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Open Access Cell‐Cell Interaction Promotes Rat Marrow Stromal Cell Differentiation Into Endothelial Cell via Activation of TACE/TNF-α Signaling

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Marrow stromal cells (MSCs) are capable of differentiating into various cell types including endothelial cells. Microenvironment is important in cell fate determination. Tumor necrosis factor-α converting enzyme (TACE), a well-characterized “sheddase,” participates in the differentiation process of multiple lineages by the proteolytic release of membrane-bound proteins such as tumor necrosis factor-α (TNF-α). We investigated the endothelial differentiation of MSCs under two coculture conditions: 1) direct MSCs-rat brain microvascular endothelial cells (rBMECs) contact coculture; and 2) indirect coculture of MSCs and rBMECs. Also, we examined the role of TACE/TNF-α signaling in the process of differentiation under direct coculture condition. We found that endothelial differentiation of MSCs was substantially enhanced in MSCs-rBMECs direct contact coculture, but not in indirect transwell coculture condition. Transcript levels of TACE and TNF-α as well as TACE protein expression were significantly upregulated in direct, but not in indirect, coculture condition. Addition of human recombinant TACE promoted gene expression of endothelial specific markers including vWF, CD31, VE-cadherin, Flk-1, and Flt-1 in the differentiating MSCs. Furthermore, inhibition of TACE with TAPI-2 or inhibition of TNF-α with Etanercept attenuated endothelial differentiation of MSCs in the direct coculture condition. We demonstrated for the first time that direct MSCs-rBMECs interaction stimulated the endothelial differentiation of MSCs via TACE/TNFα signaling.

Keywords: Cell‐cell contact; Coculture; Endothelial cell differentiation; Marrow stromal cell (MSC); TACE/TNF-α

Document Type: Research Article


Publication date: 2010-01-01

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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