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    • Even though substrate stiffness and tethering is

    2018-11-06

    Even though substrate stiffness and tethering is mostly known to affect focal adhesions (Trappmann et al., 2012; Wen et al., 2014; Levental et al., 2009), increasing evidence suggests that it may also affect cadherin-mediated intercellular adhesion (Smutny and Yap, 2010; Ladoux et al., 2010). Substrate stiffness was implicated in cadherin-dependent collective cell migration through myosin-II contractility (Ng et al., 2012). CDH2 is considered a mechano-responsive adhesion receptor, as the forces transmitted through CDH2 junctions are comparable in magnitude to those sustained by integrin–ECM coupling (Chopra et al., 2011). In general, stiffer substrates lead to greater traction forces, larger cell-spread areas and better developed CDH2 junctions (Ladoux et al., 2010). Finally, better understanding of cadherin based cell–cell interactions may be useful in development of scaffold-free tissue engineering strategies (Dvir-Ginzberg et al., 2003; Mertsching et al., 2005; Place et al., 2009). These strategies rely on directed cellular self-assembly using scaffold-free techniques including formation of spheroids or bioprinting, instead of biomaterial scaffolds to guide tissue formation, 3D organization and structure (Schiele et al., 2013; Baraniak and McDevitt, 2012; Norotte et al., 2009; Stevens et al., 2009; Napolitano et al., 2007).
    The role of CDH2 and CDH11 during development and morphogenesis In the early stages of embryogenesis, the trophoblast giant gap 26 are devoid of CDH2 or CDH11 (Simonneau et al., 1995). During gastrulation, the process in generating the three germ cell layers, CDH11 is highly expressed enabling spatial recognition and segregation of cells as they move to generate primitive tissue structures (Gumbiner, 1996; Guillot and Lecuit, 2013; Rossant and Tam, 2009). At later stages as cells undergo EMT, CDH1 is downregulated, while CDH2 is upregulated and is important for proper left–right axis development (Garcia-Castro et al., 2000). In general, gastrulation gives rise to three germ layers: ectoderm, endoderm and mesoderm. CDH2 and CDH11 are absent in cells of the endodermal lineage (Simonneau et al., 1995) but play important roles in the development of ectodermal and mesodermal lineages as described below.
    The role of CDH2 and CDH11 in mesenchymal stem cell differentiation Recently cadherins were found to regulate stem cell maintenance and differentiation. CDH1 was necessary for maintaining pluripotency of embryonic stem cells as well as for cellular reprogramming, where ectopic expression of CDH1 could substitute for the pluripotency factor Oct4 (Redmer et al., 2011). Interestingly, CDH2 was implicated in long-term engraftment of hematopoietic stem cells and establishment of hematopoiesis after bone marrow transplantation (Hosokawa et al., 2010a) but its exact role remains controversial. Some studies suggested that it might be necessary as inhibition of cadherin-mediated homophilic and heterophilic adhesion reduced the long-term repopulation activity of hematopoietic stem cells (HSCs) (Hosokawa et al., 2010b). However, others reported that CDH2 conditional knockout mice do not show defects in HSC number or function (Kiel et al., 2009). On the other hand, accumulating evidence suggests that both cadherins play important roles in MSC differentiation. MSCs provide an excellent cell source for cellular therapies to treat bone and cartilage disorders (Horwitz et al., 2002; Wakitani et al., 2002), myocardial infarction, stroke (Li et al., 2005; Wang et al., 2002), rheumatoid arthritis (Augello et al., 2007), acute lung injury (Gupta et al., 2007; Ortiz et al., 2007), graft-versus-host disease (Dander et al., 2012) and skin-graft rejection (Bartholomew et al., 2002) among others. The use of MSCs for tissue repair requires the migration and homing to the site of damaged tissue and it has been shown that both the migratory and proliferation potential of these cells are affected by CDH2 and CDH11 (Xu et al., 2012; Theisen et al., 2007). MSCs have also been shown to have differentiation potential and anti-inflammatory properties (Myers et al., 2010), which are enhanced when cultured as 3D spheroid aggregates (Bartosh et al., 2010; Alimperti et al., 2014b). Interestingly, both CDH2 and CDH11 were shown to be critical in the response of synovial fibroblasts to inflammation (Agarwal and Brenner, 2006; Chang et al., 2011), suggesting that cadherins may also be important in mediating the anti-inflammatory effects of MSCs. Finally, CDH2 and CDH11 have been shown to be critical for MSC differentiation and their expression levels are regulated differently in osteogenic, chondrogenic or myogenic lineages as described below (Fig. 2).