Identification of neurexophilin 3 as a novel maturation factor for induced pluripotent stem cell-derived dopaminergic neuron progenitors. Mus musculus

To develop more potent cell transplantation therapy for neurodegenerative disorder such as Parkinson’s disease (PD), the condition of the host brain environment should be considered to improve the outcome of grafted neurons. However, we never know which condition of host brain environment is suitable and supportive for the donor cells. In addition, what endogenous factor(s) do contribute to improve the engraftment of donor cells in host brain? Therefore, the identification of such effective factor(s) strongly contribute to improve the overcome of cell transplantation therapy. Here, we constructed the experimental approach to identify the effective soluble factor(s) for cell-grafting by comparison between various parkinsonian mouse brain condition and transplantation outcome using induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neuron progenitors. According to our experimental approach, we have identified secreted peptide, neurexophilin 3 (NXPH3) that enhance the survival of grafted-iPSC-derived DA neurons. Grafted-iPSC-derived DA neurons were increased by local supplement of NXPH3 protein. In addition, the expression level of NXPH3 in putamen of PD patients was significantly decreased than that of normal controls by using postmortem samples. These findings would be expected to contribute the new experimental strategy to indentify the endogenous effective factors for cell-grafting as in vivo application of stem cell technology. Overall design: Mice were divided into three groups as follows: (i) 1 week after acute administration (four times by every 2 h) of free base MPTP HCl (20 mg/kg, 80 mg/kg in total, intraperitoneally). (ii) 8 weeks after chronic administration (once a day for 20 consecutive days) of free base MPTP HCl (4 mg/kg per day, 80 mg/kg in total). (iii) 1 week after injection (four times by every 2 h) of saline (control).