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PTX3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson's disease via inhibiting apoptosis.

ABSTRACT: Adipose-derived human mesenchymal stem cells (hADSCs) transplantation has recently emerged as a promising method in the treatment of Parkinson's disease (PD), however, the mechanism underlying has not been fully illustrated. In this study, we discovered that hADSCs protected the dopaminergic (DA) neurons in a 6-hydroxydopamine(6-OHDA) induced PD mice model. Using a transwell co-culture system, we reported that, in 6-OHDA brain slice cultures, hADSCs significantly promoted host DA neuronal viability. Within the analysis of hADSCs' exocrine proteins through RNA-seq, Human protein cytokine arrays and label-free quantitative proteomics, we identified Pentraxin3 (PTX3) as a key extracellular factor in hADSCs secretion environment. Moreover, we found that human recombinant Pentraxin3 (rhPTX3) treatment could rescue the physiological behaviour of the PD mice in-vivo, as well as prevent DA neurons from death and increase the neuronal terminals in the Ventral tegmental area(VTA)+ substantia nigra pars compacta (SNc) and striatum (STR) on the PD brain slices in-vitro. Furthermore, within testing on the pro-apoptotic markers of PD mice brain following the treatment of rhPTX3, we found that rhPTX3 can prevent the apoptosis and degeneration of DA neurons. Overall, the current study investigated that PTX3, a hADSCs secreted protein, played a potential role in protecting the DA neurons from apoptosis and degeneration in PD progression and improving the motor performances in PD mice to give a possible mechanism of how hADSCs works in the cell replacement therapy in PD. Importantly, our study also provided a potential translational implications for the development of PTX3-based therapeutics in PD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163176 | GEO | 2021/06/30

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.

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PTX3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson's disease via inhibiting apoptosis.

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