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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE60080 | GEO | 2015/06/12

SECONDARY ACCESSION(S): PRJNA257427

REPOSITORIES: GEO

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Project description:Advances in large-scale proteomics analysis have been very useful in understanding pathogenesis of diseases and elaborating therapeutic strategies. Proteomics has been employed to study Parkinson’s disease (PD), however, sparse studies reported proteome investigation after cell therapy approaches. In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins in a mouse model of PD after cell therapy. Proteins were extracted from five nigrostriatal-related brain regions of mice previously lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Protein expression was compared in non-grafted brain to 1 and 7 days after intranigral grafting of E12.5 embryonic ventral mesencephalon (VM). We found a total of 277 deregulated proteins after transplantation, which are known to be involved in lipid metabolism, oxidative phosphorylation and PD; thus, confirming that our animal model is similar to human PD and that the presence of grafted cells modulates the expression of these proteins. Notably, 7 proteins were commonly downregulated in all selected brain regions after engraftment, including Acta1, Atp6v1e1, Eci3, Lypla2, Pip4k2a, Sccpdh and Sh3gl2. These are known to be involved in the formation of lipids and recycling of dopamine (DA) vesicle at the synapse. Moreover, intranigral transplantation of VM cells decreased the expression of proteins related to oxidative stress, especially in the nigrostriatal pathway containing the DA grafted neurons. In the same regions, an upregulation of several proteins including alpha-synuclein and tyrosine hydroxylase were observed, whereas expression of tetraspanin 7 was shut down. Overall, these results suggest that intranigral transplantation of VM tissue in an animal model of PD may induce a decrease of oxidative stress in the nigrostriatal pathway and a restoration of the machinery of neurotransmitters, particularly dopamine release to promote DA transmission through a decrease of D2 dopamine receptors endocytosis. Identification of new mechanistic elements involved in the nigrostriatal reconstruction process is a promising approach to enhance the repair of this pathway in PD patients undergoing cell therapy.

Project description:Cryobanking and transplantation of ovarian tissue is a promising approach to restore fertility in cancer patients. However, ischemic stress following avascular ovarian cortex grafting is known to induce stromal tissue fibrosis and alteration in follicular development. The aim of the study is to analyse the impact of freezing-thawing and grafting procedures on gene expression in human ovarian tissue. Frozen-thawed ovarian tissue from 4 patients was xenografted for 7 days in nude mice and one non-grafted fragment was used as control. Immediately after recovery, grafts were processed for RNA extraction and histological analysis. Their expression profile was screened by whole-genome oligonucleotide array (n=4) and validated by reverse-transcriptase polymerase chain analysis (n=10). 84 of the transcripts were significantly altered after 7 days of grafting including matrix metalloproteinase-9 and -14 and angiogenic factors such as Placental growth factor and C-X-C chemokine receptor type 4 (CXCR4). Major biological processes were related to tissue remodelling including secretory processes, cellular adhesion and response to chemical and hormone stimuli. Angiopoietin signaling, interleukin-8 pathway and peroxisome proliferator-activated receptors activation were shown to be differentially regulated. On day 7, overexpression was confirmed by PCR for interleukin-8, transforming growth factor-beta 1, matrix metalloproteinase-14 and CXCR4 compared to the nongrafted control. In conclusion, new as well as known genes involved in tissue restructuration and angiogenesis were identified after human ovarian tissue transplantation. This will facilitate the development of strategies to optimize grafting techniques. In this study, ovarian tissue was obtained from 4 patients. Each biopsy was divided into 2 fragments. One fragment was frozen/thawed and placed in TRIzol reagent (Invitrogen) for RNA extraction. The other fragment was frozen-thawed and grafted in the intraperitoneal cavity of a nude mice. After 7 days graft were recovered and total RNA was extracted.

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

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