Human amniotic mesenchymal stem cell-derived exosomes alleviate cerebral Palsy–Associated neuronal damage via TSC1/mTOR/ULK1 autophagy suppression and PINK1/Parkin mitophagy restoration
Abstract
BackgroundCerebral palsy (CP) from perinatal hypoxic-ischaemic brain injury lacks effective therapies. Human amniotic mesenchymal stem cell-derived exosomes (hAMSC-exos) show neuroprotective potential, but their mechanisms remain unclear. This study investigated the effects and molecular pathways of hAMSC-exos in a neonatal rat CP model and an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal model.MethodshAMSC-exos were isolated and characterised. Severe CP was induced in postnatal day 21 rats by carotid ligation and hypoxia; hAMSC-exos or vehicle were given via tail vein 24 h later. Brain histology, ultrastructure, TSC1/mTOR/ULK1 pathway proteins, and apoptosis were assessed. In vitro, cortical neurons underwent OGD/R with or without exosomes; mitochondrial function (ATP, ROS, membrane potential), morphology, dynamics proteins (DRP1, FIS1, MFN1, MFN2), and PINK1/Parkin-mediated mitophagy were evaluated.ResultshAMSC-exos significantly ameliorated cortical neuronal degeneration, Nissl loss, and mitochondrial ultrastructural damage, and reduced autophagosome accumulation. They reversed CP-induced TSC1 upregulation, restored mTOR phosphorylation, and decreased ULK1 phosphorylation, correlating with fewer apoptotic neurons. In vitro, exosomes restored ATP content, reduced mitochondrial ROS, and normalised membrane potential. OGD/R caused excessive mitochondrial elongation via MFN1 upregulation; exosomes selectively downregulated MFN1 without affecting fission proteins (DRP1, FIS1). Moreover, exosomes restored impaired PINK1/Parkin-mediated mitophagy, increasing co-localisation of phospho-PINK1, phospho-Parkin, and LAMP1 with mitochondria, and rescued their phosphorylated protein levels.ConclusionhAMSC-exos protect against hypoxic-ischaemic injury through coordinated regulation of mitochondrial quality control, involving suppression of excessive TSC1/mTOR/ULK1-mediated autophagy (in vivo) and restoration of PINK1/Parkin-mediated mitophagy (in vitro), collectively preserving mitochondrial integrity and reducing neuronal apoptosis. These findings support hAMSC-exos as a promising cell-free therapeutic strategy for CP.
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BibTeX
@article{zhou2026human,
title = {{Human amniotic mesenchymal stem cell-derived exosomes alleviate cerebral Palsy–Associated neuronal damage via TSC1/mTOR/ULK1 autophagy suppression and PINK1/Parkin mitophagy restoration}},
author = {Yu Zhou and Fuli Yan and Zhouzhou Li and Luna He and Jing Gao and Xuefeng Yu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1965262},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1965262},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Human amniotic mesenchymal stem cell-derived exosomes alleviate cerebral Palsy–Associated neuronal damage via TSC1/mTOR/ULK1 autophagy suppression and PINK1/Parkin mitophagy restoration
AU - Yu Zhou
AU - Fuli Yan
AU - Zhouzhou Li
AU - Luna He
AU - Jing Gao
AU - Xuefeng Yu
PY - 2026
DA - 2026/11/04
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1965262
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1965262
AB - BackgroundCerebral palsy (CP) from perinatal hypoxic-ischaemic brain injury lacks effective therapies. Human amniotic mesenchymal stem cell-derived exosomes (hAMSC-exos) show neuroprotective potential, but their mechanisms remain unclear. This study investigated the effects and molecular pathways of hAMSC-exos in a neonatal rat CP model and an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal model.MethodshAMSC-exos were isolated and characterised. Severe CP was induced in postnatal day 21 rats by carotid ligation and hypoxia; hAMSC-exos or vehicle were given via tail vein 24 h later. Brain histology, ultrastructure, TSC1/mTOR/ULK1 pathway proteins, and apoptosis were assessed. In vitro, cortical neurons underwent OGD/R with or without exosomes; mitochondrial function (ATP, ROS, membrane potential), morphology, dynamics proteins (DRP1, FIS1, MFN1, MFN2), and PINK1/Parkin-mediated mitophagy were evaluated.ResultshAMSC-exos significantly ameliorated cortical neuronal degeneration, Nissl loss, and mitochondrial ultrastructural damage, and reduced autophagosome accumulation. They reversed CP-induced TSC1 upregulation, restored mTOR phosphorylation, and decreased ULK1 phosphorylation, correlating with fewer apoptotic neurons. In vitro, exosomes restored ATP content, reduced mitochondrial ROS, and normalised membrane potential. OGD/R caused excessive mitochondrial elongation via MFN1 upregulation; exosomes selectively downregulated MFN1 without affecting fission proteins (DRP1, FIS1). Moreover, exosomes restored impaired PINK1/Parkin-mediated mitophagy, increasing co-localisation of phospho-PINK1, phospho-Parkin, and LAMP1 with mitochondria, and rescued their phosphorylated protein levels.ConclusionhAMSC-exos protect against hypoxic-ischaemic injury through coordinated regulation of mitochondrial quality control, involving suppression of excessive TSC1/mTOR/ULK1-mediated autophagy (in vivo) and restoration of PINK1/Parkin-mediated mitophagy (in vitro), collectively preserving mitochondrial integrity and reducing neuronal apoptosis. These findings support hAMSC-exos as a promising cell-free therapeutic strategy for CP.
SN - 1663-9812
ER -