miR-145 Regulates Diabetes-Bone Marrow Stromal Cell-Induced Neurorestorative Effects in Diabetes Stroke Rats

Document Type

Article

Publication Date

12-1-2016

Publication Title

Stem Cells Transl Med

Keywords

ATP Binding Cassette Transporter 1, Animals, Axons, Blood-Brain Barrier, Bone Marrow Cells, Capillaries, Cell Proliferation, Cell Survival, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Gene Knockdown Techniques, Male, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, MicroRNAs, Myocytes, Smooth Muscle, Neovascularization, Physiologic, Oligodendroglia, Rats, Wistar, Receptor, IGF Type 1, Stroke, Treatment Outcome, Vascular Remodeling, White Matter, Zonula Occludens-1 Protein

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 × 106 cells 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.

SIGNIFICANCE: 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.

Medical Subject Headings

ATP Binding Cassette Transporter 1; Animals; Axons; Blood-Brain Barrier; Bone Marrow Cells; Capillaries; Cell Proliferation; Cell Survival; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Knockdown Techniques; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; MicroRNAs; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Oligodendroglia; Rats, Wistar; Receptor, IGF Type 1; Stroke; Treatment Outcome; Vascular Remodeling; White Matter; Zonula Occludens-1 Protein

PubMed ID

27460851

Volume

5

Issue

12

First Page

1656

Last Page

1667

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