Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

Abstract

Aims: Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models. Methods:We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI. Results:We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/ Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown.Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro. Conclusion:Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.

Fucoxanthin ameliorates traumatic brain injury by suppressing the blood–brain barrier disruption

“…However, the protection of HucMSC-derived exosome on apoptosis and ferroptosis was attenuated when mitophagy was inhibited and PINK1 was knockdown. 23 Consistent with these results, the present study indicated that mitophagy was activated in ECs after TBI. Suppression of mitophagy by Mdivi-1 reversed the inhibitory effects of fucoxanthin on TBI-induced BBB damage, EC apoptosis and ferroptosis.…”

“…Growing studies have suggested that mitophagy could regulate apoptosis and ferroptosis after TBI. 23 Therefore, we wondered whether mitophagy was involved in the protection of fucoxanthin on BBB. We firstly used the double IF staining of LC3 and CD31, the results revealed that TBI increased the co-localization of LC3-positive and CD31-positive cells compared to the sham group, suggesting the formation of autophagosome in ECs ( Figure 7 A).…”

“…The in vivo (mouse) TBI model was performed using a Controlled Cortical Impact (CCI) model according to our previous study. 23 Mice were anesthetized with 3% isoflurane and subsequently placed on the stereotaxic apparatus. The area to be impacted lies on the right frontal skull (2.5 mm lateral to the midline and 0.5 mm anterior to bregma).…”

Mechanisms and therapeutic targets of mitophagy after intracerebral hemorrhage

“…Mitophagy promotion can enhance ICH recovery and inhibit the oxidative stress response and ferroptosis caused by heme accumulation. In a study on traumatic brain injury, mitophagy mediated by the PINK1/Parkin pathway was found to protect neurons from iron-induced death [ 45 ]. Nrf2 participates in this protective mechanism when mitophagy is activated.…”

Latest progress in low-intensity pulsed ultrasound for studying exosomes derived from stem/progenitor cells

“…Exosomes are important for intercellular communication, and they are involved in the integration of cells in physiological and pathological states by delivering biomolecules, thereby causing a series of biochemical changes in receptor molecules. They function in immune regulation ( 5 ), reproduction ( 6 ), tumor angiogenesis ( 7 ), cell differentiation and regeneration ( 8 ), apoptosis ( 9 ), and inflammatory responses ( 10 ). MiRNAs are endogenous non-coding single-stranded RNAs of 21–23 nucleotides that bind directly to the 3′-untranslated regions (3′ UTRs) of target mRNAs and regulate post-transcriptional gene expression negatively or positively ( 11 ).…”