PMID- 25637797 OWN - NLM STAT- MEDLINE DCOM- 20151215 LR - 20181202 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 290 DP - 2015 Apr 2 TI - Enhanced angiogenesis promoted by human umbilical mesenchymal stem cell transplantation in stroked mouse is Notch1 signaling associated. PG - 288-99 LID - S0306-4522(15)00093-7 [pii] LID - 10.1016/j.neuroscience.2015.01.038 [doi] AB - Cellular therapy has provided hope for restoring neurological function post stroke through promoting endogenous neurogenesis, angiogenesis and synaptogenesis. The current study was based on the observation that transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) promoted the neurological function improvement in stroked mice and meanwhile enhanced angiogenesis in the stroked hemisphere. Grafted hUCMSCs secreted human vascular endothelial growth factor A (VEGF-A). Notch1 signaling was activated after stroke and also in the grafted hUCMSCs. To address the potential mechanism that might mediate such pro-angiogenic effect, we established a hUCMSC-neuron co-culture system. Neurons were subjected to oxygen glucose deprivation (OGD) injury before co-culturing to mimic the in vivo cell transplantation. Consistent with the in vivo data, co-culture medium claimed from hUCMSC-OGD neuron co-culture system significantly promoted the capillary-like tube formation of brain-derived endothelial cells. Moreover, coincident with our in vivo data, Notch 1 signaling activation was detected in hUCMSCs after co-cultured with OGD neurons as demonstrated by the up-regulation of key Notch1 signaling components Notch1 and Notch1 intercellular domain (NICD). In addition, OGD-neuron co-culture also increased the VEGF-A production by hUCMSCs. To verify whether Notch1 activation was involved in the pro-angiogenic effect, gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was added into the co-culture medium before co-culture. It turned out that DAPT significantly prevented the Notch1 activation in hUCMSCs after co-culture with OGD neurons. More importantly, the pro-angiogenic effect of hUCMSCs was remarkably abolished by DAPT addition as demonstrated by inhibited capillary-like tube formation and less VEGF-A production. Regarding how Notch1 signaling was linked with VEGF-A secretion, we provided some clue that Notch1 effector Hes1 mRNA expression was significantly up-regulated by OGD-neuron co-culturing and down-regulated after additional treatment of DAPT. In summary, our data provided evidence that the VEGF-A secretion from hUCMSCs after being triggered by OGD neurons is Notch1 signaling associated. This might be a possible mechanism that contributes to the angiogenic effect of hUCMSC transplantation in stroked brain. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Zhu, J AU - Zhu J AD - Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China. Electronic address: zhujuehua@hotmail.com. FAU - Liu, Q AU - Liu Q AD - Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China. Electronic address: conneym@163.com. FAU - Jiang, Y AU - Jiang Y AD - Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China. Electronic address: jiangyjnju@gmail.com. FAU - Wu, L AU - Wu L AD - Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China. Electronic address: lilywu_yeah@yahoo.com. FAU - Xu, G AU - Xu G AD - Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China. Electronic address: gelinxu@gmail.com. FAU - Liu, X AU - Liu X AD - Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China. Electronic address: xfliu2@vip.163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150128 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Basic Helix-Loop-Helix Transcription Factors) RN - 0 (Homeodomain Proteins) RN - 0 (NOTCH1 protein, human) RN - 0 (Notch1 protein, mouse) RN - 0 (RNA, Messenger) RN - 0 (Receptor, Notch1) RN - 0 (Transcription Factor HES-1) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 149348-15-2 (HES1 protein, human) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism MH - Animals MH - Basic Helix-Loop-Helix Transcription Factors/metabolism MH - Cell Hypoxia/drug effects/physiology MH - Coculture Techniques MH - *Cord Blood Stem Cell Transplantation MH - Disease Models, Animal MH - Fetal Blood/drug effects/physiology MH - Glucose/deficiency MH - Homeodomain Proteins/metabolism MH - Humans MH - Male MH - *Mesenchymal Stem Cell Transplantation MH - Mesenchymal Stem Cells/drug effects/physiology MH - Mice, Inbred C57BL MH - Neovascularization, Physiologic/*physiology MH - Neurons/drug effects/physiology MH - RNA, Messenger/metabolism MH - Random Allocation MH - Receptor, Notch1/*metabolism MH - Signal Transduction/drug effects MH - Stroke/*physiopathology/*therapy MH - Transcription Factor HES-1 MH - Vascular Endothelial Growth Factor A/metabolism OTO - NOTNLM OT - Hes1 OT - Notch1 signaling OT - VEGF-A OT - angiogenesis OT - human umbilical mesenchymal stem cells OT - stroke EDAT- 2015/02/01 06:00 MHDA- 2015/12/17 06:00 CRDT- 2015/02/01 06:00 PHST- 2014/09/12 00:00 [received] PHST- 2014/11/18 00:00 [revised] PHST- 2015/01/08 00:00 [accepted] PHST- 2015/02/01 06:00 [entrez] PHST- 2015/02/01 06:00 [pubmed] PHST- 2015/12/17 06:00 [medline] AID - S0306-4522(15)00093-7 [pii] AID - 10.1016/j.neuroscience.2015.01.038 [doi] PST - ppublish SO - Neuroscience. 2015 Apr 2;290:288-99. doi: 10.1016/j.neuroscience.2015.01.038. Epub 2015 Jan 28.