shown in studies on engrafted differentiated hES cells (13) or primate ES cells (23) 16 to 20 wk after transplantation. The PDiPS cell-derived DA neurons showed functional effects as demonstrated by a significant reduction in amphetamine-and apomorphine-induced rotations 16 wk after transplantation.…”

“…Differentiated cells were harvested at day 42 in vitro and transplanted into the striatum of adult Sprague-Dawley rats at a density of 100,000 viable cells per microliter. The surgical procedures and behavioral tests have been described in detail (14,23). Amphetamine and apomorphine were applied at doses of 4 mg/kg i.p.…”

“…Immunostainings of brain sections were performed as previously described (14,23). Cell counts of DA neurons in 6-OHDA-lesioned rats were obtained by applying the fractionator probe.…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…Various stem cell types are currently being considered as sources of dopamine neurons, including lineage-specific stem cells, pluripotent stem cells, and re-programmed somatic cells Isacson and Kordower, 2008;Sanchez-Pernaute et al, 2008;Pruszak and Isacson, 2009;Hargus et al, 2010). However, the transplantation of proliferative populations of neurons into the brain suffers from major safety concerns, most importantly the possibility that stem cell transplants may give rise to unchecked proliferation of tissue, eventually resulting in the formation of brain tumors (Li et al, 2008a;Amariglio et al, 2009;Brundin et al, 2010).…”

Cell Therapeutics in Parkinson's Disease

“…So far, the most promising results have been obtained using embryonic stem (ES) cells [52][53][54][55][56][57][58][59][60][61][62] or therapeutically cloned ES cells [63]. The examples shown (Fig.…”