title: miR-145 Regulates Diabetes-Bone Marrow Stromal Cell-Induced Neurorestorative Effects in Diabetes Stroke Rats.
abstract: : In rats with type 1 diabetes (T1DM), the therapeutic effects and underlying mechanisms of action of stroke treatment were compared between bone-marrow stromal cells (BMSCs) derived from T1DM rats (DM-BMSCs) and BMSCs derived from normal rats (Nor-BMSCs). The novel role of microRNA-145 (miR-145) in mediating DM-BMSC treatment-induced benefits was also investigated. T1DM rats (n = 8 per group) underwent 2 hours of middle cerebral artery occlusion (MCAo) and were treated 24 hours later with the one of the following (5 × 106cells administered i.v.): (a) phosphate-buffered saline (PBS); (b) Nor-BMSCs; (c) DM-BMSCs; (d) DM-BMSCs with miR-145 overexpression (miR-145+/+DM-BMSCs); or (e) Nor-BMSCs with miR-145 knockdown. Evaluation of functional outcome, vascular and white-matter remodeling and microRNA expression was made, and in vitro studies were performed. In vitro, DM-BMSCs exhibited decreased miR-145 expression and increased survival compared with Nor-BMSCs. Capillary tube formation and axonal outgrowth in cultured primary cortical neurons were significantly increased by DM-BMSC-conditioned medium compared with Nor-BMSCs, and significantly decreased by miR-145+/+DM-BMSC-conditioned medium compared with DM-BMSCs. In T1DM rats in which stroke had been induced (T1DM stroke rats), DM-BMSC treatment significantly improved functional outcome, increased vascular and white matter remodeling, decreased serum miR-145 expression, and increased expression of the miR-145 target genes adenosine triphosphate-binding cassette transporter 1 (ABCA1) and insulin-like growth factor 1 receptor (IGFR1), compared with Nor-BMSCs or PBS treatment. However, miR-145+/+DM-BMSCs significantly increased serum miR-145 expression and decreased brain ABCA1 and IGFR1 expression, as well as attenuated DM-BMSC-induced neurorestorative effects in T1DM-MCAo rats. DM-BMSCs exhibited decreased miR-145 expression. In T1DM-MCAo rats, DM-BMSC treatment improved functional outcome and promoted neurorestorative effects. The miR-145/ABCA1/IGFR1 pathway may contribute to the enhanced DM-BMSCs' functional and neurorestorative effects in T1DM stroke rats.
  
  
  
  In rats with type 1 diabetes (T1DM), the therapeutic effects and underlying mechanisms of action of stroke treatment were compared between bone-marrow stromal cells (BMSCs) derived from T1DM rats (DM-BMSCs) and BMSCs derived from normal rats (Nor-BMSCs). In vitro, DM-BMSCs and derived exosomes decreased miR-145 expression and increased DM-BMSC survival, capillary tube formation, and axonal outgrowth, compared with Nor-BMSCs; these effects were decreased by DM-BMSCs in which miR-145 was overexpressed. In vivo, compared with Nor-BMSC or phosphate-buffered saline treatment, DM-BMSC treatment improved functional outcome and vascular and white matter remodeling, decreased serum miR-145 expression, and increased expression of the miR-145 target genes ABCA1 and IGFR1. microRNA-145 mediated the benefits induced by DM-BMSC treatment.
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, People's Republic of China.|Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Cui
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, People's Republic of China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.|Department of Physics, Oakland University, Rochester, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.|Department of Physics, Oakland University, Rochester, Michigan, USA.
authors.forename: Poornima
authors.initials: P
authors.lastname: Venkat
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yan
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Ruizhou
authors.initials: R
authors.lastname: Ning
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, People's Republic of China jieli@neuro.hfh.edu guiyuncui99@126.com.
authors.forename: Guiyun
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA jieli@neuro.hfh.edu guiyuncui99@126.com.|Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology*; D002196:Capillaries / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000628:therapy; D055785:Gene Knockdown Techniques; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D009836:Oligodendroglia / Q000378:metabolism; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020521:Stroke / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D066253:Vascular Remodeling; D066127:White Matter / Q000473:pathology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D035683:MicroRNAs; D017526:Receptor, IGF Type 1; D062826:Zonula Occludens-1 Protein; C577833:Abca1 protein, mouse; C542511:MIRN145 microRNA, rat
keywords: Bone marrow stem cells; MicroRNA 145; Neurorestoration; Stroke; Type 1 diabetes mellitus