Human ESC-derived immunity- and matrix- regulatory cells ameliorated white matter damage and vascular cognitive impairment in rats subjected to chronic cerebral hypoperfusion

Objectives This study investigated the ability of immunity- and matrix- regulatory cells (IMRCs) to improve cognitive function in a rat model of vascular cognitive impairment. Materials and Methods A chronic cerebral hypoperfusion (CCH) model was established in rats via permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). The rats then received intravenous injections of IMRCs or saline. A single injection of different doses of IMRCs (1 x 10(6) cells/rat, 2 x 10(6) cells/rat, or 4 x 10(6) cells/rat) was administered via tail vein 72 h after establishment of the model. To evaluate functional recovery, the rats were subjected to behavioural tests after 30 days of CCH. Imaging, western blotting, immunofluorescence staining, and quantitative real-time PCR were used to analyse neuroinflammation and white matter injury after 14 and 40 days of CCH. RNA sequencing (RNA-seq) was used to profile gene expression changes in copine 1 (CPNE1) in response to IMRCs treatment. Results Intravenous injection of 4 x 10(6) IMRCs alleviated white matter damage and ameliorated cognitive deficits in rats subjected to CCH. Immunofluorescence staining suggested that activation of microglia and astrocytes was reduced, and RNA sequencing showed that CPNE1 expression was significantly elevated following treatment with IMRCs. Conclusions Intravenous injection of IMRCs protected against CCH-induced white matter injury and cognitive impairment inhibition of microglial activation and regulation of microglia polarization.