PDF(Pubmed)
Abstract：
Mesenchymal stromal cells (MSCs) display heterogeneity in origin and functional role in tissue homeostasis. Subsets of MSCs derived from the neural crest express nestin and serve as niches in bone marrow, but the possibility of coaxing MSCs into nestin-expresing cells for enhanced supportive activity is unclear. In this study, as an approach to the chemical coaxing of MSC functions, we screened libraries of clinically approved chemicals to identify compounds capable of inducing nestin expression in MSCs. Out of 2000 clinical compounds, we chose vorinostat as a candidate to coax the MSCs into neural crest-like fates. When treated with vorinostat, MSCs exhibited a significant increase in the expression of genes involved in the pluripotency and epithelial-mesenchymal transition (EMT), as well as nestin and CD146, the markers for pericytes. In addition, these nestin-induced MSCs exhibited enhanced differentiation towards neuronal cells with the upregulation of neurogenic markers, including SRY-box transcription factor 2 (Sox2), SRY-box transcription factor 10 (Sox10) and microtubule associated protein 2 (Map2) in addition to nestin. Moreover, the coaxed MSCs exhibited enhanced supporting activity for hematopoietic progenitors without supporting leukemia cells. These results demonstrate the feasibility of the drug repositioning of MSCs to induce neural crest-like properties through the chemical coaxing of cell fates.
摘要：
间充质基质细胞（MSC）在组织稳态中的起源和功能作用方面表现出异质性。来自神经c的MSCs亚群表达巢蛋白并在骨髓中充当壁龛，但是诱导MSCs进入巢蛋白表达细胞以增强支持活性的可能性尚不清楚。在这项研究中,作为MSC功能的化学哄骗方法，我们筛选了临床批准的化学品文库,以鉴定能够诱导MSCs中巢蛋白表达的化合物.在2000种临床化合物中，我们选择伏立诺他作为候选物,将MSCs诱导为神经嵴样命运.当用伏立诺他治疗时，MSCs表现出参与多能性和上皮间质转化（EMT）的基因表达显着增加，以及巢蛋白和CD146，周细胞的标记。此外,这些巢蛋白诱导的MSCs表现出增强的向神经元细胞的分化与神经源性标志物的上调，包括SRY-box转录因子2（Sox2），SRY-box转录因子10(Sox10)和微管相关蛋白2(Map2)以及巢蛋白。此外，经诱导的MSCs对造血祖细胞的支持活性增强,而不支持白血病细胞.这些结果证明了药物重新定位MSC以通过细胞命运的化学诱导诱导神经rest样特性的可行性。
