Growth differentiation factor 7 pretreatment enhances the therapeutic capacity of bone marrow-derived mesenchymal stromal cells against cerebral ischemia-reperfusion injury

• Published in: Chemico-biological interactions 2023-12, Vol.386, p.110779-110779, Article 110779
• Main Authors: Tao, Hongmiao, Li, Lin, Dong, Lihua, Chen, Haohao, Shan, Xiaoyun, Zhuge, Lujie, Lou, Hongqiang
• Format: Article
• Language: English
• Subjects: AMPK; BMSCs; Cerebral I/R injury; Exosomes; GDF7
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2023.110779

Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation is a promising therapeutic strategy for cerebral ischemia/reperfusion (I/R) injury; however, the clinical outcome is barely satisfactory and demands further improvement. The present study aimed to investigate whether preconditioning of BMSCs by recombinant human growth differentiation factor 7 (rhGDF7) could enhance its therapeutic capacity against cerebral I/R injury. Mouse BMSCs and primary neurons were co-cultured and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation. To investigate the role of exosomal microRNA-369-3p (miR-369-3p), inhibitors, RNAi and the miR-369-3p antagomir were used. Meanwhile, mice were intravenously injected with rhGDF7-preconditioned BMSCs and then received cerebral I/R surgery. Markers of inflammation, oxidative stress and neural damage were evaluated. To inhibit AMP-activated protein kinase (AMPK), compound C was used in vivo and in vitro. Compared with cell-free transwell or vehicle-preconditioned BMSCs, rhGDF7-preconditioned BMSCs significantly prevented OGD/R-induced inflammation, oxidative stress and neural damage in vitro. Meanwhile, rhGDF7-preconditioned BMSCs could prevent I/R-induced cerebral inflammation and oxidative stress in vivo. Mechanistically, rhGDF7 preconditioning significantly increased exosomal miR-369-3p expression in BMSCs and then transferred exosomal miR-369-3p to primary neurons, where it bound to phosphodiesterase 4 D (Pde4d) 3′-UTR and downregulated PDE4D expression, thereby preventing I/R-induced inflammation, oxidative stress and neural damage through activating AMPK pathway. Our study identify GDF7 pretreatment as a promising adjuvant reagent to improve the therapeutic potency of BMSCs for cerebral I/R injury and ischemic stroke. •rhGDF7-preconditioned BMSCs prevent I/R-induced inflammation and oxidative stress.•rhGDF7-preconditioned BMSCs prevent neural I/R damage.•rhGDF7 preconditioning increases exosomal miR-369-3p expression in BMSCs.•rhGDF7-preconditioned BMSCs transfer exosomal miR-369-3p to neurons.•Neural miR-369-3p activates AMPK to prevent neural I/R damage via inhibiting PDE4D.