Expression pattern of the G protein-coupled receptor GPR17 after traumatic brain injury in human subjects

The discovery that quiescent stem-like neural cells are still present in the adult mammalian brain and spinal cord has raised the possibility of recruiting these cells to repair the diseased CNS. Specifically, two distinct types of these precursors are activated in the injured brain parenchyma: reactive GFAP-positive hypertrophic astrocytes reacquiring multipotency, and oligodendrocyte precursor cells (OPCs) that normally give rise to mature myelinating oligodendrocytes, and, maybe, after injury, also to astrocytes and neurons. Recently, we have demonstrated that the new purinergic membrane receptor GPR17 can act as a sensor of damage and a trigger for repair in rodent brain after ischemia. In particular, it is sequentially involved in the death of irreversibly damaged neurons inside the lesion, in the activation of microglia/microphages infiltrating the lesioned area, and in the proliferation of quiescent parenchymal OPCs. Here, for the first time, we provide evidence for the presence of GPR17 in both neurosurgical and autoptic samples from patients with traumatic brain injury. In brain parenchyma, GPR17 specifically decorated shrunk neurons undergoing cell death inside the traumatic core or in the peritraumatic area, as well as GFAP-positive astrocytes. GPR17 was also specifically expressed by OPCs at different stages of differentiation, from early precursors to ramified immature pre-oligodendrocytes that also expressed typical markers like O4 and CNPase. In autoptic samples, there was a statistically significant negative correlation between GPR17 presence in OPCs and length of patients' post-traumatic survival period, indicating that induction of GPR17 in OPCs is quite early after damage and follows a strict temporal window. Finally, in neurosurgical samples, GPR17 was also present in microglia/macrophages infiltrating the lesion core. Globally these findings validate GPR17 as a key actor in orchestrating the death of irreversibly damaged neurons after injury and the subsequent lesion remodelling and repair in human brain. They also set the basis for future GPR17-based therapies in currently incurable human neurodegenerative diseases.