1. Introduction
Brain cells are composed of neurons and glial cells. The two cell types work together to monitor the microenvironment of brain. Neurons, which is main functional cell of nervous system, communicate via chemical and electrical synapses, in a process known as synaptic transmission. And glial cells give not only structural support but also functional help through the release of neuromodulators, axonal myelin formation, and the regulation of synaptic activity. These cells play various roles for maintaining the brain tissue homeostasis and neuronal integrity (2).
Astrocytes, oligodendrocytes, and microglia are representative glia cells in brain.
Astrocytes and oligodendrocytes connected with the vasculature are equipped with glycolytic machinery and efficiently provide nutrients and energy substrates from blood to the neurons and their long-extended axons (3).
Microglia are brain resident immune cells and represent around 10% of adult central nervous system (CNS) cells, with variable cell density across distinct regions.
Recent microglia originate from early erythromyeloid progenitors (EMPs) in the extraembryonic yolk sac, which seed the CNS of the embryo,differentiating into matured microglia through a stepwise developmental program was elucidated by fate-mapping studies. Remarkably, microglia self-renew through low-rate proliferation in combination with apoptosis throughout life, without any involvement from bone-marrow-derived monocytes to the microglial pool, at least under homeostatic conditions (4).
Microglia participate in various physiological functions, such as pruning, regulating plasticity, and neurogenesis, to maintain homeostasis (5). Multibranched resting microglia exist in a quiescent state in healthy conditions; however, upon sensing a disturbance in homeostasis, microglia become more rounded and amoeboid-shaped and increase phagocytosis and secretion of pro-inflammatory cytokines (6). Activated microglia induce inflammatory environments by producing a variety of inflammatory molecules, including nitric oxide (NO), tumor necrosis
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factor (TNF-α), interleukin 1-β (IL1-β), and reactive oxygen species (ROS) that have been closely associated with the pathogenesis of neural damage resulting from ischemia, inflammation and primary neurodegeneration (7). Furthermore, many studies have been reported that activated microglia cause neurological diseases such as neurodegenerative disorders, multiple sclerosis (MS), stroke, and neuropathic pain disease (8-11).
Controlling of microglia-mediated inflammation has been considered a therapeutic strategy in brain diseases. Several anti-inflammatory drugs such as glucocorticoids, minocycline, endocannabinoids, and nonsteroidal anti-inflammatory drugs are effective in regulating microglial activation and exert neuroprotective effects in the brain following different types of injuries and neurodegenerative diseases (12, 13). Although several drugs reduce the symptoms of brain diseases, they are frequently associated with side effects (14, 15).
Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, for example adipocytes, osteocytes, and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with both the innate and adaptive immune systems, leading to the modulation of several effector functions to immune cells (16).
Especially, bone marrow-derived mesenchymal stem cells (BM-MSCs) can meet many of the needs and requirements of a cell system delivery for nervous tissue transplantation and repair owing to their capability of turning into nonmesenchymal lineages. Besides, BM-MSCs have ability that rapidly and extensively expanding in vitro under culture conditions. Thus, small amount of BM-MSCs can produce sufficient cells for transplantation. Moreover, the BM-MSCs are immune controlled cells, which make them the best choice for allogeneic transplantation, avoiding tissue-rejection effects and the use of immune suppressive drugs. There are several other advantages, such as their capability of releasing paracrine factors, the ability
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of homing to injury sites, as well as integrating and surviving within the host tissue;
suitability for stable transfection by exogenous genes; the lack of important ethical problems compared to embryonic stem cells; and their safety and efficacy (17).
For the last two decades, the ability of BM-MSCs to reduce symptoms of brain diseases such as stroke, Parkinson’s disease, and multiple system atrophy has been investigated (18-21). Moreover, BM-MSCs have a therapeutic effect which is downregulating ability of excessive inflammation in the brain (19, 22, 23).
Particularly, the immunomodulation of BM-MSCs play an important role in the treatment of inflammatory diseases, including neurodegenerative disorders.
The observation that BM-MSCs neuroprotective effect may occur through the interaction with local neural cells is consistent with experiments addressing the interaction between BM-MSCs and microglia. BM-MSCs are able to inhibit LPS-stimulated microglia activation and the production of inflammatory factors through diffusible molecules and that BM-MSCs sense inflammatory molecules, released by the activated microglia, thus increasing significantly the production of neurotrophic factors, which are involved in neuroprotection (7).
Importantly, this immunomodulatory ability is highly flexible according to complex changes in the inflammatory niche. Given the dynamic inflammation in neurodegenerative diseases, BM-MSC-mediated immunomodulation in cell therapy for these diseases deserves more attention (24).
Although many studies have reported the effects of BM-MSC transplantation in brain disease animal models in reducing neuroinflammation induced by microglia (23, 25, 26), the underlying mechanisms of BM-MSCs in targeting microglia-mediated neuroinflammation and the cellular network of activated microglia are still unclear. Additionally, even though mutual reactions between BM-MSC and activated microglia were investigated in vitro (27), their interactions were analysed in targeted approaches with limitations to elucidate the corresponding mechanisms. In this study, the relationship between rat bone marrow-derived mesenchymal stem cells
(rBM-- 4 (rBM--
MSCs) and activated microglia was evaluated using bidirectional transcriptomic analysis.
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