BDNF-modified human umbilical cord mesenchymal stem cells-derived dopaminergic-like neurons improve rotation behavior of Parkinson's disease rats through neuroprotection and anti-neuroinflammation

Mol Cell Neurosci. 2022 Dec;123:103784. doi: 10.1016/j.mcn.2022.103784. Epub 2022 Oct 11.

Abstract

Parkinson's disease (PD) is a neurodegenerative disease still without any cure. Brain-derived neurotrophic factor (BDNF) has shown therapeutic potential in PD, which is limited by its short half-life and inability to penetrate the blood-brain barrier. Stem cells not only present migration, differentiation and neurotrophy characteristics, but also can be used as delivery vectors for BDNF. This study aimed to investigate the therapeutic effects and possible mechanisms of BDNF-modified human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived dopaminergic (DAergic)-like neurons in the PD rats. Results showed that transplantation of BDNF-modified hUC-MSCs-derived DAergic-like neurons improved the apomorphine induced rotation behavior of PD rats, increased the dopamine concentration and the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (Iba-1) in the striatum, promoted the expression of tyrosine hydroxylase (TH), nuclear receptor-related factor 1 (Nurr1), pituitary homeobox 3 (Pitx3), BDNF, tyrosine kinase B (TrkB), phosphatidylinositol-3-hydroxykinase (PI3K), phosphorylated protein kinase B (p-Akt), heat shock protein 60 (Hsp60), toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) and inhibited the neural apoptosis in the substantia nigra (SN) and striatum. Results suggest that BDNF-modified hUC-MSCs-derived DAergic-like neurons improve the rotation of PD rats might through neuroprotection and anti-neuroinflammation by regulating the BDNF-TrkB-PI3K/Akt and Hsp60-TLR4/MyD88 signaling pathways, respectively.

Keywords: Anti-neuroinflammation; Brain-derived neurotrophic factor; Dopaminergic-like neurons; Human umbilical cord mesenchymal stem cells; Neuroprotection; Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Humans
  • Mesenchymal Stem Cell Transplantation* / methods
  • Mesenchymal Stem Cells*
  • Myeloid Differentiation Factor 88 / metabolism
  • Myeloid Differentiation Factor 88 / pharmacology
  • Neurodegenerative Diseases* / metabolism
  • Neurons / metabolism
  • Neuroprotection
  • Parkinson Disease* / metabolism
  • Parkinson Disease* / therapy
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Toll-Like Receptor 4 / metabolism
  • Umbilical Cord / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Dopamine
  • Proto-Oncogene Proteins c-akt
  • Toll-Like Receptor 4
  • Myeloid Differentiation Factor 88
  • Phosphatidylinositol 3-Kinases