title: Hypothermia augments neuroprotective activity of mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy.
abstract: Though hypothermia is the only clinically available treatment for neonatal hypoxic-ischemic encephalopathy (HIE), it is not completely effective in severe cases. We hypothesized that combined treatment with hypothermia and transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) would synergistically attenuate severe HIE compared to stand-alone therapy. To induce hypoxia-ischemia (HI), male Sprague-Dawley rats were subjected to 8% oxygen for 120 min after unilateral carotid artery ligation on postnatal day (P) 7. After confirmation of severe HIE involving >50% of the ipsilateral hemisphere volume as determined by diffusion-weighted brain magnetic resonance imaging (MRI) within 2 h after HI, intraventricular MSC transplantation (1 × 105 cells) and/or hypothermia with target temperature at 32°C for 24 h were administered 6 h after induction of HI. Follow-up brain MRI at P12 and P42, sensorimotor function tests at P40-42, evaluation of cytokines in the cerebrospinal fluid (CSF) at P42, and histologic analysis of peri-infarct tissues at P42 were performed. Severe HI resulted in progressively increased brain infarction over time as assessed by serial MRI, increased number of cells positive for terminal deoxynucleotidyl transferase nick-end labeling, microgliosis and astrocytosis, increased CSF cytokine levels, and impaired function in behavioral tests such as rotarod and cylinder tests. All of the abnormalities observed in severe HIE showed greater improvement after combined treatment with hypothermia and MSC transplantation than with either therapy alone. Overall, these findings suggest that combined treatment with hypothermia and human UCB-derived MSC transplantation might be a novel therapeutic modality to improve the prognosis of severe HIE, an intractable disease that currently has no effective treatment.
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Won Soon
authors: WS
authors: Park
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Se In
authors: SI
authors: Sung
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: So Yoon
authors: SY
authors: Ahn
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Hye Soo
authors: HS
authors: Yoo
authors: Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Dong Kyung
authors: DK
authors: Sung
authors: Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Geun Ho
authors: GH
authors: Im
authors: Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul, Korea.
authors: Soo Jin
authors: SJ
authors: Choi
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Yun Sil
authors: YS
authors: Chang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000517:prevention & control*; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents