BDNF-overexpressing MSCs delivered by hydrogel in acute ischemic stroke treatment

BACKGROUND: Ischemic stroke treatment is a challenge worldwide. The efficacy and safety of mesenchymal stem cells (MSCs) for stroke have been confirmed. However, poor survival of MSCs in the ischemic environment limits the therapy efficacy. Changes in MSC status in the ischemic environment after transplantation is difficult to monitor. This study aimed to deliver brain-derived neurotrophic factor (BDNF)-overexpressing MSCs by hydrogel (H-B-MSCs) to promote recovery after ischemic stroke. METHODS: MSCs were transfected with lentivirus carrying luc2 and BDNF cassette. The properties of hydrogel were tested after synthesis with thiolated gelatin (Gel-SH), thiolated hyaluronic acid (HA-SH), and polyethylene glycol diacrylate (PEGDA). Oxygen-glucose deprivation (OGD) test was carried out to confirm the protective effects of hydrogel in the ischemic environment. Three days after stroke induction, H-B-MSCs, hydrogel carrying MSCs (H-MSCs), or phosphate-buffered saline (PBS) was injected into the brains of mice, respectively. Bioluminescence imaging (BLI) was performed at 3, 7, 14, and 21 days post-cell-transplantation to monitor the dynamic status of MSCs. In the meantime, histology, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), western blot, and behavior tests were carried out at different time points. RESULTS: Hydrogel with good biocompatibility was synthesized. Lentivirus transfection significantly increased the expression of BDNF. BDNF-MSCs could be tracked by BLI in vitro. In vitro OGD/reperfusion (OGD/R) test results suggested that MSCs carried by hydrogel could survive longer in an environment with low oxygen and glucose. H-B-MSCs significantly improved functional recovery after ischemic stroke. Furthermore, H-B-MSCs treatment promoted neurogenesis, white matter recovery, and angiogenesis after ischemic stroke. MSC dynamics could be monitored in vivo with BLI. CONCLUSIONS: We effectively established a robust MSC delivery system with hydrogel. Prolonged survival of transplanted BDNF-MSCs with a hydrogel delivery system could promote the recovery of ischemic stroke via the continuous release of BDNF.