Mesenchymal Stem Cell-Derived Neuron-Like Cell Transplantation Combined with Electroacupuncture Improves Synaptic Plasticity in Rats with Intracerebral Hemorrhage via mTOR/p70S6K Signaling

Abstract

Previous studies have shown that the combination of mesenchymal stem cell (MSC) transplantation and electroacupuncture (EA) stimulation is a neuroprotective strategy for treating intracerebral hemorrhage (ICH). However, the underlying mechanisms by which the combined treatment promotes neuroprotection remain unclear. This study was designed to investigate the effects of the combined treatment on synaptic plasticity and elucidate their underlying mechanisms. Therefore, rat ICH models were established by injecting collagenase and heparin, and the animals were randomly divided into model control (MC), EA stimulation (EA), MSC-derived neuron-like cell transplantation (MSC-dNLCs), and MSC-dNLC transplantation combined with EA stimulation (MSC-dNLCs+EA) groups. We observed the ultrastructure of the brain and measured the brain water content (BWC) and the levels of the microtubule-associated protein 2 (MAP2), galactocerebrosidase (GALC), and glial fibrillary acidic protein (GFAP) proteins. We also measured the levels of the phosphorylated mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (p70S6K) proteins, as well as the expression of synapse-related proteins. The BWC increased in rats after ICH and decreased significantly in ICH rats treated with MSC-dNLC transplantation, EA stimulation, or combined therapy. Meanwhile, after ICH, the number of blood vessels increased more evidently, but only the combined treatment reduced the number of blood vessels among rats receiving the three treatments. Moreover, the levels of MAP2, GALC, postsynaptic density 95 (PSD95), and synaptophysin (SYP) proteins, as well as the levels of the phosphorylated mTOR and p70S6k proteins, increased in the MSC-dNLCs+EA group compared with those in the MSC-dNLCs and EA groups. Compared with the MC group, GFAP expression was significantly reduced in the MSC-dNLCs, EA, and MSC-dNLCs+EA groups, but the differences among the three treatment groups were not significant. In addition, the number of synapses increased only in the MSC-dNLCs+EA group compared to the MC group. Based on these data, the combination of MSC-dNLC transplantation and EA stimulation exerts a synergistic effect on improving the consequences of ICH by relieving cerebral edema and glial scarring, promoting the survival of neurons and oligodendrocytes, and activating mTOR/p70S6K signaling to enhance synaptic plasticity.

Electroacupuncture Therapy Effectively Protects the Rat Brain after Intracerebral Hemorrhage

“…By using 18 F-FDG micro-PET scanning to detect the bleeding area [9][10][11], the results showed that Ea treatment reduced the hemorrhagic focal area. This is significant as the extent of a brain injury is closely associated with brain edema and the duration of edema [12,13]. Our results showed that the brain water content increased in rats by Day 7 after ICH and that Ea therapy was associated with brain edema alleviation.…”

“…The mNSS test was used to assess neurobehavioral deficits through a series of motor, sensory, balance, and reflex measurements [10]. The score of 0-18 indicated the degree of injury (normal score, 0; slight injury, 1-6; moderate injury, 7-12; serious injury, [13][14][15][16][17][18]. ICH rats with final scores of higher than 8 were included in subsequent experiments.…”

Global trends and hotspots in research on acupuncture for stroke: a bibliometric and visualization analysis

“…The combined intervention of mesenchymal stem cell (MSC) transplantation and EA is a neuroprotection strategy for intracerebral hemorrhage (ICH) [ 49 ]. The combination of two methods, by relieving cerebral edema and glial scar, promotes neuronal and oligodendrocyte survival, activates mammalian target of rapamycin (mTOR) / 70 kDa ribosomal protein S6 kinase (p70S6K) proteins signaling, and enhances synaptic plasticity [ 50 ]. Relevant evidence suggests that the effect of acupuncture in ICH may be related to the modification of microglia polarization via the miR-34a-5p/Krüppel-like factor 4 (Klf4) signaling pathway [ 51 ].…”

Pretreated MSCs with IronQ Transplantation Attenuate Microglia Neuroinflammation via the cGAS-STING Signaling Pathway

“…The ICH animal model was established following the methodology outlined in our previous study. 28 , 36 Shortly, anesthetized mice were secured by immobilizing the bilateral external ear hilum and incisor to a stereotaxic apparatus. The anterior and posterior fontanels were positioned at the horizontal plane to ensure stability.…”