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

Abstract

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.

• Authors: Hongmiao Tao, Lin Li, Lihua Dong, Haohao Chen, Xiaoyun Shan, Lujie Zhuge, Hongqiang Lou
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 386 Pg. 110779 (Dec 01 2023) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 37879595 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• growth differentiation factor 7
• AMP-Activated Protein Kinases
• MicroRNAs
• MIRN369 microRNA, human

Topics

• Mice
• Humans
• Animals
• AMP-Activated Protein Kinases (metabolism)
• Bone Marrow (metabolism)
• Mesenchymal Stem Cells (metabolism)
• Inflammation (metabolism)
• Reperfusion Injury (metabolism)
• MicroRNAs (genetics, metabolism)
• Apoptosis (physiology)