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    • br Experimental Procedures See Supplemental Experimental Pro

    2018-11-09


    Experimental Procedures See Supplemental Experimental Procedures for additional details.
    Author Contributions
    Acknowledgments Derivation and characterization of H1-ECs and RNA-seq experiments were supported by NIH in collaboration with the Defense Advanced Research Projects Agency and the US Food and Drug Administration as part of the Microphysiological Systems (MPS) program (NIH grants 1UH2TR000506-01 and 4UH3TR000506-03). PEG hydrogel development was supported by NIH R21EB016381-01, NIH RO1 HL093282, and the Environmental Protection Agency STAR Center grant 835737. W.L.M. is a founder and stockholder for Stem Pharm, Inc. and Tissue Regeneration Systems, Inc.
    Introduction A frequently used source of mesenchymal stem purchase Nocodazole (MSCs) is bone marrow. Such MSCs are commonly used as immune-suppressants for the treatment of steroid-refractory graft-versus-host disease after transplantation of hematopoietic stem cell-containing preparations, as MSCs elicit a weak allogeneic immune response when delivered into a non-identical, non-matched recipient (Nauta and Fibbe, 2007; Pittenger et al., 1999; Schu et al., 2012). However, bone marrow extraction is a highly invasive procedure and only 0.01% to 0.001% of the collected cells are MSCs. Therefore, more easily accessible sources of MSCs are needed. In contrast to bone marrow, MSCs can be easily harvested from various other adult human tissues, including cord blood, placenta, peripheral blood, adipose tissue, and the vessel wall (Gotherstrom et al., 2005; Jin et al., 2013; Klein et al., 2011; Zhu et al., 2014). However, variations of the quality of obtained donor cells and tissue sources, as well as subsequent cell culture, have caused numerous inconsistencies in the reported in vivo effectiveness of MSCs (Galipeau, 2013; Kimbrel et al., 2014; Tyndall, 2014; Wagner and Ho, 2007). Although these rare post-natal stem cells can be rapidly expanded in vitro to obtain the numbers necessary for therapeutic use, vigorous ex vivo expansion can result in replicative senescence and lead to a decline of their plasticity (e.g., alterations in cell-cycle or apoptosis pattern while maintaining the normal karyotype and phenotypic characteristics) and in vivo potency over time (Ho et al., 2013; Kyriakou et al., 2008; Liu et al., 2012; Miura et al., 2006; Rombouts and Ploemacher, 2003). Finally, tissue stem cells may have accumulated many DNA abnormalities (caused by sunlight, toxins, and errors during DNA replication) during a lifetime (Janzen et al., 2006; Mimeault and Batra, 2009). These potential drawbacks may limit their usefulness. An alternative method to circumvent many of these issues is to obtain MSCs by their generation from induced pluripotent stem cells (iPSCs) in vitro. Use of allogeneic standardized, validated, and officially approved iPSC banks would allow the generation of “off-the-shelf” MSCs with comparable properties and in large quantities (Jung et al., 2012; Kimbrel et al., 2014; Okano et al., 2013; Lindvall and Kokaia, 2010). The classical method for differentiating iPSCs toward MSCs is the use of medium that contains a high serum concentration or MSC-typical growth factors such as basic fibroblast growth factor after dissociation of embryoid bodies (Frobel et al., 2014; Jung et al., 2012; Liu et al., 2012). We have previously shown that vascular wall-derived MSCs (VW-MSCs) particularly were more potent than bone marrow-derived MSCs in protecting lung endothelial cells from the adverse late effects of radiotherapy (Klein et al., 2016a, 2016b). These findings support the assumption that tissue-specific stem cells support the tissue type from which they originate, which is a central advantage for the use of VW-MSCs for the protection and curative treatment of vascular structures (Ergun et al., 2011; Klein, 2016; Klein et al., 2016a). Previous reports have already demonstrated that bone marrow-derived MSCs were less effective for MSC therapy than other stem cell sources, e.g., when compared with adipose tissue-derived or fetal MSCs, respectively (Montesinos et al., 2009; Prasanna et al., 2010; Ribeiro et al., 2013; Wang et al., 2014; Wegmeyer et al., 2013; Zhang et al., 2009).