Human induced pluripotent stem cell-derived neurons improve motor asymmetry in a 6-hydroxydopamine-induced rat model of Parkinson's disease.

Since human embryonic stem cells and human fetal neural stem cells have immune rejection and ethical issues, recent advancements in induced pluripotent stem cells (iPS cells) provide new possibilities to study autologous cell therapy for Parkinson's disease (PD). We isolated human skin fibroblasts from normal individuals and patients with PD; we generated iPS cells by transfecting these human skin fibroblasts with retroviral reprogramming factors of OCT4, SOX2, KLF4 and c-MYC and induced iPS cells to differentiate neural stem cells (NSCs) and then into neurons and dopamine neurons in vitro. We found that iPS cell-derived NSC transplant into the striatum of the 6-hydroxydopamine (OHDA)-induced PD rats improved their functional defects of rotational asymmetry at 4, 8, 12 and 16 weeks after transplantation. iPS cell-derived NSCs were found to survive and integrate into the brain of transplanted PD rats and differentiated into neurons, including dopamine neurons in vivo. Transplantation of iPS cell-derived NSCs has therapeutic potential for PD. Our study provided experimental proof for future clinical application of iPS cells in cell-based treatment of PD.

Han F ，Wang W ，Chen B ，Chen C ，Li S ，Lu X ，Duan J ，Zhang Y ，Zhang YA ，Guo W ，Li G ... -  《-》

Potential application of induced pluripotent stem cells in cell replacement therapy for Parkinson's disease.

Chen LW ，Kuang F ，Wei LC ，Ding YX ，Yung KK ，Chan YS ... -  《-》

Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology.

Chang YL ，Chen SJ ，Kao CL ，Hung SC ，Ding DC ，Yu CC ，Chen YJ ，Ku HH ，Lin CP ，Lee KH ，Chen YC ，Wang JJ ，Hsu CC ，Chen LK ，Li HY ，Chiou SH ... -  《-》

Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons.

The main motor symptoms of Parkinson's disease are due to the loss of dopaminergic (DA) neurons in the ventral midbrain (VM). For the future treatment of Parkinson's disease with cell transplantation it is important to develop efficient differentiation methods for production of human iPSCs and hESCs-derived midbrain-type DA neurons. Here we describe an efficient differentiation and sorting strategy for DA neurons from both human ES/iPS cells and non-human primate iPSCs. The use of non-human primate iPSCs for neuronal differentiation and autologous transplantation is important for preclinical evaluation of safety and efficacy of stem cell-derived DA neurons. The aim of this study was to improve the safety of human- and non-human primate iPSC (PiPSC)-derived DA neurons. According to our results, NCAM(+) /CD29(low) sorting enriched VM DA neurons from pluripotent stem cell-derived neural cell populations. NCAM(+) /CD29(low) DA neurons were positive for FOXA2/TH and EN1/TH and this cell population had increased expression levels of FOXA2, LMX1A, TH, GIRK2, PITX3, EN1, NURR1 mRNA compared to unsorted neural cell populations. PiPSC-derived NCAM(+) /CD29(low) DA neurons were able to restore motor function of 6-hydroxydopamine (6-OHDA) lesioned rats 16 weeks after transplantation. The transplanted sorted cells also integrated in the rodent brain tissue, with robust TH+/hNCAM+ neuritic innervation of the host striatum. One year after autologous transplantation, the primate iPSC-derived neural cells survived in the striatum of one primate without any immunosuppression. These neural cell grafts contained FOXA2/TH-positive neurons in the graft site. This is an important proof of concept for the feasibility and safety of iPSC-derived cell transplantation therapies in the future.

Sundberg M ，Bogetofte H ，Lawson T ，Jansson J ，Smith G ，Astradsson A ，Moore M ，Osborn T ，Cooper O ，Spealman R ，Hallett P ，Isacson O ... -  《-》

Intrastriatal transplantation of stem cells from human exfoliated deciduous teeth reduces motor defects in Parkinsonian rats.

This study explored the neural differentiation and therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) in a rat model of Parkinson's disease (PD). The SHED were isolated from fresh dental pulp and were induced to differentiate to neurons and dopamine neurons by inhibiting similar mothers against dpp (SMAD) signaling with Noggin and increase conversion of dopamine neurons from SHED with CHIR99021, Sonic Hedgehog (SHH) and FGF8 in vitro. The neural-primed SHED were transplanted to the striatum of 6-hydroxydopamine (6-OHDA)-induced PD rats to evaluate their neural differentiation and functions in vivo. These SHED were efficiently differentiated to neurons (62.7%) and dopamine neurons (42.3%) through a newly developed method. After transplantation, the neural-induced SHED significantly improved recovery of the motor deficits of the PD rats. The grafted SHED were differentiated into neurons (61%), including dopamine neurons (22.3%), and integrated into the host rat brain by forming synaptic connections. Patch clamp analysis showed that neurons derived from grafted SHED have the same membrane potential profile as dopamine neurons, indicating these cells are dopamine neuron-like cells. The potential molecular mechanism of SHED transplantation in alleviating motor deficits of the rats is likely to be mediated by neuronal replacement and immune-modulation as we detected the transplanted dopamine neurons and released immune cytokines from SHED. Using neural-primed SHED to treat PD showed significant restorations of motor deficits in 6-OHDA-induced rats. These observations provide further evidence that SHED can be used for cell-based therapy of PD.

Zhang N ，Lu X ，Wu S ，Li X ，Duan J ，Chen C ，Wang W ，Song H ，Tong J ，Li S ，Liu Y ，Kang X ，Wang X ，Han F ... -  《-》