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    • The activity of CXCL through CXCR

    2018-10-24

    The activity of CXCL12(5-67) through CXCR3 receptor has been shown before (Denoyer et al., 2012; Zhu et al., 2009). Here we aimed to confirm this finding using CXCL9, a natural ligand of CXCR3. NSCs pre-treated with CXCL9 were not susceptible to the CXCL12(5-67) apoptotic effects. The effect of CXCL12(5-67) on NSCs in this set of experiments were less prominent then before, but still significant. This result can be explained by the fact that the pramiracetam were kept for 1h at 4°C, which keeps the viability but reduces the metabolic activity, enzymatic reactions rates, as well as transcription and translational processes (Hunt et al., 2005; Sonna et al., 2002).
    Conclusions
    Methods
    Author contributions
    Competing interests
    Introduction Hematopoietic stem cells (HSCs) are capable of self-renewal and of differentiating into mature blood cells (Jagannathan-Bogdan & Zon, 2013) and the cross talk between HSCs and Bone marrow stromal cells (BMSCs), in the bone marrow microenvironment, is essential for HSCs regulation (Morrison & Scadden, 2014). This homeostasis may be interrupted by mutations in the HSC, caused by errors induced by aging, environment, hereditary factors among other factors (Wilson et al., 2008). The most frequent hematological disease of aging are the myelodysplastic syndromes (MDS), in which acquired mutations in HSC lead to deregulation of signaling pathways, conferring risk of clonal expansion and progression to acute myeloid leukemia (AML) (Albitar et al., 2002). Nowadays, the differentiation between both MDS and AML is mainly based on the number of immature, supposedly neoplastic, cells in the bone marrow, being 20% the cutoff number (MDS - <20% and AML - 20% or more) Patients with MDS have low or high risk to evolve to AML, depending on genetic, epigenetic and/or immunological factors (Vardiman et al., 2009). Recent studies have shown that the cross-talk between leukemic stem cells, which are a small fraction of leukemic cells capable of self-renewal, and BMSCs is essential for leukemogenesis (Lee et al., 2015). Similarly, myelodysplastic cells require a type of cancer stem cell for myelodysplastic syndrome (MDS) development (Woll et al., 2014). For a better knowledge of the interaction between leukemic and stromal cells, our group performed a microarray study using bone marrow cells from MDS patients and found VEGFA overexpression in progenitor CD34+ cells and SEMA3A overexpression in BMSCs (Baratti et al., 2010). SEMA3A is a secreted protein characterized by its role in migration and guidance of axons in the developing nervous system. SEMA3A can only bind to neuropilin 1 receptor (NRP1), however neuropilins are unlikely to transduce SEMA3A signals on their own due to their short intracellular domain, thereby, complex formation with Plexin A receptors is necessary for signal transduction (Neufeld et al., 2012). NRP1 serve as co-receptors for VEGFA; VEGFA is a proangiogenic factor widely known and, due to alternative splicing, the VEGFA gene generates multiple isoforms among which VEGF165 is the most abundant. VEGFR1 and VEGFR2 are the main receptors for VEGF165, however the complex formation with NRP1 co-receptor can enhance their signaling (Neufeld et al., 1999). Studies have described increased VEGFA mRNA (Fiedler et al., 1997), plasma levels (Aguayo et al., 2002) and protein expression (Verstovsek et al., 2002) in AML patients and correlation with a worse prognosis (Gerber & Ferrara, 2003), however the role of VEGFA in MDS remains controversial (Aguayo et al., 2002; Verstovsek et al., 2002; Bellamy et al., 2001; Wimazal et al., 2006; Gianelli et al., 2013). An antagonistic role of VEGFA and SEMA3A has been implicated in several solid tumors (Chekhonin et al., 2013; Bender & Mac Gabhann, 2015); while VEGFA increases tumor growth and metastasis (Chekhonin et al., 2013), SEMA3A is associated to lower migration and invasion rates (Pellet-Many et al., 2008), and to a better prognosis (Janssen et al., 2012). Moreover, there is a disagreement as to whether VEGF165 and SEMA3A opposite effects could be due to NRP1 binding competition (Pellet-Many et al., 2008). The aim of this study is to better understand the interaction of VEGFA and SEMA3A in the bone marrow of MDS and AML patients.