PMID- 31394992
OWN - NLM
STAT- MEDLINE
DCOM- 20200320
LR  - 20201001
IS  - 1524-4628 (Electronic)
IS  - 0039-2499 (Print)
IS  - 0039-2499 (Linking)
VI  - 50
IP  - 10
DP  - 2019 Oct
TI  - MiR-126 Mediates Brain Endothelial Cell Exosome Treatment-Induced 
      Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice.
PG  - 2865-2874
LID - 10.1161/STROKEAHA.119.025371 [doi]
AB  - Background and Purpose- Stroke patients with type 2 diabetes mellitus (T2DM) 
      exhibit increased vascular and white matter damage and have worse prognosis 
      compared with nondiabetic stroke patients. We investigated the neurorestorative 
      effects of exosomes derived from mouse brain endothelial cells (EC-Exo) as 
      treatment for stroke in T2DM mice and investigated the role of miR-126 in 
      mediating EC-Exo-derived therapeutic benefits in T2DM-stroke mice. Methods- 
      Adult, male BKS.Cg-m+/+Lepr(db)/J (T2DM) mice were subjected to photothrombotic 
      stroke model. T2DM mice were intravenously injected at 3 days after stroke with 
      (1) PBS; (2) liposome mimic (vehicle control, 3x10(10)); (3) EC-Exo (3x10(10)); 
      (4) knockdown of miR-126 in EC-Exo (miR-126(-)(/-) EC-Exo, 3x10(10)). Behavioral 
      and cognitive tests were performed, and mice were sacrificed at 28 days after 
      stroke. Results- Compared with non-DM stroke mice, T2DM-stroke mice exhibit 
      significantly decreased serum and brain tissue miR-126 expression. Endothelial 
      cells and EC-Exo contain high levels of miR-126 compared with other cell types or 
      exosomes derived from other types of cells, respectively (smooth muscle cells, 
      astrocytes, and marrow stromal cells). Compared with PBS or liposome mimic 
      treatment, EC-Exo treatment of T2DM-stroke mice significantly improves 
      neurological and cognitive function, increases axon density, myelin density, 
      vascular density, arterial diameter, as well as induces M2 macrophage 
      polarization in the ischemic boundary zone. MiR-126(-/-) EC-Exo treatment 
      significantly decreases miR-126 expression in serum and brain, as well as 
      attentuates EC-Exo treatment-induced functional improvement and does not 
      significantly increase axon and myelin density, vascular density, arterial 
      diameter or induce M2 macrophage polarization in T2DM-stroke mice. In vitro, 
      EC-Exo treatment significantly increases primary cortical neuron axonal outgrowth 
      and increases endothelial capillary tube formation whereas miR-126(-/-) EC-Exo 
      attentuates EC-Exo induced capillary tube formation and axonal outgrowth. 
      Conclusions- EC-Exo treatment of stroke promotes neurorestorative effects in T2DM 
      mice. MiR-126 may mediate EC-Exo-induced neurorestorative effects in T2DM mice. 
      Visual Overview- An online visual overview is available for this article.
FAU - Venkat, Poornima
AU  - Venkat P
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
FAU - Cui, Chengcheng
AU  - Cui C
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
FAU - Chopp, Michael
AU  - Chopp M
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
AD  - Department of Physics, Oakland University, Rochester, MI (M.C.).
FAU - Zacharek, Alex
AU  - Zacharek A
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
FAU - Wang, Fengjie
AU  - Wang F
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
FAU - Landschoot-Ward, Julie
AU  - Landschoot-Ward J
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
FAU - Shen, Yi
AU  - Shen Y
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
FAU - Chen, Jieli
AU  - Chen J
AD  - From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., 
      M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).
LA  - eng
GR  - R01 HL143432/HL/NHLBI NIH HHS/United States
GR  - R01 NS099030/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190809
PL  - United States
TA  - Stroke
JT  - Stroke
JID - 0235266
RN  - 0 (MIRN126 microRNA, mouse)
RN  - 0 (MicroRNAs)
SB  - IM
MH  - Animals
MH  - Brain/pathology
MH  - Diabetes Mellitus, Experimental
MH  - *Diabetes Mellitus, Type 2
MH  - Endothelial Cells/metabolism
MH  - Exosomes/*metabolism
MH  - Male
MH  - Mice
MH  - MicroRNAs/*metabolism
MH  - Stroke/*pathology
PMC - PMC6756941
MID - NIHMS1535516
OTO - NOTNLM
OT  - endothelial cells
OT  - exosomes
OT  - mice
OT  - stroke
OT  - vascular remodeling
COIS- Conflicts of Interest/Disclosures: The authors have no conflicts of interest to 
      disclose. Intellectual Property relating to the topic of this manuscript is 
      subject to patent application (62/586,102) fully owned by Henry Ford Health 
      System.​
EDAT- 2019/08/10 06:00
MHDA- 2020/03/21 06:00
PMCR- 2020/10/01
CRDT- 2019/08/10 06:00
PHST- 2019/08/10 06:00 [pubmed]
PHST- 2020/03/21 06:00 [medline]
PHST- 2019/08/10 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - 10.1161/STROKEAHA.119.025371 [doi]
PST - ppublish
SO  - Stroke. 2019 Oct;50(10):2865-2874. doi: 10.1161/STROKEAHA.119.025371. Epub 2019 
      Aug 9.