White matter and SVZ serve as endogenous sources of glial progenitor cells for self-repair in neonatal rats with ischemic PVL

摘要

Mounting evidence suggests that endogenous progenitor cells may initiate cerebral WM repair. This study was designed to determine whether endogenous glial progenitor cells derived from either the subventricular zone (SVZ) or the white matter (WM) contribute to WM repair in a neonatal rat model of ischemic periventricular leukomalacia (PVL). Additionally, the role of G protein-coupled receptor 17 (GPR17), recently shown to act as a sensor for WM damage, was explored to assess its potential recruitment and activation of endogenous glial progenitor cells for such WM self-repair. Our in vivo and in vitro models consisted of five-day-old neonatal rats or cultured glial progenitor cells derived from both the SVZ and WM of these rats, randomly divided into sham/control and induced ischemic PVL/oxygen-glucose deprivation (OGD) groups. The WM of all PVL rats showed either mild or severe histopathological changes, with significantly increased in vivo apoptosis and poor myelination compared to those of the sham group. Significantly more apoptotic and necrotic cells were also detected in the OGD glial progenitor cell cultures derived from the SVZ and WM at all time intervals. The glial progenitor cells were significantly increased in both the SVZ (NG2+/GPR17-/BrdU+) and WM (NG2+/GPR17+/BrdU+) within 72 h after PVL; preOLs were also increased significantly in both the SVZ (O4 +/GPR17-/BrdU+) and WM (O4+/ GPR17+/BrdU+) within 7 d after PVL in vivo or OGD in vitro. However, the more differentiated CNPase+/GPR17 -/BrdU+ and MBP+/GPR17-/BrdU + OLs in the SVZ and WM remained significantly less than those in the sham groups up to 14 d or 21 d after OGD or PVL, respectively. Hence, both the WM and SVZ were found to be potential endogenous sources of glial progenitor cells for WM repair in PVL rats. However their endogenous self-repair capacity appeared to be limited, since the more mature OLs did not completely recover from experimental ischemia, even after 14-21 d.