MicroRNA-210 Promotes Accumulation of Neural Precursor Cells Around Ischemic Foci After Cerebral Ischemia by Regulating the SOCS1-STAT3-VEGF-C Pathway

J Am Heart Assoc. 2018 Feb 25;7(5):e005052. doi: 10.1161/JAHA.116.005052.

Abstract

Background: Neural precursor cell (NPC) migration toward lesions is key for neurological functional recovery. The neovasculature plays an important role in guiding NPC migration. MicroRNA-210 (miR-210) promotes angiogenesis and neurogenesis in the subventricular zone and hippocampus after cerebral ischemia; however, whether miR-210 regulates NPC migration and the underlying mechanism is still unclear. This study investigated the role of miR-210 in NPC migration.

Methods and results: Neovascularization and NPC accumulation was detected around ischemic foci in a mouse model of middle cerebral artery occlusion (MCAO) and reperfusion. Bone marrow-derived endothelial progenitor cells (EPCs) were found to participate in neovascularization. miR-210 was markedly upregulated after focal cerebral ischemia/reperfusion. Overexpressed miR-210 enhanced neovascularization and NPC accumulation around the ischemic lesion and vice versa, strongly suggesting that miR-210 might be involved in neovascularization and NPC accumulation after focal cerebral ischemia/reperfusion. In vitro experiments were conducted to explore the underlying mechanism. The transwell assay showed that EPCs facilitated NPC migration, which was further promoted by miR-210 overexpression in EPCs. In addition, miR-210 facilitated VEGF-C (vascular endothelial growth factor C) expression both in vitro and in vivo. Moreover, the luciferase reporter assay demonstrated that miR-210 directly targeted the 3' untranslated region of SOCS1 (suppressor of cytokine signaling 1), and miR-210 overexpression in HEK293 cells or EPCs decreased SOCS1 and increased STAT3 (signal transducer and activator of transcription 3) and VEGF-C expression. When EPCs were simultaneously transfected with miR-210 mimics and SOCS1, the expression of STAT3 and VEGF-C was reversed.

Conclusions: miR-210 promoted neovascularization and NPC migration via the SOCS1-STAT3-VEGF-C pathway.

Keywords: brain ischemia; cell migration; miR‐210; vascular endothelial growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Brain / physiopathology
  • Cell Hypoxia
  • Cell Movement*
  • Disease Models, Animal
  • Endothelial Progenitor Cells / metabolism*
  • Endothelial Progenitor Cells / pathology
  • Gene Expression Regulation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / metabolism*
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neovascularization, Physiologic
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neurogenesis
  • Recovery of Function
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism*
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism*

Substances

  • MIRN210 microRNA, human
  • MIRN210 microRNA, mouse
  • MicroRNAs
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Socs1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor C
  • enhanced green fluorescent protein
  • vascular endothelial growth factor C, mouse
  • Green Fluorescent Proteins