Protective Effects of Transforming Growth Factor-β1 Knockdown in Human Umbilical Cord Mesenchymal Stem Cells against Subarachnoid Hemorrhage in a Rat Model.

BACKGROUND: Emerging evidence indicates a beneficial effect of mesenchymal stem cell (MSC) transplantation in subarachnoid hemorrhage (SAH). Chronic hydrocephalus is a common complication after SAH, which is associated with subarachnoid fibrosis promoted by transforming growth factor-β1 (TGF-β1). This study investigated the effect of human umbilical cord derived MSCs (hUC-MSCs) with TGF-β1 knockdown on chronic hydrocephalus after SAH.

METHODS: About 0.5 mL autologous blood was injected into the cerebellomedullaris cistern of 6-week SD rats to establish SAH model. hUC-MSCs or hUC-MSCs carrying TGF-β1 knockdown (1 × 105 cells) were intraventricularly transplanted at 1 day before surgery and at P10. Neurological behavior score and water maze test were performed to assess neurological functions. Hydrocephalus was evaluated by Nissl staining. Concentrations of proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. The levels of TGF-β1, p-Smad2/3, and Smad2/3 were measured using western blotting.

RESULTS: Intraventricular hUC-MSCs transplantation significantly attenuated SAH-induced chronic hydrocephalus, upregulation of inflammatory cytokines, and behavioral impairment. Knockdown of TGF-β1 in hUC-MSCs enhanced these effects. hUC-MSCs also reduced the upregulation of TGF-β1 levels and Smad2/3 phosphorylation after SAH, and this effect was also enhanced by TGF-β1 knockdown.

CONCLUSION: Transplantation of hUC-MSCs exerts beneficial effect after SAH, possibly be through inhibiting TGF-β1/Smad2/3 signaling pathway. Knockdown of TGF-β1 in hUC-MSCs enhanced these effects.