MiR-126 Contributes to Human Umbilical Cord Blood Cell-Induced Neurorestorative Effects After Stroke in Type-2 Diabetic Mice

被引:63
作者
Chen, Jieli [1 ,2 ]
Ning, Ruizhuo [1 ]
Zacharek, Alex [1 ]
Cui, Chengcheng [1 ]
Cui, Xu [1 ]
Yan, Tao [1 ]
Venkat, Poornima [1 ,3 ]
Zhang, Yi [1 ]
Chopp, Michael [1 ,3 ]
机构
[1] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA
[2] Tianjin Med Univ, Gen Hosp, Tianjin Geriatr Inst, Dept Geriatr, Tianjin, Peoples R China
[3] Oakland Univ, Dept Phys, Rochester, MI USA
关键词
microRNA126; Human umbilical cord blood cell; Type-2; diabetes; White matter; Stroke; IMPROVES FUNCTIONAL RECOVERY; NEURAL PROGENITOR CELLS; MESENCHYMAL STEM-CELLS; ACUTE ISCHEMIC-STROKE; WHITE-MATTER; PLASMINOGEN-ACTIVATOR; M2; MACROPHAGES; MICROGLIA/MACROPHAGE POLARIZATION; VASCULAR STABILIZATION; ADOPTIVE TRANSFER;
D O I
10.1002/stem.2193
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Diabetes mellitus (DM) is a high risk factor for stroke and leads to more severe vascular and white-matter injury than stroke in non-DM. We tested the neurorestorative effects of delayed human umbilical cord blood cell (HUCBC) treatment of stroke in type-2 diabetes (T2DM). db/db-T2DM and db/+-non-DM mice were subjected to distal middle cerebral artery occlusion (dMCAo) and were treated 3 days after dMCAo with: (a) non-DM + Phosphate buffered saline (PBS); (b) T2DM + PBS; (c) T2DM + naive-HUCBC; (d) T2DM + miR-126(-/-) HUCBC. Functional evaluation, vascular and white-matter changes, neuroinflammation, and miR-126 effects were measured in vivo and in vitro. T2DM mice exhibited significantly decreased serum and brain tissue miR-126 expression compared with non-DM mice. T2DM + HUCBC mice exhibited increased miR-126 expression, increased tight junction protein expression, axon/myelin, vascular density, and M2-macrophage polarization. However, decreased blood-brain barrier leakage, brain hemorrhage, and miR-126 targeted gene vascular cell adhesion molecule-1 and monocyte chemotactic protein 1 expression in the ischemic brain as well as improved functional outcome were present in HUCBC-treated T2DM mice compared with control T2DM mice. MiR-126(-/-) HUCBC-treatment abolished the benefits of naive-HUCBC-treatment in T2DM stroke mice. In vitro, knock-in of miR-126 in primary cultured brain endothelial cells (BECs) or treatment of BECs with naive-HUCBCs significantly increased capillary-like tube formation, and increased axonal outgrowth in primary cultured cortical neurons; whereas treatment of BECs or cortical neurons with miR-126(-/-) HUCBC attenuated HUCBC-treatment-induced capillary tube formation and axonal outgrowth. Our data suggest delayed HUCBC-treatment of stroke increases vascular/white-matter remodeling and anti-inflammatory effects; MiR-126 may contribute to HUCBC-induced neurorestorative effects in T2DM mice.
引用
收藏
页码:102 / 113
页数:12
相关论文
共 60 条
[1]   Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation [J].
Alexander, JS ;
Elrod, JW .
JOURNAL OF ANATOMY, 2002, 200 (06) :561-574
[2]   Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders [J].
Armstead, William M. ;
Ganguly, Kumkum ;
Kiessling, J. W. ;
Riley, John ;
Chen, Xiao-Han ;
Smith, Douglas H. ;
Stein, Sherman C. ;
Higazi, Abd A. R. ;
Cines, Douglas B. ;
Bdeir, Khalil ;
Zaitsev, Sergei ;
Muzykantov, Vladimir R. .
JOURNAL OF NEUROCHEMISTRY, 2010, 113 (02) :303-312
[3]   Adipose Tissue MicroRNAs as Regulators of CCL2 Production in Human Obesity [J].
Arner, Erik ;
Mejhert, Niklas ;
Kulyte, Agne ;
Balwierz, Piotr J. ;
Pachkov, Mikhail ;
Cormont, Mireille ;
Lorente-Cebrian, Silvia ;
Ehrlund, Anna ;
Laurencikiene, Jurga ;
Heden, Per ;
Dahlman-Wright, Karin ;
Tanti, Jean-Francois ;
Hayashizaki, Yoshihide ;
Ryden, Mikael ;
Dahlman, Ingrid ;
van Nimwegen, Erik ;
Daub, Carsten O. ;
Arner, Peter .
DIABETES, 2012, 61 (08) :1986-1993
[4]   Junctional adhesion molecules and interendothelial junctions [J].
Aurrand-Lions, M ;
Johnson-Leger, C ;
Lamagna, C ;
Ozaki, H ;
Kita, T ;
Imhof, BA .
CELLS TISSUES ORGANS, 2002, 172 (03) :152-160
[5]   Ectopic expression of angiopoietin-1 promotes neuronal differentiation in neural progenitor cells through the Akt pathway [J].
Bai, Yun ;
Cui, Ming ;
Meng, Zhijun ;
Shen, Li ;
He, Qihua ;
Zhang, Xiaoyan ;
Chen, Fengrong ;
Xiao, Junjun .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2009, 378 (02) :296-301
[6]   Endothelial cell-to-cell junctions: Molecular organization and role in vascular homeostasis [J].
Bazzoni, G ;
Dejana, E .
PHYSIOLOGICAL REVIEWS, 2004, 84 (03) :869-901
[7]   Delayed Pituitary Adenylate Cyclase-Activating Polypeptide Delivery After Brain Stroke Improves Functional Recovery by Inducing M2 Microglia/Macrophage Polarization [J].
Brifault, Coralie ;
Gras, Marjorie ;
Liot, Donovan ;
May, Victor ;
Vaudry, David ;
Wurtz, Olivier .
STROKE, 2015, 46 (02) :520-U322
[8]   Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients - A systematic overview [J].
Capes, SE ;
Hunt, D ;
Malmberg, K ;
Pathak, P ;
Gerstein, HC .
STROKE, 2001, 32 (10) :2426-2432
[9]   Niaspan increases angiogenesis and improves functional recovery after stroke [J].
Chen, Jieli ;
Cui, Xu ;
Zacharek, Alex ;
Jiang, Hao ;
Roberts, Cynthia ;
Zhang, Chunling ;
Lu, Mei ;
Kapke, Alissa ;
Feldkamp, Carolyn S. ;
Chopp, Michael .
ANNALS OF NEUROLOGY, 2007, 62 (01) :49-58
[10]   Adverse Effects of Bone Marrow Stromal Cell Treatment of Stroke in Diabetic Rats [J].
Chen, Jieli ;
Ye, Xinchun ;
Yan, Tao ;
Zhang, Chunling ;
Yang, Xiao-Ping ;
Cui, Xu ;
Cui, Yishen ;
Zacharek, Alex ;
Roberts, Cynthia ;
Liu, Xinfeng ;
Dai, Xiangguo ;
Lu, Mei ;
Chopp, Michael .
STROKE, 2011, 42 (12) :3551-3558