Exogenous mitochondria added on benefits for cellular prion protein overexpression in adipose-derived mesenchymal stem cells treatment on intracranial hemorrhage rat

We examined whether combined exogenous mitochondria (Ex^Mito) and cellular prion protein overexpression (Ove-PrP^C) in adipose-derived mesenchymal stem cell (Ove-PrP^C in ADMSCs) therapy is superior to a single therapy for protecting the brain against intracranial hemorrhage (ICH) in rats. In vitro, compared with the control group, Ex^Mito transfusion into recipient cells (i.e., N2a cells) significantly increased under hypoxic conditions (P < 0.001) and augmented ρ0 cell proliferation and cell-cycle activation (P < 0.001). PrP^C-OE in ADMSCs exhibited higher resistance to H₂O₂-induced cell senescence and mitochondrial and DNA damage compared to ADMSCs (P < 0.001). Rats were categorized into group 1 (sham-control), 2 (ICH), 3 [ICH + Ex^Mito (350 μg) by intracranial injection at 3 h after ICH], 4 [ICH + PrP^C-OE in ADMSCs (6.0 × 10⁵ cells) and intracranial injection and 1.2 × 10⁶ cells by intravenous injection)], and 5 (ICH + combined Ex^Mito + PrP^C-OE in ADMSCs). By day 28, the brain infarct volume, brain infarct area, inflammatory cell infiltration, and biomarkers for DNA and mitochondrial damage were highest in group 2, lowest in group 1, and significantly lower in group 5 than in groups 3 and 4. NeuN cells exhibited the opposite pattern for brain infarct volume, and neurological function (corner test) significantly improved in groups 3 and 4, with further improvement in group 5 compared with that in group 2 (P < 0.0001). Combined Ex^Mito + PrP^C-OE ADMSCs therapy was superior to either therapy alone in mitigating the ICH-induced brain damage.