Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice

J Cereb Blood Flow Metab. 2020 Dec;40(12):2374-2386. doi: 10.1177/0271678X19892777. Epub 2019 Dec 22.

Abstract

Endothelial progenitor cell transplantation is a potential therapeutic approach in brain ischemia. However, whether the therapeutic effect of endothelial progenitor cells is via affecting complement activation is unknown. We established a mouse focal ischemia model (n = 111) and transplanted endothelial progenitor cells into the peri-infarct region immediately after brain ischemia. Neurological outcomes and brain infarct/atrophy volume were examined after ischemia. Expression of C3, C3aR and pro-inflammatory factors were further examined to explore the role of endothelial progenitor cells in ischemic brain. We found that endothelial progenitor cells improved neurological outcomes and reduced brain infarct/atrophy volume after 1 to 14 days of ischemia compared to the control (p < 0.05). C3 and C3aR expression in the brain was up-regulated at 1 day up to 14 days (p < 0.05). Endothelial progenitor cells reduced astrocyte-derived C3 (p < 0.05) and C3aR expression (p < 0.05) after ischemia. Endothelial progenitor cells also reduced inflammatory response after ischemia (p < 0.05). Endothelial progenitor cell transplantation reduced astrocyte-derived C3 expression in the brain after ischemic stroke, together with decreased C3aR and inflammatory response contributing to neurological function recovery. Our results indicate that modulating complement C3/C3aR pathway is a novel therapeutic target for the ischemic stroke.

Keywords: Astrocyte; C3; endothelial progenitor cell; ischemia; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Atrophy / pathology
  • Brain / metabolism*
  • Brain / pathology
  • Brain Infarction / metabolism
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology
  • Brain Ischemia / therapy
  • Case-Control Studies
  • Complement Activation / physiology
  • Complement C3 / metabolism*
  • Disease Models, Animal
  • Endothelial Progenitor Cells / metabolism*
  • Endothelial Progenitor Cells / transplantation
  • Inflammation / metabolism
  • Male
  • Mice
  • Receptors, G-Protein-Coupled / metabolism*
  • Recovery of Function
  • Up-Regulation

Substances

  • C3 protein, mouse
  • C3a-derived anaphylatoxin receptor, mouse
  • Complement C3
  • Receptors, G-Protein-Coupled