PMID- 29719282
OWN - NLM
STAT- MEDLINE
DCOM- 20180801
LR  - 20190212
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Linking)
VI  - 46
IP  - 5
DP  - 2018
TI  - Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally 
      Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral 
      Artery Occlusion Rats Within the First 7 Days After Stroke.
PG  - 1951-1970
LID - 10.1159/000489384 [doi]
AB  - BACKGROUND/AIMS: Neurotrophic effects and immunosuppression are the main 
      therapeutic mechanisms of mesenchymal stem cells (MSCs) in stroke treatment. 
      Neurotrophins are produced by graft cells, host neurons, astrocytes, and even 
      microglia/macrophages. Meanwhile, MSCs can increase inflammation if they are not 
      sufficiently induced by pro-inflammatory cytokines. We examined whether 
      intravenously transplanted bone marrow MSCs (BM-MSCs) increase inflammation in 
      distal middle cerebral artery occlusion (dMCAO) rats, how long the increased 
      inflammation effect persists for, and what the final therapeutic outcomes will 
      be. We also tested the neurotrophic role of BM-MSCs and attempted to identify the 
      neurotrophin-producing cells. METHODS: At 1 h after dMCAO was performed on 
      Sprague-Dawley rats, allogeneic BM-MSCs were transplanted intravenously. The 
      infarct volume was examined by Tetrazolium Red staining at 2 days (day 2), and 
      the behavioral tests (cylinder test and grid walking test) were performed at 2, 4 
      (day 4) and 7 days (day 7) after transplantation. The concentrations of 
      inflammation related cytokines and neurotrophins in the ischemic cortex, 
      ipsilateral striatum, and serum, were measured using ELISA at days 2-7. The cell 
      source of neurotrophins was observed by immunohistochemistry. RESULTS: The 
      transplanted cells were mainly found in the infarct border zone (IBZ) of the 
      brain. Infarct volume was reduced and behavioral outcomes were improved at 2 days 
      after ischemia. In the striatum and circulation, BM-MSC transplantation increased 
      inflammation at day 2 and decreased it at day 7. At days 2-7, insulin-like growth 
      factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) concentrations in 
      the ischemic core of the cortex were significantly higher in the BM-MSC group 
      than in the ischemia vehicle group. IGF-1 and BDNF were derived mainly from host 
      microglia/macrophages in the ischemic core, and transplanted cells in the IBZ. At 
      day 2, BM-MSC transplantation significantly increased the number of IGF-1+CD68+ 
      and BDNF+Iba-1+ double positive cells in the ischemic core cortex. CONCLUSIONS: 
      Although increased inflammation, BM-MSCs were still beneficial to dMCAO recovery 
      at day 2. The immunopromoting effect of MSCs was transient and shifted to an 
      immunosuppressive action at day 7. The neurotrophic factors IGF-1 and BDNF, which 
      were mainly derived from transplanted BM-MSCs and host microglia/macrophages, 
      contributed to the therapeutic effects from day 2 to day 7.
CI  - (c) 2018 The Author(s). Published by S. Karger AG, Basel.
FAU - Li, XiaoBo
AU  - Li X
AD  - Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical 
      School of Yangzhou University, Yangzhou, China.
FAU - Huang, Min
AU  - Huang M
AD  - Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical 
      School of Yangzhou University, Yangzhou, China.
FAU - Zhao, RenChao
AU  - Zhao R
AD  - Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical 
      School of Yangzhou University, Yangzhou, China.
FAU - Zhao, ChunSong
AU  - Zhao C
AD  - Department of Cell Biology, Xuanwu Hospital, Capital Medical University, Beijing, 
      China.
FAU - Liu, Yao
AU  - Liu Y
AD  - Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical 
      School of Yangzhou University, Yangzhou, China.
FAU - Zou, HaiQiang
AU  - Zou H
AD  - Department of Neurology, The General Hospital of Guangzhou Military Command, 
      Guangzhou, China.
FAU - Chen, Ling
AU  - Chen L
AD  - Department of Neurosurgery, Chinese PLA (People's Liberation Army) General 
      Hospital and PLA Medical College, Beijing, China.
FAU - Guan, YunQian
AU  - Guan Y
AD  - Department of Cell Biology, Xuanwu Hospital, Capital Medical University, Beijing, 
      China.
FAU - Zhang, Y Alex
AU  - Zhang YA
AD  - Department of Cell Biology, Xuanwu Hospital, Capital Medical University, Beijing, 
      China.
LA  - eng
PT  - Journal Article
DEP - 20180426
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (Cytokines)
SB  - IM
MH  - Administration, Intravenous
MH  - Animals
MH  - Cell Movement
MH  - Cells, Cultured
MH  - Cytokines/analysis
MH  - Infarction, Middle Cerebral Artery/pathology/*therapy
MH  - Inflammation/*etiology/pathology
MH  - Male
MH  - Mesenchymal Stem Cell Transplantation/*adverse effects/*methods
MH  - Rats, Sprague-Dawley
OTO - NOTNLM
OT  - Cerebral ischemia
OT  - Macrophages
OT  - Mesenchymal stem cell
OT  - Microglia
OT  - Transplantation
EDAT- 2018/05/03 06:00
MHDA- 2018/08/02 06:00
CRDT- 2018/05/03 06:00
PHST- 2017/06/24 00:00 [received]
PHST- 2018/03/05 00:00 [accepted]
PHST- 2018/05/03 06:00 [pubmed]
PHST- 2018/08/02 06:00 [medline]
PHST- 2018/05/03 06:00 [entrez]
AID - 000489384 [pii]
AID - 10.1159/000489384 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2018;46(5):1951-1970. doi: 10.1159/000489384. Epub 2018 Apr 
      26.