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    • It seems that D R improves

    2018-11-08

    It seems that D1R improves HSC transplantation likely through affecting both HSCs and their niches. Activation of Notch signaling in HSCs by D1R bound to ECs might promote HSC expansion principally through their enhanced proliferation, and decreased apoptosis might also contribute to the ex vivo expansion to certain extent. The gene profiling experiment indicated that D1R stimulated the expressions of a group of stemness-related genes in HSCs, consistent with a role of forced Notch activation in promoting HSC expansion. In addition to the direct effects on HSCs, D1R might also promote HSC engraftment through influencing, structurally and/or functionally, stem cell niches. Ex vivo, D1R promotes the formation of adhesive structures between HSCs and HUVECs, whose survival is necessary for the expansion of HSCs. D1R significantly promoted the recovery of the structure and organization of BM SECs after radiation, consistent with the role of Notch signaling in regulating EC proliferation and differentiation (Dou et al., 2008). In addition to BM, the application of D1R also leads to increased hematopoiesis in the liver and spleen, which are hematopoietic tissues in rodents. D1R could bind to ECs in BM as well as in the liver and spleen, and modulates their activity in supporting HSCs. D1R might also modulate HSCs to increase their homing to hematopoietic tissues. Notch signaling regulates the hcv protease inhibitors of CXCR4, a critical receptor for HSC homing (Kelly et al., 2010; Delaney et al., 2010a; Blank et al., 2008). Moreover, adhesion molecules such as some members of the integrin family are critically involved in HSC homing to BM niches (Wagers et al., 2002). Indeed, the mRNA levels of the αv, α5, α6, and β1 integrins were upregulated in the presence of mD1R compared with that of the controls (supplementary Fig. S10). It is possible that the interaction between HSCs and ECs mediated by Notch signaling helped the homing and proliferation of HSCs in the hematopoietic tissues including BM, spleen, and liver of mice treated with D1R, because Notch signaling has been demonstrated to crosstalk with many important signaling pathways involved in stem cell niches (Blank et al., 2008).
    Authorship and disclosures
    Competing interests
    Introduction Directed cell migration (chemotaxis) towards a stimulus is a well defined function of many mammalian and non-mammalian cells and is vital throughout embryonic and postnatal life (Petrie et al., 2009). A key example is the homing or migration of hematopoietic stem/progenitor cells (HSPCs) to specific microenvironmental niches, where their fate is determined (Bianco, 2011; Lawal and Calvi, 2011; Mazo et al., 2011; Mercier et al., 2011; Nagasawa et al., 2011; Calderón and Boehm, 2012; Park et al., 2012) or mobilization from these niches using small molecule strategies or in disease states (Kolonin and Simmons, 2009; Shiozawa and Taichman, 2010; Mohty and Ho, 2011; Psaila et al., 2012). Importantly, in the clinical setting, prior manipulation or expansion of HSPCs can compromise or enhance their homing or migratory capacities and this can affect transplant outcomes (Aljitawi, 2012). This is particularly pertinent for cord blood where HSPC content is limited, engraftment and hematological reconstitution are delayed compared to bone marrow or mobilized peripheral blood, one cord blood unit will engraft in preference to another in double cord blood transplants, and expansion/manipulation ex vivo prior to transplant is used to reduce delayed engraftment (Dahlberg et al., 2011; Nagasawa et al., 2011; Petropoulou and Rocha, 2011; Watt, 2011; Aljitawi, 2012; Broxmeyer, 2012; Christopherson et al., 2012; Csaszar et al., 2012; Ramirez et al., 2012). The CXC chemokine, CXCL12, is a key chemo-attractant for HSPC homing to bone marrow, also regulating HSPC motility, homing to, and retention, survival, and proliferation in this niche (Peled et al., 1999; Dar et al., 2006; Watt and Forde, 2008; Sharma et al., 2011; Bonig and Papayannopoulou, 2013). The cognate receptors for CXCL12 are CXCR4 and CXCR7, although the latter is poorly expressed on human HSPCs (Hartmann et al., 2008; Sun et al., 2010). However, where expressed on other cells, CXCR7 is thought to act as a decoy receptor or co-receptor for CXCR4 (Naumann et al., 2010; Sun et al., 2010). CXCL12/CXCR4 deficient mice demonstrate defects in hematopoietic, immune, circulatory and central nervous systems (Zou et al., 1998; reviewed in Watt and Forde, 2008). Co-operation and cross talk between CXCL12/CXCR4, other receptors/proteins, and signaling molecules are thought to fine tune cellular responses and/or specificity for microenvironmental niches (Forde et al., 2007; Christopherson et al., 2012; Schiraldi et al., 2012).