Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke

Kuan Hung Chen; Chih Hung Chen; Christopher Glenn Wallace; Chun Man Yuen; Gour Shenq Kao; Yi Ling Chen; Pei Lin Shao; Yung Lung Chen; Han Tan Chai; Kun Chen Lin; Chu Feng Liu; Hsueh Wen Chang; Mel S. Lee; Hon Kan Yip

doi:10.18632/oncotarget.12902

Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke

Kuan Hung Chen, Chih Hung Chen, Christopher Glenn Wallace, Chun Man Yuen, Gour Shenq Kao, Yi Ling Chen, Pei Lin Shao, Yung Lung Chen, Han Tan Chai, Kun Chen Lin, Chu Feng Liu, Hsueh Wen Chang, Mel S. Lee, Hon Kan Yip^*

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

196 Scopus citations

Abstract

We tested the hypothesis that combined xenogenic (from mini-pig) adiposederived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) and enhance neurological recovery in rat after acute ischemic stroke (AIS) induced by 50-min left middle cerebral artery occlusion. Adult-male Sprague-Dawley rats (n = 60) were divided equally into group 1 (sham-control), group 2 (AIS), group 3 [AIS-ADMSC (1.2×10⁶ cells)], group 4 [AISexosome (100μg)], and group 5 (AIS-exosome-ADMSC). All therapies were provided intravenously at 3h after AIS procedure. BIZ determined by histopathology (by day- 60) and brain MRI (by day-28) were highest in group 2, lowest in group 1, higher in groups 3 and 4 than in group 5, but they showed no difference between groups 3 and 4 (all p < 0.0001). By day-28, sensorimotor functional results exhibited an opposite pattern to BIZ among the five groups (p < 0.005). Protein expressions of inflammatory (inducible nitric oxide synthase/tumor necrosis factor-a/nuclear factor-κB/interleukin-1β/matrix metalloproteinase-9/plasminogen activator inhibitor-1/RANTES), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/Poly-ADP-ribose polymerase), and fibrotic (Smad3/transforming growth factor-β) biomarkers, and cellular expressions of brain-damaged (γ-H2AX+/XRCC1-CD90+/p53BP1-CD90+), inflammatory (CD11+/CD68+/glial fibrillary acid protein+) and brain-edema (aquaporin-4+) markers showed a similar pattern of BIZ among the groups (all n < 0.0001). In conclusion, xenogenic ADMSC/ADMSC-derived exosome therapy was safe and offered the additional benefit of reducing BIZ and improving neurological function in rat AIS.

Original language	English
Pages (from-to)	74537-74556
Number of pages	20
Journal	Oncotarget
Volume	7
Issue number	46
DOIs	https://doi.org/10.18632/oncotarget.12902
State	Published - 2016

Keywords

Brain infarct size
Exosomes
Ischemic stroke
Neurological function
Pathology Section
Xenogenic adipose-derived mesenchymal stem cell

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Chen, K. H., Chen, C. H., Wallace, C. G., Yuen, C. M., Kao, G. S., Chen, Y. L., Shao, P. L., Chen, Y. L., Chai, H. T., Lin, K. C., Liu, C. F., Chang, H. W., Lee, M. S., & Yip, H. K. (2016). Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget, 7(46), 74537-74556. https://doi.org/10.18632/oncotarget.12902

@article{ed37d5a9eda04e789f5e84a9d3099ea0,

title = "Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke",

abstract = "We tested the hypothesis that combined xenogenic (from mini-pig) adiposederived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) and enhance neurological recovery in rat after acute ischemic stroke (AIS) induced by 50-min left middle cerebral artery occlusion. Adult-male Sprague-Dawley rats (n = 60) were divided equally into group 1 (sham-control), group 2 (AIS), group 3 [AIS-ADMSC (1.2×106 cells)], group 4 [AISexosome (100μg)], and group 5 (AIS-exosome-ADMSC). All therapies were provided intravenously at 3h after AIS procedure. BIZ determined by histopathology (by day- 60) and brain MRI (by day-28) were highest in group 2, lowest in group 1, higher in groups 3 and 4 than in group 5, but they showed no difference between groups 3 and 4 (all p < 0.0001). By day-28, sensorimotor functional results exhibited an opposite pattern to BIZ among the five groups (p < 0.005). Protein expressions of inflammatory (inducible nitric oxide synthase/tumor necrosis factor-a/nuclear factor-κB/interleukin-1β/matrix metalloproteinase-9/plasminogen activator inhibitor-1/RANTES), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/Poly-ADP-ribose polymerase), and fibrotic (Smad3/transforming growth factor-β) biomarkers, and cellular expressions of brain-damaged (γ-H2AX+/XRCC1-CD90+/p53BP1-CD90+), inflammatory (CD11+/CD68+/glial fibrillary acid protein+) and brain-edema (aquaporin-4+) markers showed a similar pattern of BIZ among the groups (all n < 0.0001). In conclusion, xenogenic ADMSC/ADMSC-derived exosome therapy was safe and offered the additional benefit of reducing BIZ and improving neurological function in rat AIS.",

keywords = "Brain infarct size, Exosomes, Ischemic stroke, Neurological function, Pathology Section, Xenogenic adipose-derived mesenchymal stem cell",

author = "Chen, {Kuan Hung} and Chen, {Chih Hung} and Wallace, {Christopher Glenn} and Yuen, {Chun Man} and Kao, {Gour Shenq} and Chen, {Yi Ling} and Shao, {Pei Lin} and Chen, {Yung Lung} and Chai, {Han Tan} and Lin, {Kun Chen} and Liu, {Chu Feng} and Chang, {Hsueh Wen} and Lee, {Mel S.} and Yip, {Hon Kan}",

year = "2016",

doi = "10.18632/oncotarget.12902",

language = "英语",

volume = "7",

pages = "74537--74556",

journal = "Oncotarget",

issn = "1949-2553",

number = "46",

}

Chen, KH, Chen, CH, Wallace, CG, Yuen, CM, Kao, GS, Chen, YL, Shao, PL, Chen, YL, Chai, HT, Lin, KC, Liu, CF, Chang, HW, Lee, MS & Yip, HK 2016, 'Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke', Oncotarget, vol. 7, no. 46, pp. 74537-74556. https://doi.org/10.18632/oncotarget.12902

Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. / Chen, Kuan Hung; Chen, Chih Hung; Wallace, Christopher Glenn et al.
In: Oncotarget, Vol. 7, No. 46, 2016, p. 74537-74556.

Research output: Contribution to journal › Journal Article › peer-review

TY - JOUR

T1 - Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke

AU - Chen, Kuan Hung

AU - Chen, Chih Hung

AU - Wallace, Christopher Glenn

AU - Yuen, Chun Man

AU - Kao, Gour Shenq

AU - Chen, Yi Ling

AU - Shao, Pei Lin

AU - Chen, Yung Lung

AU - Chai, Han Tan

AU - Lin, Kun Chen

AU - Liu, Chu Feng

AU - Chang, Hsueh Wen

AU - Lee, Mel S.

AU - Yip, Hon Kan

PY - 2016

Y1 - 2016

N2 - We tested the hypothesis that combined xenogenic (from mini-pig) adiposederived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) and enhance neurological recovery in rat after acute ischemic stroke (AIS) induced by 50-min left middle cerebral artery occlusion. Adult-male Sprague-Dawley rats (n = 60) were divided equally into group 1 (sham-control), group 2 (AIS), group 3 [AIS-ADMSC (1.2×106 cells)], group 4 [AISexosome (100μg)], and group 5 (AIS-exosome-ADMSC). All therapies were provided intravenously at 3h after AIS procedure. BIZ determined by histopathology (by day- 60) and brain MRI (by day-28) were highest in group 2, lowest in group 1, higher in groups 3 and 4 than in group 5, but they showed no difference between groups 3 and 4 (all p < 0.0001). By day-28, sensorimotor functional results exhibited an opposite pattern to BIZ among the five groups (p < 0.005). Protein expressions of inflammatory (inducible nitric oxide synthase/tumor necrosis factor-a/nuclear factor-κB/interleukin-1β/matrix metalloproteinase-9/plasminogen activator inhibitor-1/RANTES), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/Poly-ADP-ribose polymerase), and fibrotic (Smad3/transforming growth factor-β) biomarkers, and cellular expressions of brain-damaged (γ-H2AX+/XRCC1-CD90+/p53BP1-CD90+), inflammatory (CD11+/CD68+/glial fibrillary acid protein+) and brain-edema (aquaporin-4+) markers showed a similar pattern of BIZ among the groups (all n < 0.0001). In conclusion, xenogenic ADMSC/ADMSC-derived exosome therapy was safe and offered the additional benefit of reducing BIZ and improving neurological function in rat AIS.

AB - We tested the hypothesis that combined xenogenic (from mini-pig) adiposederived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) and enhance neurological recovery in rat after acute ischemic stroke (AIS) induced by 50-min left middle cerebral artery occlusion. Adult-male Sprague-Dawley rats (n = 60) were divided equally into group 1 (sham-control), group 2 (AIS), group 3 [AIS-ADMSC (1.2×106 cells)], group 4 [AISexosome (100μg)], and group 5 (AIS-exosome-ADMSC). All therapies were provided intravenously at 3h after AIS procedure. BIZ determined by histopathology (by day- 60) and brain MRI (by day-28) were highest in group 2, lowest in group 1, higher in groups 3 and 4 than in group 5, but they showed no difference between groups 3 and 4 (all p < 0.0001). By day-28, sensorimotor functional results exhibited an opposite pattern to BIZ among the five groups (p < 0.005). Protein expressions of inflammatory (inducible nitric oxide synthase/tumor necrosis factor-a/nuclear factor-κB/interleukin-1β/matrix metalloproteinase-9/plasminogen activator inhibitor-1/RANTES), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/Poly-ADP-ribose polymerase), and fibrotic (Smad3/transforming growth factor-β) biomarkers, and cellular expressions of brain-damaged (γ-H2AX+/XRCC1-CD90+/p53BP1-CD90+), inflammatory (CD11+/CD68+/glial fibrillary acid protein+) and brain-edema (aquaporin-4+) markers showed a similar pattern of BIZ among the groups (all n < 0.0001). In conclusion, xenogenic ADMSC/ADMSC-derived exosome therapy was safe and offered the additional benefit of reducing BIZ and improving neurological function in rat AIS.

KW - Brain infarct size

KW - Exosomes

KW - Ischemic stroke

KW - Neurological function

KW - Pathology Section

KW - Xenogenic adipose-derived mesenchymal stem cell

UR - http://www.scopus.com/inward/record.url?scp=84996605938&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.12902

DO - 10.18632/oncotarget.12902

M3 - 文章

C2 - 27793019

AN - SCOPUS:84996605938

SN - 1949-2553

VL - 7

SP - 74537

EP - 74556

JO - Oncotarget

JF - Oncotarget

IS - 46

ER -

Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke

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Keywords

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