br Experimental section br Acknowledgments
Acknowledgments This work was supported by the National Natural Science Foundation of China (NSFC, Grant No. 81573285 and No. 81602965), the Natural Science Basic Research Plan in Shaanxi Province of China (Program No. 2018JM7071 and No. 2017JQ8002), and the Fundamental Research Funds for the Central Universities (2015qngz13).
Introduction In the last year, significant efforts have been devoted to the identification of synthetic substrates able to support the expansion and/or differentiation of pluripotent stem cells. Biomaterials functionalized with stem cell niche-related proteins and/or pro-differentiating drugs could potentially be used to stimulate stem cell proliferation and differentiation within damaged or diseased regions of the body (Chandra and Lee, 2015, Vazin and Schaffer, 2010). However, the efficacy of their delivery for stimulating the generation and maturation of new differentiated TCS 2510 mg may be limited either by the finite half-life of the proteins and by the drug kinetic release (Tong et al., 2015). Given the limited success of these approaches, strategies based on functional materials, such as various natural and synthetic polymers, have been proposed (Lutolf et al., 2009, Murphy et al., 2014). These artificial matrixes are able to accelerate stem cell expansion and differentiation without the addition of bioactive molecules. Several studies showed that polymers trigger biological responses through direct or synergistic interactions with cellular receptors, cytokines, or growth factors (Wang and Dong, 2015). Both polymers intrinsic (i.e. surface charge) and extrinsic properties (i.e. ability to interact with cells) played a pivotal role in dictating the type and strength of the biological responses. In particular, during the past two decades, cationic polymers have attracted tremendous attention for their application in regenerative medicine (Samal and Dubruel, 2015). Positive moieties can be provided by amino group in a variety of different forms (primary, secondary, tertiary and quaternary). The biomaterials containing quaternary amino groups, providing a permanent positive charge, have been the subject of extensive investigations in regenerative medicine, tissue engineering, and nanotechnology, due to their good hydrophilicity, high biocompatibility, and adequate chemical and thermal stability (Tabujew and Peneva, 2015). In our previous studies, we successfully synthesized poly(hydroxyethyl methacrylate) (pHEMA) derived-polymers differing in the amount of 2-methacryloyloxyethyltrimethyl ammonium chloride (METAC) (Rosso et al., 2003, De Rosa et al., 2004). We demonstrated that positively charged moieties on the polymer surface influenced the substratum adhesion of primary human fibroblasts, as well as proliferation, triggering signals that regulated cell survival, cell cycle progression, and expression of tissue-specific phenotypes. Although many technical applications and scientific developments have exploited Coulomb forces between charged polymers and oppositely charged biological macromolecules, fundamental aspects of these interactions are not well understood (Petrauskas et al., 2015). To date, there is very limited knowledge available on how charged polymers control cell-cell interactions and inter-cellular signal transduction. Cell-cell signaling pathways that lead to efficient differentiation of stem cells include the interaction of Ephrin ligands (ephrinB2) with Eph receptors (EphB4) (Nguyen et al., 2015, Gucciardo et al., 2014, Arthur et al., 2011). Receptor tyrosine kinases of the Eph family typically interact with the cell surface-associated ephrins at sites of cell–cell contact on neighboring cells (Pasquale, 2008). Eph–ephrin complexes lead to forward signal when Eph kinase activity propagate in the receptor-expressing cell, and reverse signal when tyrosine phosphorylation propagates in the ephrin-expressing cell.