Autor/a:
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Messina, Valeria; Valtieri, Mauro; Rubio, Mercedes; Falchi, Mario; Mancini, Francesca; Mayor Aparicio, Alfredo Gabriel; Alano, Pietro; Silvestrini, Francesco
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Abstract:
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The gametocytes of Plasmodium falciparum, responsible for the
transmission of this malaria parasite from humans to mosquitoes,
accumulate and mature preferentially in the human bone marrow.
In the 10 day long sexual development of P. falciparum, the
immature gametocytes reach and localize in the extravascular
compartment of this organ, in contact with several bone marrow
stroma cell types, prior to traversing the endothelial lining
and re-entering in circulation at maturity. To investigate the
host parasite interplay underlying this still obscure process,
we developed an in vitro tridimensional co-culture system in a
Matrigel scaffold with P. falciparum gametocytes and
self-assembling spheroids of human bone marrow mesenchymal cells
(hBM-MSCs). Here we show that this co-culture system sustains
the full maturation of the gametocytes and that the immature,
but not the mature, gametocytes adhere to hBM-MSCs via
trypsin-sensitive parasite ligands exposed on the erythrocyte
surface. Analysis of a time course of gametocytogenesis in the
co-culture system revealed that gametocyte maturation is
accompanied by the parasite induced stimulation of hBM-MSCs to
secrete a panel of 14 cytokines and growth factors, 13 of which
have been described to play a role in angiogenesis. Functional
in vitro assays on human bone marrow endothelial cells showed
that supernatants from the gametocyte mesenchymal cell
co-culture system enhance ability of endothelial cells to form
vascular tubes. These results altogether suggest that the
interplay between immature gametocytes and hBM-MSCs may induce
functional and structural alterations in the endothelial lining
of the human bone marrow hosting the P. falciparum transmission
stages. |