Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.

Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice.

The function of melatonin (MLT) in promoting fracture healing has been demonstrated in previous studies However, the molecular mechanism underlying therapeutic effects of MLT is not entirely clear In this study, mesenchymal stem cells (MSCs) were isolated from rat bone marrow and identified by flow cytometry We found that MLT treatment upregulated the neuropeptide Y (NPY) and NPY receptor Y1 (NPY1R) expression, and promoted the proliferation and migration of MSCs, which was suppressed by BIBP3226, an inhibitor of NPY1R Moreover, the levels of NPY and NPY1R in MSCs undergoing osteoblastic differentiation were upregulated after MLT administration MLT-induced osteoblastic differentiation of MSCs was suppressed by BIBP3226 treatment, as evidenced by decreased levels of alkaline phosphatase (ALP), collagen type I α1 chain, osteocalcin, and runt-related transcription factor 2, downregulated activity of ALP, as well as reduced calcium nodule formation Furthermore, we demonstrated that MLT could promote fracture healing in a rat model of femoral fracture, which was accompanied by the elevated expression of NPY and NPY1R The administration of BIBP3226 inhibited fracture healing mediated by MLT To sum up, our results show that MLT promotes osteoblastic differentiation of MSCs and fracture healing by NPY/NPY1R signaling

Melatonin Induces Osteoblastic Differentiation of Mesenchymal Stem Cells and Promotes Fracture Healing in a Rat Model of Femoral Fracture via Neuropeptide Y/Neuropeptide Y Receptor Y1 Signaling.

Epilepsy is a serious neurological disorder characterized by abnormal, recurrent, and synchronous discharges in the brain. Long-term recurrent seizure attacks can cause serious damage to brain function, which is usually observed in patients with temporal lobe epilepsy. Controlling seizure attacks is vital for the treatment and prognosis of epilepsy. Animal models, such as the kindling model, which was the most widely used model in the past, allow the understanding of the potential epileptogenic mechanisms and selection of antiepileptic drugs. In recent years, various animal models of epilepsy have been established to mimic different seizure types, without clear merits and demerits. Accordingly, this review provides a summary of the views mentioned above, aiming to provide a reference for animal model selection. 

Animal Models of Epilepsy: A Phenotype-oriented Review

Promoting neural transdifferentiation of BMSCs via applying synergetic multiple factors for nerve regeneration.

Acute lung injury (ALI)/acute respiratory distress syndrome is characterized by increased pulmonary inflammation, where T helper 17 (Th17) cells play an important regulatory role. Notch signaling critically regulates Th17 differentiation and is known to be linked with proximal T cell by protein kinase C theta (PKCθ). We hypothesized that PKCθ inhibition could attenuate ALI by suppressing Th17 response via the Notch signaling pathway. Male C57BL/6 mice were treated with phosphate-buffered saline (PBS), lipopolysaccharide (LPS), LPS and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT, a Notch signaling inhibitor), or LPS and PKCθ inhibitor (PI), and the bronchoalveolar lavage fluid (BALF), blood, and lung tissues were harvested at 48 h after the LPS challenge. CD4+ T cells were treated with DAPT or PI and harvested after 72 h. PKCθ inhibition markedly attenuated pathological changes and decreased the wet to dry weight ratio of the mouse lungs. The total cell and neutrophil counts, tumor necrosis factor-α (TNF- α) in BALF, myeloperoxidase activity in lung tissue, and the leukocyte count in whole blood were markedly reduced by PKCθ inhibition. The concentration of interleukin (IL)-17 and IL-22 in BALF, and the percentage of CD4+IL-17A+ T cells in the lungs were significantly downregulated by PKCθ inhibition. A similar trend was observed for the expression of retinoic acid-related orphan receptor gamma t and IL-23 receptor after PKCθ inhibition accompanied with inactivation of the Notch signaling pathway in vivo and in vitro. Collectively, these data demonstrated that PKCθ inhibition protects against LPS-induced ALI by suppressing the differentiation and pathogenicity of Th17, at least partially, through a Notch-dependent mechanism.

Protein Kinase C Theta Inhibition Attenuates Lipopolysaccharide-Induced Acute Lung Injury through Notch Signaling Pathway via Suppressing Th17 Cell Response in Mice

GABAergic neuronal cell grafting has promise for treating a multitude of neurological disorders including epilepsy, age-related memory dysfunction, Alzheimer's disease and schizophrenia However, identification of an unlimited source of GABAergic cells is critical for advancing such therapies Our previous study implied that reprogramming of bone marrow-derived mesenchymal stem cells (BMSCs) through overexpression of the Achaete-scute homolog 1 (Ascl1, also called Mash1) could generate GABAergic neuron-like cells Here, we investigated mechanisms underlying the conversion of BMSCs into GABAergic cells We inhibited γ-secretase (an enzyme that activates Notch signaling) with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or manipulated the expression of Notch signaling components such as the recombination signal binding protein for immunoglobulin kappa J region (RBPJ), hairy and enhancer of split-1 (Hes1) or Mash1 We demonstrate that inhibition of γ-secretase through DAPT down-regulates RBPJ and Hes1, up-regulates Mash1 and results in an enhanced differentiation of BMSCs into GABAergic cells On the other hand, RBPJ knockdown in BMSCs has no effect on Mash1 gene expression whereas Hes1 knockdown increases the expression of Mash1 Transduction of Mash1 in BMSCs also increases the expression of Hes1 but not RBPJ Moreover, increased GABAergic differentiation in BMSCs occurs with concurrent Mash1 overexpression and Hes1-silencing Thus, the Mash1-dependent Notch signaling pathway regulates GABAergic neuron-like differentiation of BMSCs These results also suggest that genetic engineering of BMSCs is a useful avenue for obtaining GABAergic neuron-like donor cells for the treatment of neurological disorders

Mash1-dependent Notch Signaling Pathway Regulates GABAergic Neuron-Like Differentiation from Bone Marrow-Derived Mesenchymal Stem Cells.

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Mash1-dependent Notch Signaling Pathway Regulates GABAergic Neuron-Like Differentiation from Bone Marrow-Derived Mesenchymal Stem Cells.