Abstract WMP44: Mir-145 Mediates Bone-marrow-stromal Cell Derived From Type-one Diabetes (t1dm) Rats Induced Neurorestorative Effects in T1dm Rats
Objective: Treatment of stroke with bone-marrow-stromal cells (BMSCs) derived from type-one diabetes (T1DM) rats (DM-BMSCs) improves functional recovery compared to BMSCs derived from normal rats (Nor-BMSCs) and non treatment T1DM rats. In the study, we tested the mechanisms underlying the benefit of the treatment of T1DM stroke with DM-BMSCs.
Methods: T1DM rats induced by streptozocin in male Wistar rats were subjected to 2h middle cerebral artery occlusion (MCAo) and were treated at 24h after MCAo via tail vein with: 1) vehicle control; 2) DM-BMSCs; 3) DM-BMSCs with miR-145 overexpression (miR-145+/+DM-BMSCs)(5x10^6) (n=8/group). A battery of functional tests, vascular,white matter (WM) measurements, and cell culture experiments were performed.
Results: In vitro, DM-BMSCs exhibited reduced level of miR-145, and increased survival rate compared to Nor-BMSCs. miR-145+/+DM-BMSCs significantly decreased DM-BMSCs survival. DM-BMSCs media increased capillary tube formation and axonal outgrowth in cultured primary cortical neurons (PCNs) compared to Nor-BMSCs media. While miR-145+/+DM-BMSCs exhibited reverse effects compared to DM-BMSCs media. In vivo, DM-BMSCs improved functional outcome, vascular and WM remodeling in the ischemic border zone (IBZ) compared to T1DM-MCAo rats. However, miR-145+/+DM-BMSCs significantly attenuated DM-BMSCs induced beneficial effects. To further test the underlying mechanism of miR-145 mediated DM-BMSCs induced therapeutic effects in T1DM stroke rats, miR-145 target genes adenosine triphosphate-binding cassette transporter 1 (ABCA1) and insulin-like growth factor 1 receptor (IGFR-1) were measured in IBZ. ABCA1 and IGFR1 have neurorestorative effects. Reduction of IGF1 contributes ABCA1 deficiency induced damage in ischemic brain. We found that DM-BMSCs significantly decreased miR-145, increased ABCA1 and IGFR-1 expression in IBZ compared to Nor-BMSCs. While miR-145+/+DM-BMSCs significantly decreased ABCA1 and IGFR-1 expression in IBZ.
Conclusion: DM-BMSCs exhibit decreased miR-145 expression and increase miR-145 target gene ABCA1 and IGFR-1 expression in ischemic brain. The miR-145/ABCA1/IGFR-1 pathway may contribute to DM-BMSCs induced neurorestorative effects in T1DM stroke.
Author Disclosures: C. Cui: None. M. Chopp: None. X. Ye: None. A. Zacharek: None. R. Ning: None. T. Yan: None. X. Cui: None. P. Yu: None. C. Roberts: None. J. Chen: None.
- © 2016 by American Heart Association, Inc.