Expression and function of Uracil nucleotides/Cysteinyl-Leukotrienes dual GPR17 receptor in mouse cardiac derived stem cells
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Data di Pubblicazione:
2010
Citazione:
Expression and function of Uracil nucleotides/Cysteinyl-Leukotrienes dual
GPR17 receptor in mouse cardiac derived stem cells / S. Cosentino, M. Pesce, E. Nobili, L. Sironi, L. Castiglioni, M.C. Capogrossi, E. Tremoli, M.P. Abbracchio. ((Intervento presentato al convegno Next step : la giovane ricerca avanza tenutosi a Milano nel 2010.
Abstract:
GPR17 is a dual receptor that is activated by both uracil nucleotides and cysteinylleukotrienes,
two ligands families that are massively released in tissues undergoing hypoxia.
Our previous data showed that GPR17 is highly expressed into organs susceptible to
ischemic damage such as brain, heart and kidney. The heart contains cardiac resident stem
cells (CSCs) that are involved in myocardium renewal and, possibly, myocardial repair after
ischemia. It has been demonstrated that acute or chronic myocardial damage activates
proliferation of CSCs; however ischemic damage has also a detrimental effect on self
renewal of CSCs population by improving their senescence and limiting their self-renewal
ability that ultimately leads to CSCs population exhaustion. On this basis, we made the
hypothesis that GRP17 is involved in CSCs activation/failure following ischemia. We
therefore investigated its expression by immunofluorescence and real-time RT-PCR in a
mouse Stem Cell Antigen-1 (Sca-1) positive CSC primary cell line isolated in our laboratory
from adult mouse hearts as well as by immunofluorescence followed by confocal imaging in
myocardial tissue sections before and at various times following infarction (MI) by coronary
artery ligation.
Results on the CSCs primary line showed expression of GPR17 at high levels in
undifferentiated Sca-1+ cells and co-expression with cardiac markers Nkx 2.5 and α-
sarcomeric actin upon induction of cardiac differentiation (Figure 1). Results of ex vivo
investigation in fixed myocardial sections showed the presence of GPR17 before and after
ischemia (Figure 2). Before ischemia, GPR17 was localized in clusters of small cells
(resembling CSCs) in close association with myocytes; after infarction it was expressed in
small as well as larger cells infiltrating the ischemic tissue. Interestingly, these large cells
(that were absent in the non-ischemic tissue) were labelled by Isolectin-B4, suggesting that
they are blood-borne macrophages infiltrating the infarcted heart.
Taken together, these results suggest that GPR17 is expressed in undifferentiated and
differentiated CSCs in vitro and in vivo, and that it undergoes a dynamic regulation in cells
associated to inflammatory response after MI. These dynamic changes closely resemble those
found in the brain after induction of cerebral ischemia, when GPR17 is activated on
residential adult stem-like cells in the peri-lesional brain parenchyma and is induced in
microglia/macrophages entering the ischemic core to remodel it after injury (Ciana et al.,
2006; Lecca et al., 2008). Current analyses are ongoing to characterize GPR17 intracellular
signalling in CSCs by stimulation with specific agonists in vitro and reveal possible effects
on modification of CSCs self-renewal/proliferation/differentiation; in addition, an
immunofluorescence analysis on myocardial tissue is currently carried out in order to unveil
the identity of GPR17+ cells before and after MI in vivo.
FIGURE 1 FIGURE 2
References
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[2] Ciana, P. et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinylleukotrienes
receptor. Embo J 25, 4615-27 (2006).
[3] Lecca, D. et al. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and
a new target for brain repair. PLoS One 3, e3579 (2008).
[4] Di Virgilio, F., Ceruti, S., Bramanti, P. & Abbracchio, M. P. Purinergic signalling in
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Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Keywords:
GPR17 ; mouse ; Cardiac Stem Cell ; Sca1 ; Purinergic/Cysteinyl-Leukotriene
receptors
Elenco autori:
S. Cosentino, M. Pesce, E. Nobili, L. Sironi, L. Castiglioni, M.C. Capogrossi, E. Tremoli, M.P. Abbracchio
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