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源自人诱导多能干细胞的神经胶质祖细胞分泌的蛋白质的神经保护和抗炎特性。

Neuroprotective and anti-inflammatory properties of proteins secreted by glial progenitor cells derived from human iPSCs.

作者信息

Salikhova Diana I, Shedenkova Margarita O, Sudina Anastasya K, Belousova Ekaterina V, Krasilnikova Irina A, Nekrasova Anastasya A, Nefedova Zlata A, Frolov Daniil A, Fatkhudinov Timur Kh, Makarov Andrey V, Surin Alexander M, Savostyanov Kirill V, Goldshtein Dmitry V, Bakaeva Zanda V

机构信息

Laboratory of Cellular Biotechnology, Research Institute of Molecular and Cellular Medicine, Medical Institute of RUDN University, Moscow, Russia.

Laboratory of Stem Cell Genetics, Research Centre for Medical Genetics, Moscow, Russia.

出版信息

Front Cell Neurosci. 2024 Aug 6;18:1449063. doi: 10.3389/fncel.2024.1449063. eCollection 2024.

Abstract

Currently, stem cells technology is an effective tool in regenerative medicine. Cell therapy is based on the use of stem/progenitor cells to repair or replace damaged tissues or organs. This approach can be used to treat various diseases, such as cardiovascular, neurological diseases, and injuries of various origins. The mechanisms of cell therapy therapeutic action are based on the integration of the graft into the damaged tissue (replacement effect) and the ability of cells to secrete biologically active molecules such as cytokines, growth factors and other signaling molecules that promote regeneration (paracrine effect). However, cell transplantation has a number of limitations due to cell transportation complexity and immune rejection. A potentially more effective therapy is using only paracrine factors released by stem cells. Secreted factors can positively affect the damaged tissue: promote forming new blood vessels, stimulate cell proliferation, and reduce inflammation and apoptosis. In this work, we have studied the anti-inflammatory and neuroprotective effects of proteins with a molecular weight below 100 kDa secreted by glial progenitor cells obtained from human induced pluripotent stem cells. Proteins secreted by glial progenitor cells exerted anti-inflammatory effects in a primary glial culture model of LPS-induced inflammation by reducing nitric oxide (NO) production through inhibition of inducible NO synthase (iNOS). At the same time, added secreted proteins neutralized the effect of glutamate, increasing the number of viable neurons to control values. This effect is a result of decreased level of intracellular calcium, which, at elevated concentrations, triggers apoptotic death of neurons. In addition, secreted proteins reduce mitochondrial depolarization caused by glutamate excitotoxicity and help maintain higher NADH levels. This therapy can be successfully introduced into clinical practice after additional preclinical studies, increasing the effectiveness of rehabilitation of patients with neurological diseases.

摘要

目前,干细胞技术是再生医学中的一种有效工具。细胞疗法基于使用干/祖细胞来修复或替换受损组织或器官。这种方法可用于治疗各种疾病,如心血管疾病、神经疾病以及各种原因导致的损伤。细胞疗法的治疗作用机制基于移植细胞整合到受损组织中的作用(替代效应)以及细胞分泌生物活性分子(如细胞因子、生长因子和其他促进再生的信号分子)的能力(旁分泌效应)。然而,由于细胞运输的复杂性和免疫排斥反应,细胞移植存在一些局限性。一种可能更有效的疗法是仅使用干细胞释放的旁分泌因子。分泌因子可对受损组织产生积极影响:促进新血管形成、刺激细胞增殖并减轻炎症和细胞凋亡。在这项研究中,我们研究了源自人类诱导多能干细胞的神经胶质祖细胞分泌的分子量低于100 kDa的蛋白质的抗炎和神经保护作用。神经胶质祖细胞分泌的蛋白质在脂多糖诱导的炎症的原代神经胶质细胞培养模型中发挥抗炎作用,通过抑制诱导型一氧化氮合酶(iNOS)减少一氧化氮(NO)的产生。同时,添加的分泌蛋白中和了谷氨酸的作用,将存活神经元的数量增加到对照值。这种作用是细胞内钙水平降低的结果,细胞内钙浓度升高会触发神经元的凋亡死亡。此外,分泌蛋白减少了由谷氨酸兴奋性毒性引起的线粒体去极化,并有助于维持较高的烟酰胺腺嘌呤二核苷酸(NADH)水平。经过额外的临床前研究后,这种疗法可以成功引入临床实践,提高神经疾病患者康复的有效性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0252/11333358/7c237d33a711/fncel-18-1449063-g001.jpg

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