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Sci Rep. 2018 May 16;8(1):7665. doi: 10.1038/s41598-018-25902-x.

Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy.

Ahn SY1,2, Chang YS1,3,2, Sung DK1,2, Sung SI1,2, Park WS4,5,6.

Author information

1
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
2
Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea.
3
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
4
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. wonspark@skku.edu.
5
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. wonspark@skku.edu.
6
Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea. wonspark@skku.edu.

Abstract

Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.

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