A single intranasal dose of human mesenchymal stem cell-derived extracellular vesicles after traumatic brain injury eases neurogenesis decline, synapse loss, and BDNF-ERK-CREB signaling

Abstract

An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prevent hippocampal neurogenesis decline and synapse loss in the chronic phase of TBI. C57BL6 mice undergoing unilateral controlled cortical impact injury (CCI) received a single IN administration of different doses of EVs or the vehicle at 90 min post-TBI. Quantifying neurogenesis in the subgranular zone-granule cell layer (SGZ-GCL) through 5′-bromodeoxyuridine and neuron-specific nuclear antigen double labeling at ~2 months post-TBI revealed decreased neurogenesis in TBI mice receiving vehicle. However, in TBI mice receiving EVs (12.8 and 25.6 × 109 EVs), the extent of neurogenesis was matched to naive control levels. A similar trend of decreased neurogenesis was seen when doublecortin-positive newly generated neurons were quantified in the SGZ-GCL at ~3 months post-TBI. The above doses of EVs treatment after TBI also reduced the loss of pre-and post-synaptic marker proteins in the hippocampus and the somatosensory cortex. Moreover, at 48 h post-treatment, brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated cyclic AMP response-element binding protein (p-CREB) levels were downregulated in TBI mice receiving the vehicle but were closer to naïve control levels in TBI mice receiving above doses of hMSC-EVs. Notably, improved BDNF concentration observed in TBI mice receiving hMSC-EVs in the acute phase was sustained in the chronic phase of TBI. Thus, a single IN dose of hMSC-EVs at 90 min post-TBI can ease TBI-induced declines in the BDNF-ERK-CREB signaling, hippocampal neurogenesis, and synapses.

Mesenchymal stem cell‐derived exosomes improve neurogenesis and cognitive function of mice with methamphetamine addiction: A novel treatment approach

“…23,24 Intranasal (IN) administration of human MSC-derived extracellular vesicles in traumatic brain injury (TBI) mice increases neurogenesis in the sub-ventricular zone (SVZ) by increasing cell proliferation and enhancing the expression of DCX and NeuN. 25 Pourhadi et al also demonstrated that intranasal exosomes reduce amyloid-beta deposits and increase hippocampus preand post-synaptic protein expression to improve spatial memory in Alzheimer's disease model. 26 Based on the above, we aimed to investigate the impact of intravenous exosome delivery on cognitive function and neurogenesis markers in the DG and CA1 region of the hippocampus in METHtreated mice.…”

“…They also offer protection to the nervous system against oxidative damage in several neurological diseases 23,24 . Intranasal (IN) administration of human MSC‐derived extracellular vesicles in traumatic brain injury (TBI) mice increases neurogenesis in the sub‐ventricular zone (SVZ) by increasing cell proliferation and enhancing the expression of DCX and NeuN 25 . Pourhadi et al.…”

Extracellular vesicles from hiPSC-NSCs can prevent peripheral inflammation-induced cognitive dysfunction with inflammasome inhibition and improved neurogenesis in the hippocampus

“…Thus, normalized neurogenesis in LPS-treated mice receiving hiPSC-NSC-EVs is likely a downstream beneficial effect of EVs suppressing neuroinflammation. However, involvement of pro-neurogenic pathways, such as the activation of brain-derived neurotrophic factor-extracellular signal-regulated kinase-cyclic AMP response-element binding protein signaling, as observed in a traumatic brain injury model following the administration of human bone marrow mesenchymal stem cell-derived EVs, cannot be ruled out [ 48 ]. Such possibility is supported by hiPSC-NSC-EVs exhibiting enriched payload of proteins such as agrin efficient in promoting CREB activation [ 89 ] and agrin and PTX3 capable of directly enhancing neurogenesis [ 90 , 102 ].…”

“…Our previous studies have detailed immunohistochemical methods employed in this study [ 35 , 48 , 49 ]. In each animal, every 15th or 20th section through the whole hippocampus was processed for immunohistochemical identification of IBA-1 + microglia, GFAP + astrocytes, BrdU-positive newly born cells and doublecortin (DCX) positive newly generated neurons.…”

“…We employed western blots of hippocampal tissue lysates to quantify Syn and PSD95, as described in our recently published study [ 48 ]. The proteins in the membranes were identified using antibodies against Syn (1:5000, ProteinTech, Rosemont, IL, USA), PSD95 (1:1000, Abcam), and β-tubulin (1:10,000, Abcam) after being transferred onto a nitrocellulose membrane using the iBlot2 gel transfer device (ThermoFisher Scientific).…”