title: Astroglial Activation by an Enriched Environment after Transplantation of Mesenchymal Stem Cells Enhances Angiogenesis after Hypoxic-Ischemic Brain Injury.
abstract: Transplantation of mesenchymal stem cells (MSCs) has paracrine effects; however, the effects are known to be largely limited. Here we investigated the combination effects of cell transplantation and enriched environment (EE) in a model of hypoxic-ischemic brain injury. Brain damage was induced in seven-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O₂ for 90 min). At six weeks of age, the mice were randomly assigned to four groups: phosphate-buffered saline (PBS)-control (CON), PBS-EE, MSC-CON, and MSC-EE. Rotarod and grip strength tests were performed to evaluate neurobehavioral functions. Histologic evaluations were also performed to confirm the extent of astrocyte activation and endogenous angiogenesis. An array-based multiplex ELISA and Western blot were used to identify growth factors in vivo and in vitro. Two weeks after treatment, levels of astrocyte density and angiogenic factors were increased in MSC-EE mice, but glial scarring was not increased. Eight weeks after treatment, angiogenesis was increased, and behavioral outcomes were synergistically improved in the MSC-EE group. Astrocytes co-cultured with MSCs expressed higher levels of angiogenic factors than astrocytes cultured alone. The mechanisms of this synergistic effect included enhanced repair processes, such as increased endogenous angiogenesis and upregulation of angiogenic factors released from activated astrocytes.
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. srcho918@yuhs.ac.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. srcho918@yuhs.ac.|Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul 03722, Korea. srcho918@yuhs.ac.|Yonsei Stem Cell Research Center, Avison Biomedical Research Center, Seoul 03722, Korea. srcho918@yuhs.ac.
authors.forename: Sung-Rae
authors.initials: SR
authors.lastname: Cho
authors.affiliation: Graduate Program of Nano Science and Technology, Yonsei University, Seoul 03722, Korea. hwal@yuhs.ac.
authors.forename: Hwal
authors.initials: H
authors.lastname: Suh
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. onlyjin112@naver.com.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. onlyjin112@naver.com.
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. hkim1@yuhs.ac.|Graduate Program of Nano Science and Technology, Yonsei University, Seoul 03722, Korea. hkim1@yuhs.ac.|Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Korea. hkim1@yuhs.ac.
authors.forename: Hyongbum Henry
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. zugula@naver.com.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. zugula@naver.com.|Yonsei Stem Cell Research Center, Avison Biomedical Research Center, Seoul 03722, Korea. zugula@naver.com.|Department of Rehabilitation Medicine, Hallym University Burn Institute, Burn Center, Hangang Sacred Heart Hospital, Seoul 03722, Korea. zugula@naver.com.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Department of Rehabilitation Medicine, Hallym University Burn Institute, Burn Center, Hangang Sacred Heart Hospital, Seoul 03722, Korea. pmrseo@hallym.or.kr.
authors.forename: Cheong Hoon
authors.initials: CH
authors.lastname: Seo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D001808:Blood Vessels / Q000503:physiopathology*; D015153:Blotting, Western; D001930:Brain Injuries / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A
keywords: angiogenesis; astrocytes; enriched environment; hypoxic-ischemic brain injury; mesenchymal stem cells