title: MiR-126 Contributes to Human Umbilical Cord Blood Cell-Induced Neurorestorative Effects After Stroke in Type-2 Diabetic Mice.
abstract: Diabetes mellitus (DM) is a high risk factor for stroke and leads to more severe vascular and white-matter injury than stroke in non-DM. We tested the neurorestorative effects of delayed human umbilical cord blood cell (HUCBC) treatment of stroke in type-2 diabetes (T2DM). db/db-T2DM and db/+-non-DM mice were subjected to distal middle cerebral artery occlusion (dMCAo) and were treated 3 days after dMCAo with: (a) non-DM + Phosphate buffered saline (PBS); (b) T2DM + PBS; (c) T2DM + naïve-HUCBC; (d) T2DM + miR-126(-/-) HUCBC. Functional evaluation, vascular and white-matter changes, neuroinflammation, and miR-126 effects were measured in vivo and in vitro. T2DM mice exhibited significantly decreased serum and brain tissue miR-126 expression compared with non-DM mice. T2DM + HUCBC mice exhibited increased miR-126 expression, increased tight junction protein expression, axon/myelin, vascular density, and M2-macrophage polarization. However, decreased blood-brain barrier leakage, brain hemorrhage, and miR-126 targeted gene vascular cell adhesion molecule-1 and monocyte chemotactic protein 1 expression in the ischemic brain as well as improved functional outcome were present in HUCBC-treated T2DM mice compared with control T2DM mice. MiR-126(-/-) HUCBC-treatment abolished the benefits of naïve-HUCBC-treatment in T2DM stroke mice. In vitro, knock-in of miR-126 in primary cultured brain endothelial cells (BECs) or treatment of BECs with naïve-HUCBCs significantly increased capillary-like tube formation, and increased axonal outgrowth in primary cultured cortical neurons; whereas treatment of BECs or cortical neurons with miR-126(-/-) HUCBC attenuated HUCBC-treatment-induced capillary tube formation and axonal outgrowth. Our data suggest delayed HUCBC-treatment of stroke increases vascular/white-matter remodeling and anti-inflammatory effects; MiR-126 may contribute to HUCBC-induced neurorestorative effects in T2DM mice.
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.|Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, People's Republic of China.
authors: Jieli
authors: J
authors: Chen
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Ruizhuo
authors: R
authors: Ning
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Alex
authors: A
authors: Zacharek
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Chengcheng
authors: C
authors: Cui
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Xu
authors: X
authors: Cui
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Tao
authors: T
authors: Yan
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.|Department of Physics, Oakland University, Rochester, Michigan, USA.
authors: Poornima
authors: P
authors: Venkat
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.|Department of Physics, Oakland University, Rochester, Michigan, USA.
authors: Michael
authors: M
authors: Chopp
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism; D005312:Fetal Blood / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000097:blood / Q000378:metabolism*; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D017208:Rats, Wistar; D020127:Recovery of Function; D020521:Stroke / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D062725:Tight Junction Proteins / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C527111:MIRN126 microRNA, human; C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs; D062725:Tight Junction Proteins; D019010:Vascular Cell Adhesion Molecule-1
keywords: Human umbilical cord blood cell; Stroke; Type-2 diabetes; White matter; microRNA126