Dataset Information

Multi-compartment quantitative proteomics revealing potential mechanisms underlying the treatment effects of mesenchymal-derived extracellular vesicles in a monkey model of cortical injury

ABSTRACT: Cortical injury frequently causes motor dysfunction, significantly impairing activities of daily living, and currently, there are no effective therapeutic options available. Previous studies demonstrated that intravenous infusion of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) exerts beneficial effects following cortical injury in primary motor cortex via reducing injury-induced microglial neuroinflammation, neuronal excitotoxicity, synapse loss, oligodendrocyte damage and myelination deficits in the rhesus monkey. However, the specific molecules within MSC-EVs responsible for these therapeutic effects and the underlying molecular mechanisms remain largely unexplored. In this study, employing quantitative proteomics strategy, we first identified the protein composition of MSC-EVs, then analyzed the global protein expression changes associated with cortical injury and treatment effect in brain tissue, cerebrospinal fluid (CSF), and plasma samples from monkeys following cortical injury. A total of 4124/1241/431 monkey proteins were reliably quantified in tissue/CSF/plasma samples, respectively. Further informatics analysis revealed not only the enriched biological processes aligned with previous findings, but also several potential treatment markers. This first-time comprehensive investigation of quantitative proteomics in multi-compartment samples from rhesus monkey enhanced our understanding of the treatment effects of MSC-EVs, paving the way for novel treatment and biomarker discovery.

INSTRUMENT(S):

ORGANISM(S): Macaca Mulatta (rhesus Macaque)

TISSUE(S): Brain, Blood Plasma, Cerebrospinal Fluid

SUBMITTER: Shuo Qian

LAB HEAD: Jun Qu

PROVIDER: PXD059286 | Pride | 2026-06-15

REPOSITORIES: Pride

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			Action	DRS
	20210812_TMoore_CSF_A1_1_240K_clm185_WC18_65cm_HCD_OT_AGtrap_val50_11to32B_180m_4ul_01.mzXML	Mzxml
	20210812_TMoore_CSF_A1_1_240K_clm185_WC18_65cm_HCD_OT_AGtrap_val50_11to32B_180m_4ul_01.raw	Raw
	20210812_TMoore_CSF_A1_2_240K_clm185_WC18_65cm_HCD_OT_AGtrap_val50_11to32B_180m_4ul_01.mzXML	Mzxml
	20210812_TMoore_CSF_A1_2_240K_clm185_WC18_65cm_HCD_OT_AGtrap_val50_11to32B_180m_4ul_01.raw	Raw
	20210812_TMoore_CSF_A1_3_240K_clm185_WC18_65cm_HCD_OT_AGtrap_val50_11to32B_180m_4ul_01.mzXML	Mzxml

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Publications

Multicompartment Quantitative Proteomics Revealing Potential Mechanisms Underlying the Treatment Effects of Mesenchymal-Derived Extracellular Vesicles in a Monkey Model of Cortical Injury.

Qian Shuo S McCann Ryan P RP Shen Shichen S Zhu Xiaoyu X Tsillas Christina M CM Xin Hongqi H Wang Mingjin M Zhang Yi Y Zhang Zheng Gang ZG Chopp Michael M Medalla Maria M Moore Tara L TL Qu Jun J

Journal of proteome research 20251001 11

Previous studies have demonstrated that mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) enhance functional recovery after cortical injury in rhesus monkeys by reducing chronic microglial inflammation, neuronal damage, and myelination deficits. However, the signaling pathways underlying these therapeutic effects remain largely unexplored. In this study, employing a reliable quantitative proteomics platform UHR-IonStar, we identified the protein cargo of MSC-EVs infused intraveno ...[more]

PMID: 41032466

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Project description:Primary cortical neurons were isolated from E15 mice and after 5 days in vitro were untreated or treated for 24 h with mesenchymal stem cell conditioned medium and then untreated or treated for a further 24 h with NMDA. Neuron gene expression was profiled and compared between the four different conditions (neurons, neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA) to investigate the molecular mechanisms of MSC neuroprotection. Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to activation of endogenous CNS repair processes and immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of MSC in simplified MSC-neuron co-culture systems and in mice using models of glutamate excitotoxicity. MSC protected primary cortical neurons against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC cm), but not control NIH3T3 cells, was sufficient for this effect. MSC cm neuroprotection in mouse cortical neurons was reduced by neutralizing antibodies to bFGF and associated with altered gene expression in neurons towards an immature phenotype as well as reduced neuronal Grin1, Grin2a and Grin2b mRNA levels in response to NMDA stimulation. Further, MSC cm neuroprotection in rat retinal ganglion cells was associated with absence of glutamate-induced calcium influx. Adoptive transfer of EGFP+MSC in a mouse kainic acid seizure model reduced CA3 neuron damage and hippocampal astrocytosis and resulted in the increased expression of neuronal genes that are upregulated by MSC cm, Bmi1, Ddx4, Ezh1, in the hippocampus. These results show that MSC mediate direct neuroprotection against glutamate excitotoxicity by secreting bFGF, reducing glutamate receptor expression and function and altering neuron gene expression towards an immature pattern, and provide evidence for a link between the therapeutic effects of MSC and the activation of endogenous repair processes following CNS injury. In vitro cultures primary cortical neurons from mice were protected from glutamate excitotoxicity when pre-treated with MSC cm. Global gene expression changes induced in neurons before and after treatment with MSC cm and/or NMDA were investigated using a cDNA spotted macroarray filter. Four samples were analysed in duplicate: neurons alone (untreated), neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA.