| Abstract |
Mesenchymal stem cells (MSCs) constitute a population of multipotent adherent cells
capable of differentiating into multiple lineages of the mesenchyme. To date, bone
marrow represents the best characterized source of MSCs. However, BM-MSCs
harvesting and processing exhibits major drawbacks and limitations. Thus alternative
sources of MSCs is of great importance. A recently identified source of MSCs is the
amniotic fluid (In 't Anker et al., 2004; Tsai et al., 2004). The main characteristics of
the amniotic fluid-derived mesenchymal stem cells (AF-MSCs) are their ease of
isolation during scheduled amniocentesis, their high expansion potential in vitro and
their ability to differentiate into multiple lineages (Roubelakis et al., 2007). These
characteristics make AF-MSCs ideal for use in several therapeutic applications. So
far, extensive studies have shown that MSCs derived from adult tissues exert a
profound inhibitory effect on T cell proliferation in vitro and in vivo. However, there is
a limited number of studies describing the immunomodulatory properties of AF-MSCs
(Roelen et al., 2009; Sessarego et al., 2008). Therefore, the purpose of this study is
to elucidate the effect of AF-MSCs in lymphocyte proliferation and the molecular
mechanisms that underlie this effect. In this study, was initially tested the effect of
AF-MSCs on T cells and found that AF-MSCs inhibit T-cell proliferation triggered by
mitogenic stimuli in a dose-dependent manner, but have no effect on resting / nonactivated
T cells. Interestingly enough, AF-MSCs committed to differentiate into
adipocytes exerted the same immunosuppressive effect to activated T cells.
Furthermore, we aimed to elucidate whether the suppressive effects of AF-MSCs on
activated T cells were contact-dependent or mediated through the release of soluble
factors. For this reason activated T cells were cultured in the presence of AF-MSCs
conditioned medium as described by Di Nicola (Di Nicola et al., 2002). Interestingly,
soluble molecules from the culture supernatant of AF-MSCs failed to suppress
activated T cells, indicating that cell-cell contact play major role in AF-MSCs
mediated immunosuppression. Additionally, to determine whether AF-MSCs mediate
their inhibitory effect through cell death, activated T cells that were in co-culture with
AF-MSCs were analyzed by flow cytometry. Indeed, data reported that AF-MSCs
inhibit T-cell proliferation by inducing apoptosis of activated T cells. Further studies
showed that this apoptosis could be related to indoleamine (ido), an inhibitory
molecule expressed in high levels in AF-MSCs when co-cultured with activated T
cells. Additionally, in this study, CD90 (Thy-1) antigen and the adhesion molecule
CD54 (ICAM-1) were found to play an important role in contact-mediated
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suppression of the immune system. More importantly, we introduced, for the first
time, the role of adenosine in AF-MSCs mediated T-cell suppression. In particular,
the increased expression levels of the surface molecule CD73 (5’ectonucleotidase) in
AF-MSCs suggested that this might be responsible for the elevated levels of
adenosine production extracellularly and in this way mediated T-cell suppression. In
the present work, it is described, for the first time, the effect of activated T cells on
AF-MSCs development. To conclude, taking into consideration that amniotic fluid
constitutes an easily accessible and rich source of MSCs, the aim of this study was
to elucidate the immunomodulatory properties of AF-MSCs in order to establish AFMSCs
as a safe and effective therapeutic tool in regenerative medicine.
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