Identification of Neurexophilin 3 as a Novel Supportive Factor for Survival of Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors

Abstract

Abstract Successful cell transplantation for Parkinson's disease (PD) depends on both an optimal host brain environment and ideal donor cells. We report that a secreted peptide, neurexophilin 3 (NXPH3), supports the survival of mouse induced pluripotent stem cell-derived (iPSC-derived) dopaminergic (DA) neurons in vitro and in vivo. We compared the gene expression profiles in the mouse striatum from two different environments: a supportive environment, which we defined as 1 week after acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and a nonsupportive environment, defined as 8 weeks after chronic administration of MPTP. NXPH3 expression was higher in the former condition and lower in the latter compared with untreated controls. When we injected mouse iPSC-derived neural cells along with NXPH3 into the mouse striatum, the ratio of tyrosine hydroxylase-positive DA neurons per graft volume was higher at 8 weeks compared with cell injections that excluded NXPH3. In addition, quantitative polymerase chain reaction analyses of the postmortem putamen revealed that the expression level of NXPH3 was lower in PD patients compared with normal controls. These findings will contribute to optimizing the host brain environment and patient recruitment in cell therapy for PD. Significance This study identified neurexophilin 3 (NXPH3), a secreted peptide, through comparison of gene expression profiles in the mouse striatum from various environments generated by different doses of dopaminergic (DA) neuron toxin. When mouse induced pluripotent stem cell-derived neural cells along with NXPH3 were injected into the mouse striatum, the ratio of DA neurons per graft volume was higher at 8 weeks compared with cell injections without NXPH3. In addition, quantitative polymerase chain reaction analyses of the postmortem putamen revealed that the expression level of NXPH3 was lower in patients with Parkinson's disease (PD) compared with controls without PD. These findings contribute to optimization of the host brain environment and patient recruitment in cell therapy.