Oncotarget

Research Papers: Pathology:

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 and Hon-Kan Yip _

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Oncotarget. 2016; 7:74537-74556. https://doi.org/10.18632/oncotarget.12902

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Abstract

Kuan-Hung Chen1,8,*, Chih-Hung Chen2,*, Christopher Glenn Wallace3, Chun-Man Yuen4, Gour-Shenq Kao5, Yi-Ling Chen5, Pei-Lin Shao6, Yung-Lung Chen5, Han-Tan Chai5, Kun-Chen Lin1, Chu-Feng Liu7, Hsueh-Wen Chang8, Mel S. Lee9 and Hon-Kan Yip5,6,10,11,12

1 Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

2 Department of Internal Medicine, Division of General Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

3 Department of Plastic Surgery, University Hospital of South Manchester, Manchester, UK

4 Department of Surgery, Division of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

5 Department of Internal Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

6 Department of Nursing, Asia University, Taichung, Taiwan

7 Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

8 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

9 Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

10 Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

11 Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

12 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

* These authors have contributed equally to this work

Correspondence to:

Hon-Kan Yip, email:

Keywords: xenogenic adipose-derived mesenchymal stem cell, exosomes, ischemic stroke, brain infarct size, neurological function, Pathology Section

Received: August 15, 2016 Accepted: October 14, 2016 Published: October 25, 2016

Abstract

We tested the hypothesis that combined xenogenic (from mini-pig) adipose-derived 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 [AIS-exosome (100&#x3bc;g)], 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-α/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.


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