Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
Stem Cells Dev. 2021 Apr;30(8):418-427. doi: 10.1089/scd.2020.0195. Epub 2021 Mar 23.
Mesenchymal stem cells (MSCs) represent a population of adult stem cells that have potent immunoregulatory, anti-inflammatory, and antiapoptotic properties. In addition, they have ability to migrate to the site of inflammation or injury, where they contribute to the regeneration and healing process. For these properties, MSCs have been used as therapeutic cells in several models, including treatment of damages or disorders of the ocular surface. If the damage of the ocular surface is extensive and involves a limbal region where limbal stem cell reside, MSC therapy has been proved as the effective treatment approach. Although the anti-inflammatory properties of MSCs have been well characterized, mechanisms of antiapoptotic action of MSCs are not well recognized. Using a chemically damaged cornea in a mouse model, we showed that the injury decreases expression of the gene for antiapoptotic molecule Bcl-2 and increases the expression of proapoptotic genes and . These changes were attenuated by local transplantation of MSCs after corneal damage. The antiapoptotic effect of MSCs was tested in an in vitro model of co-cultivation of corneal explants with MSCs. The apoptosis of corneal cells in the explants was induced by proinflammatory cytokines and was significantly inhibited in the presence of MSCs. The antiapoptotic effect of MSCs was mediated by paracrine action, as confirmed by separation of the explants in inserts or by supernatants from MSCs. In addition, MSCs decreased the expression of genes for the molecules associated with endoplasmic reticulum stress Atf4, Bip, and p21, which are associated with apoptosis. The results show that MSCs inhibit the expression of proapoptotic genes and decrease the number of apoptotic cells in the damaged corneas, and this action might be one of the mechanisms of the therapeutic action of MSCs.
间充质干细胞（MSCs）是一种成体干细胞，具有强大的免疫调节、抗炎和抗凋亡特性。此外，它们还有向炎症或损伤部位迁移的能力，在那里它们有助于再生和愈合过程。由于这些特性，MSCs 已被用于多种模型的治疗细胞，包括治疗眼表面的损伤或疾病。如果眼表面的损伤广泛且涉及到角膜缘干细胞所在的角膜缘区域，则 MSC 治疗已被证明是有效的治疗方法。尽管 MSCs 的抗炎特性已经得到很好的描述，但 MSCs 抗凋亡作用的机制尚不清楚。我们使用小鼠模型中的化学损伤角膜来表明，损伤会降低抗凋亡分子 Bcl-2 的基因表达，并增加促凋亡基因 和 的表达。这些变化在角膜损伤后局部移植 MSC 时得到了减轻。我们在角膜外植体与 MSC 共培养的体外模型中测试了 MSC 的抗凋亡作用。角膜细胞在外植体中的凋亡是由促炎细胞因子诱导的，而在 MSC 存在下则明显受到抑制。MSC 的抗凋亡作用是通过旁分泌作用介导的，这一点通过将外植体插入或 MSC 的上清液分离得到了证实。此外，MSC 还降低了与内质网应激相关的分子 Atf4、Bip 和 p21 的基因表达，这些分子与凋亡有关。结果表明，MSC 抑制了促凋亡基因的表达，减少了受损角膜中的凋亡细胞数量，这一作用可能是 MSC 治疗作用的机制之一。
