HucMSCs-Derived Extracellular Vesicles Deliver RPS27A Protein to Manipulate the MDM2-P53 Axis and Ameliorate Neurological Dysfunction in Parkinson's Disease

  • J Neuroimmune Pharmacol. 2025 May 8;20(1):52. doi: 10.1007/s11481-025-10209-2.
Jinyu Xu  #  1  2 ,  Hongbing Lei  #  3 ,  Chunhui Yang  1  4 ,  Yiqing Qiu  1 ,  Xi Wu  5
Affiliations
  • 1. Department of Neurosurgery, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, No.168, Changhai Road, Yangpu District, Shanghai, 200433, P.R. China.
  • 2. Department of Neurosurgery, 411 Hospital Affiliated to Shanghai University, Shanghai, 200081, P.R. China.
  • 3. Department of Neurosurgery, Shanghai Mental Health Center, Shanghai, 201108, P.R. China.
  • 4. Department of Neurosurgery, The Yang Zhi Rehabilitation Hospital Affiliated to Tongji University, Shanghai, 201613, P.R. China.
  • 5. Department of Neurosurgery, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, No.168, Changhai Road, Yangpu District, Shanghai, 200433, P.R. China. [email protected].
  • # Contributed equally.
PMID: 40338442 DOI: 10.1007/s11481-025-10209-2
Abstract

Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson's disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cord MSCs (hucMSCs) and the possible mechanisms involved. SH-SY5Y cells were induced with MPP+, and the impact of hucMSCs-EV on the damage to SH-SY5Y cells was examined. Mice were induced with PD-like symptoms by MPTP and the effects of hucMSCs-EV on neurological damage in mouse brain tissue were detected as well. HucMSCs-EV inhibited Apoptosis and oxidative stress in MPP+-induced SH-SY5Y cells. HucMSCs-EV suppressed behavioral deficits and neuronal Apoptosis in MPTP-induced mice, with an increased number of dopamine neurons in brain tissues and decreased p-alpha-syn expression in dopamine neurons. The expression of ribosomal protein S27A (RPS27A) in SH-SY5Y cells was elevated after co-culture of neurons and hucMSCs-EV, and RPS27A silencing abated the effect of hucMSCs-EV in vivo and in vitro. RPS27A bound to the MDM2 promoter, thus promoting P53 ubiquitination and degradation. MDM2 overexpression strengthened the therapeutic effect of hucMSCs-EV. We conclude that hucMSCs-EV promote the interaction between RPS27A and MDM2 by delivering RPS27A, which regulates the MDM2-P53 axis to promote degradation of P53 to ameliorate neurological damage in PD.

Keywords
Extracellular vesicles; Human umbilical cord mesenchymal stem cells; MDM2-P53 axis; Parkinson’s disease; RPS27A.
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