Previously, we demonstrated that NO/cGMP signaling facilitates the migration of cultured human neuronal precursor (NT2) cells (Tegenge and Bicker, 2009). Since the NT2 cell line was obtained from a human teratocarcinoma (Andrews, 1984) and we cannot rule out effects of genetic rearrangements in the cancer cells, it is problematic to relate these findings to normal human neural development. Multi-potent human neuronal progenitor cells can be obtained from cells of ectodermal lineage and are restricted in fate to develop into neurons, astrocytes and oligodendrocytes. Stem cells can also be isolated from both developing human brain and restricted areas of adult human brain. Studies over the past decade have focused mainly on the use of stem cells in transplantation therapy for various diseases models. However, stem cells derived neuronal progenitor cells have the potential to investigate the molecular and cellular basis of human brain development.
In this study, we used fetal human neural progenitor cells (hNPCs) cultured as neurospheres to investigate the role of NO/cGMP signaling in neuronal migration. hNPCs derive from 16 to 20-week old female or male fetal whole brain homogenates, which have the capacity to differentiate into neuronal and glial cells (Moors et al., 2009; Breier, 2009). Culturing proliferating human neurospheres on laminin coated adhesive substrates resulted in cells that migrate out of the spheres
which were accompanied by differentiation into both neuronal and glial cells. Intriguingly, cells that migrate out respond to exogenous stimulation of NO and synthesize increasing level of cGMP.
These results provide first experimental evidence that functional NO-sensitive sGC is expressed early during human brain development. The cGMP positive cells at the forefront of migration were co-stained for either nestin or GFAP but not for -tubulin. Thus, compared to NT2 cell culture that lack GFAP positive cells, the hNPCs may mimic aspects of radial neuroblast migration during human brain development.
Application of small bioactive enzyme inhibitors and activators in human neurosphere culture implicate that NO/cGMP/PKG signaling is key regulator of neuronal progenitor migration.
Compared to the NT2 cell culture, in hNPCs inverted U-shaped dose-response curve for the NO donor NOC-18 was obtained at relatively smaller dose range (1-100 µM). Our data demonstrate that at 10 µM NOC-18 appeared to facilitate neuronal progenitor cell migration while at relatively higher concentration (100 µM) inhibition of cell migration was observed. These result suggest that NO could play dual role on neuronal migration depending on the concentration. Such dual role of NO on cell migration and neurite outgrowth that depends on concentration has been reported previously (Elferink, and VanUffelen, 1996; Trimm and Rehder, 2004). Furthermore, we directly showed the involvement of sGC and PKG in NO induced facilitation of hNPCs migration. Here, co-application of NO donor with enzyme inhibitors of sGC or PKG resulted in blocked of NO induced facilitation of hNPCs migration suggesting that low concentration of NO facilitates neuronal progenitor migration via sGC and PKG signaling pathway.
In summary, this study provides the first evidence for the involvement of NO signaling in human neuronal development. Since neuronal migration is controlled by a complex combination of chemical signals, it would be interesting to comprehend how the NO signal regulates neuronal migration in combination with other known signals. Understanding the cellular and molecular mechanisms of neuronal migration may offer hopes to develop new therapeutic agents for human congential disorders associated with defective neuronal migration. Our findings have further implications in adult neurogenesis. In recent years research in NSC biology focus on restoration of damaged neural networks in the various neurodegenerative diseases by promoting endogenous neurogenesis or transplantation of NSC. To this end, manipulation of NO/cGMP signaling may facilitate migration and integration of endogenous or transplanted neuronal progenitor cells into the existing neuronal network which could promote functional recovery in various neurodegenerative diseases.
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