GPR37 modulates progenitor cell dynamics in a mouse model of ischemic stroke

Emerging Roles for the Orphan GPCRs, GPR37 and GPR37 L1, in Stroke Pathophysiology

“…Ten days following stroke, Gpr37 -/- mice exhibited significantly reduced glial scar formation [ 68 ], potentially implying an enhanced regenerative response in these mice. Consistent with this notion, β-gal (proxy for GPR37) was found to be increased within Sox2 expressing neural stem/progenitor cells (NSPCs) which were significantly more abundant within the peri infarct region of Gpr37 -/- mice with respect to wild-type mice [ 23 ]. The final fate of these cells was not determined, but it is intriguing to think that, in the presence of diminished glial scar formation, these cells could undergo neuronal differentiation and enhance the regenerative capacity of Gpr37 -/- mice at longer timepoints following ischemic injury.…”

“…Interestingly, GPR37 has been found to be intricately involved in mediating astrogliosis following ischemic stroke. Acutely (24–72 h) following induction of MCAO, mice lacking GPR37 exhibited a larger infarct volume and substantially decreased activation of reactive astrocytes within the peri-infarct zone [ 23 ]. Within Gpr37 -/- mice, the GPR37 promoter is linked to the LacZ reporter, allowing β-gal to be used as a proxy for GPR37 expression within these mice.…”

“…GPR37 is also expressed by specific neuronal subsets such as dopaminergic neurons of the substantia nigra [ 20 ], hippocampal neurons [ 21 ], as well as the optic nerve and spinal cord [ 21 ]. The expression of GPR37 has also been noted within neural progenitor cells (NPCs) [ 22 , 23 ] and peripheral macrophages [ 24 ]. In contrast to GPR37, GPR37 L1 is highly enriched within astrocytes and OPCs [ 19 , 25 ] as well as quiescent NPCs within the subventricular zone of the lateral ventricle (SVZ) [ 26 ].…”

“…Notably, prosaposin is upregulated in animal models of ischemic stroke [ 35 , 36 ] and generally thought to be functioning in a neuroprotective manner [ 37 ]. A recent study highlighting the role of GPR37 in mediating glial cell responses following stroke examined prosaposin levels within the peri-infarct region of wild-type and GPR37 knock-out ( Gpr37 -/- ) mice and did not observe detectable differences in prosaposin expression [ 23 ]. Similar to studies proposing HA as the endogenous ligand for GPR37, there have been a number of studies which have failed to recapitulate specific prosaposin/prosaptide-mediated effects on GPR37/GPR37 L1 signaling [ 32 , 38 , 39 ].…”

“…This suggests that under physiological conditions, both receptors are being rapidly processed into their proteolytically cleaved counterparts. Intriguingly, following middle the cerebral artery occlusion (MCAO), protein expression of a cleaved form of GPR37 (~40 kD) was found to be upregulated within the peri-infarct region [ 23 ].…”