Abstract 165: Microrna-126 Contributes to Human Umbilicus Cord Blood Cell Induced Neurorestorative Effects in Type Two Diabetes Mice
Introduction: Human umbilical cord blood cell (HUCBC) treatment of stroke induces neurorestorative effects in non-diabetic rats. Whether HUCBC induces neurorestorative effects in type two diabetes (T2DM) has not been investigated. In this study, we tested the neurorestorative therapeutic effects and underlying mechanisms of action of HUCBC treatment of stroke in T2DM mice.
Methods: BKS.Cg-m+/+Leprdb/J (db/db)-T2DM mice were subjected to extraluminal permanent distal MCAo (dMCAo) and were treated with: 1) PBS control; 2) HUCBC (1x106) at 3 days after dMCAo. A battery of functional tests was performed. Mice were sacrificed at 14 days after dMCAo. Vascular and white matter (WM) changes and microRNA were measured.
Results: HUCBC treatment of stroke in T2DM mice does not decrease lesion volume (12.7±3.0% vs control: 14.5±3.2%), but significantly improves functional outcome, increases axon (Bielschowsky silver), myelin (Luxol fast blue) and arteriolar (a-SMA) density in the ischemic boundary zone (IBZ) compared to T2DM-dMCAo control mice (p<0.05). To test the mechanisms of HUCBC induced neurorestorative effects, serum and ischemic brain miR-126 expression were measured. T2DM mice exhibit significantly decreased miR-126 expression in serum and in the IBZ compared to db+ (no-DM) control mice (p<0.05). While HUCBC treatment in T2DM mice significantly increased miR-126 expression compared to non-treatment T2DM mice. In vitro, we found that HUCBC secretes miR-126 enriched exosomes and also stimulates brain endothelial cell miR-126 expression. Co-culture of brain endothelial cells (BECs) with primary cortical neurons (PCNs) increases PCN axon outgrowth. Knockdown of miR-126 in BECs not only decreases capillary tube formation, but also decreases PCN axonal outgrowth compared to miR-126-/-Con-BECs (p<0.05). Knockdown miR-126 in HUCBC (miR-126-/-HUCBC) treatment of stroke in T2DM mice significantly decreases miR-126 expression in blood serum and attenuates HUCBC induced functional outcome after stroke in T2DM mice.
Conclusion: HUCBC treatment initiated 3 days after stroke improves functional outcome, increases WM and vascular remodeling in T2DM mice. Increasing miR-126 contribute to HUCBC induced neurorestorative effects in T2DM.
Author Disclosures: J. Chen: Consultant/Advisory Board; Modest; consultant to Saneron CCEL Therapeutics, Inc. R. Ning: None. A. Zacharek: None. Y. Cui: None. T. Yan: None. C. Roberts: None. N. Kuzmin-Nichols: Ownership Interest; Modest; inventor on cord blood patents/applications. C.D. Sanberg: Ownership Interest; Modest; inventor on cord blood patents/applications. M. Chopp: None.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate – Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota, Wisconsin.
- © 2015 by American Heart Association, Inc.