Positive Effect of YB-1 and Mesenchymal Stromal Cells on Primary Hippocampal Culture under Conditions of ACE2 Receptor Blockade

IF 1.1 Q4 CELL BIOLOGY
D. Yu. Zhdanova, A. V. Chaplygina, N. V. Bobkova, R. A. Poltavtseva, G. T. Sukhikh
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引用次数: 0

Abstract

Despite the fact that the current situation with COVID-19 incidence is not an emergency, new strains of SARS-CoV-2 coronavirus continue to appear in the world, some of them with higher virulence compared to the original virus. Studies have shown that patients with Alzheimer’s disease (AD) had a high risk of severe COVID-19, but the molecular and cellular mechanism of this predisposition is not fully elucidated. In this study, we developed a cellular model of the initial stage of COVID-19 on primary hippocampal culture of 5xFAD mice, a model of the familial AD, using the specific ACE2 receptor inhibitor MLN-4760. This model is based on the experimentally proven decrease in ACE2 receptor activity observed in COVID-19 patients due to internalization of the receptor inside the cell after binding to coronavirus. Using immunochemical staining with specific antibodies for detection of neurons (marker MAP2) and astroglia (marker GFAP) it was found that 24 h after addition of MLN-4760 (0.2 nmol per 1 mL of medium) to the culture medium there was a decrease in the density of astrocytes and neurons, a change in their morphology with a sharp reduction in the length and density of neurites, which led to the death of the cell culture. The transgenic culture turned out to be more sensitive to the effect of the inhibitor compared to the control hippocampal culture of native mice. In the second part of the study the possibilities of preventing the destructive effect of MLN-4760 on the hippocampal culture were studied. It was shown that administration of YB-1, an endogenous multifunctional stress protein, promoted restoration of cell culture structure and resulted in stimulation of neurite growth and astroglia activation. Introduction of multipotent mesenchymal stromal cells (MMSCs) after ACE2 blockade was also accompanied by improved culture survival, restoration of cell morphology, and increased density of astrocytes and neurons. These results suggest that YB-1 and cell therapy using MMSCs are promising options for the development of new effective methods to prevent the pathologic effects of the virus on brain tissue, which is an important link in the treatment of SARS-CoV-2 virus infection.

Abstract Image

在ACE2受体阻断条件下,YB-1和间充质间质细胞对原代海马培养的积极影响
尽管目前COVID-19的发病率并不紧急,但世界上仍不断出现新的SARS-CoV-2冠状病毒株,其中一些病毒的毒力比原病毒更高。研究表明,阿尔茨海默病(AD)患者具有严重COVID-19的高风险,但这种易感性的分子和细胞机制尚未完全阐明。在本研究中,我们使用特异性ACE2受体抑制剂MLN-4760,在家族性AD模型5xFAD小鼠的原代海马培养中建立了COVID-19初始阶段的细胞模型。该模型基于实验证明,在COVID-19患者中观察到的ACE2受体活性下降,这是由于该受体与冠状病毒结合后在细胞内内化。用检测神经元(标记MAP2)和星形胶质细胞(标记GFAP)的特异性抗体免疫化学染色发现,在培养基中加入MLN-4760 (0.2 nmol / 1ml培养基)24 h后,星形胶质细胞和神经元的密度下降,形态改变,神经突的长度和密度急剧减少,导致细胞培养死亡。结果表明,转基因培养物对该抑制剂的作用比正常小鼠海马培养物更敏感。第二部分研究了防止MLN-4760对海马培养物破坏作用的可能性。结果表明,内源性多功能应激蛋白YB-1可促进细胞培养结构的恢复,刺激神经突生长和星形胶质细胞活化。在ACE2阻断后引入多能间充质基质细胞(MMSCs)也伴随着培养存活率的提高、细胞形态的恢复以及星形胶质细胞和神经元密度的增加。这些结果表明,YB-1和利用MMSCs进行细胞治疗是开发新的有效方法来防止病毒对脑组织的病理影响的有希望的选择,这是治疗SARS-CoV-2病毒感染的重要环节。
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来源期刊
CiteScore
1.40
自引率
0.00%
发文量
28
期刊介绍: Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology   is an international peer reviewed journal that publishes original articles on physical, chemical, and molecular mechanisms that underlie basic properties of biological membranes and mediate membrane-related cellular functions. The primary topics of the journal are membrane structure, mechanisms of membrane transport, bioenergetics and photobiology, intracellular signaling as well as membrane aspects of cell biology, immunology, and medicine. The journal is multidisciplinary and gives preference to those articles that employ a variety of experimental approaches, basically in biophysics but also in biochemistry, cytology, and molecular biology. The journal publishes articles that strive for unveiling membrane and cellular functions through innovative theoretical models and computer simulations.
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