Rosner Margit, Hengstschläger Markus
Institute of Medical Genetics, Center of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Stem Cells. 2021 Dec;39(12):1718-1732. doi: 10.1002/stem.3441. Epub 2021 Aug 4.
Three-dimensional (3D) cell migration is an integral part of many physiologic processes. Although being well studied in the context of adult tissue homeostasis and cancer development, remarkably little is known about the invasive behavior of human stem cells. Using two different kinds of invasion assays, this study aimed at investigating and characterizing the 3D migratory capacity of human amniotic fluid stem cells (hAFSCs), a well-established fetal stem cell type. Eight hAFSC lines were found to harbor pronounced potential to penetrate basement membrane (BM)-like matrices. Morphological examination and inhibitor approaches revealed that 3D migration of hAFSCs involves both the matrix metalloprotease-dependent mesenchymal, elongated mode and the Rho-associated protein kinase-dependent amoeboid, round mode. Moreover, hAFSCs could be shown to harbor transendothelial migration capacity and to exhibit a motility-associated marker expression pattern. Finally, the potential to cross extracellular matrix was found to be induced by mTORC1-activating growth factors and reduced by blocking mTORC1 activity. Taken together, this report provides the first demonstration that human stem cells exhibit mTORC1-dependent invasive capacity and can concurrently make use of mesenchymal and amoeboid 3D cell migration modes, which represents an important step toward the full biological characterization of fetal human stem cells with relevance to both developmental research and stem cell-based therapy.
三维（3D）细胞迁移是许多生理过程不可或缺的一部分。尽管在成人组织稳态和癌症发展的背景下已得到充分研究，但对于人类干细胞的侵袭行为却知之甚少。本研究使用两种不同的侵袭试验，旨在研究和表征人羊水干细胞（hAFSCs，一种成熟的胎儿干细胞类型）的3D迁移能力。发现8种hAFSC系具有穿透基底膜（BM）样基质的显著潜力。形态学检查和抑制剂方法表明，hAFSCs的3D迁移涉及基质金属蛋白酶依赖性间充质、伸长模式和Rho相关蛋白激酶依赖性阿米巴样、圆形模式。此外，hAFSCs可显示具有跨内皮迁移能力并表现出与运动相关的标志物表达模式。最后，发现细胞外基质穿越潜力由mTORC1激活生长因子诱导，并通过阻断mTORC1活性而降低。综上所述，本报告首次证明人类干细胞具有mTORC1依赖性侵袭能力，并可同时利用间充质和阿米巴样3D细胞迁移模式，这是朝着与发育研究和干细胞治疗相关的胎儿人类干细胞的完整生物学表征迈出的重要一步。
