Gangliosides of myelosupportive stroma cells are transferred to myeloid progenitors and are required for their survival and proliferation

Abstract

In previous studies, we have shown that the myelopoiesis dependent upon myelosupportive stroma required production of growth factors and heparan-sulphate proteoglycans, as well as generation of a negatively charged sialidase-sensitive intercellular environment between the stroma and the myeloid progenitors. In the present study, we have investigated the production, distribution and role of gangliosides in an experimental model of in vitro myelopoiesis dependent upon AFT-024 murine liver-derived stroma. We used the FDC-P1 cell line, which is dependent upon GM-CSF (granulocyte/macrophage colony-stimulating factor) for both survival and proliferation, as a reporter system to monitor bioavailability and local activity of GM-CSF. G(M3) was the major ganglioside produced by stroma, but not by myeloid cells, and it was required for optimal stroma myelosupportive function. It was released into the supernatant and selectively incorporated into the myeloid progenitor cells, where it segregated into rafts in which it co-localized with the GM-CSF-receptor alpha chain. This ganglioside was also metabolized further by myeloid cells into gangliosides of the a and b series, similar to endogenous G(M3). In these cells, G(M1) was the major ganglioside and it was segregated at the interface by stroma and myeloid cells, partially co-localizing with the GM-CSF-receptor alpha chain. We conclude that myelosupportive stroma cells produce and secrete the required growth factors, the cofactors such as heparan sulphate proteoglycans, and also supply gangliosides that are transferred from stroma to target cells, generating on the latter ones specific membrane domains with molecular complexes that include growth factor receptors.

Reservoir host competence and the role of domestic and commensal hosts in the transmission of Trypanosoma cruzi

“…Comparison of the age-specific infectiousness of T. cruzi-seropositive dogs before and 1-2 years after suppression of domestic bug infestations revealed insignificant differences over time (Gürtler et al, 1992b). Similarly, the experimental effects of reinoculations on infectiousness in dogs, monkeys and mice were also slight and transient or nil (Andrade et al, 2006;Bustamante et al, 2007;Machado et al, 2001;Riarte et al, 1995). However, when dogs were inoculated successively with two stocks of T. cruzi, both genotypes were recovered from three out of eight dogs and one of the genotypes predominated during the follow-up (Machado et al, 2001).…”

Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease

“…GM3 significantly promoted OC development and function, as shown by increased OC numbers and surface in situ and serum CTX levels, and both of these effects were effectively inhibited by NB-DNJ. Exogenous GM3 has been shown previously to incorporate into cell membranes and lipid rafts of myeloid cells and to promote downstream cell signaling (50,51). It is possible, therefore, that disruption of lipid rafts in OC precursors by NB-DNJ prevents the OC-activating effect of exogenous GM3.…”

“…The inhibitory effect of NB-DNJ on de mote cell proliferation in response to GM-CSF (50,51). Alternatively, exogenous GM3 might act indirectly by promoting secretion of pro-osteoclastogenic factors from other BM cells, such as osteoblasts, monocytes/macrophages, and T cells.…”

Metabolic pathways and intracellular trafficking of gangliosides

“…In addition, they are expressed in cell‐type‐ and developmental‐specific patterns and are major components of nerve cells, where they can represent more than 10% of the total lipid content and, on the neuronal surface, contribute more than 30% of the N ‐acetylneuraminic acid (NeuAc or sialic acid) (1, 2). Gangliosides have been implicated in many physiological processes, including growth, differentiation, migration, and apoptosis through modulating both cell signaling processes and cell‐to‐cell and cell‐to‐matrix interactions (3–11). Moreover, gangliosides have been associated with a wide range of pathological processes, being receptors for viruses (i.e., simian virus 40, SV40), toxins [i.e., cholera (CTx); tetanus and botulinus toxins], lectins and antibodies (12–15).…”