Protective Effect of Human-Neural-Crest-Derived Nasal Turbinate Stem Cells against Amyloid-β Neurotoxicity through Inhibition of Osteopontin in a Human Cerebral Organoid Model of Alzheimer’s Disease
Jung Yeon Lim,
Jung Eun Lee,
Soon A Park,
Sang In Park,
Jung-Min Yon,
Jeong-Ah Park,
Sin-Soo Jeun,
Seung Joon Kim,
Hong Jun Lee,
Sung Won Kim,
Seung Ho Yang
Affiliations
Jung Yeon Lim
Department of Otolaryngology—Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Jung Eun Lee
Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Kyonggi-do, Korea
Soon A Park
Department of Neurosurgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Sang In Park
Institute of Catholic Integrative Medicine (ICIM), Incheon St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
Jung-Min Yon
Department of Otolaryngology—Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Jeong-Ah Park
Department of Otolaryngology—Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Sin-Soo Jeun
Department of Neurosurgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Seung Joon Kim
Division of Pulmonology, Critical Care and Allergy, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Hong Jun Lee
College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Korea
Sung Won Kim
Department of Otolaryngology—Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Seung Ho Yang
Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Kyonggi-do, Korea
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer’s disease (AD). We generated hBOs from human induced pluripotent stem cells, investigated their characteristics according to neuronal markers and electrophysiological features, and then evaluated the protective effect of hNTSCs against amyloid-β peptide (Aβ1–42) neurotoxic activity in vitro in hBOs and in vivo in a mouse model of AD. Treatment of hBOs with Aβ1–42 induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Aβ1–42 exposure. Cytokine array showed a significantly decreased level of osteopontin (OPN) in hBOs with hNTSC coculture compared with hBOs only in the presence of Aβ1–42. Silencing OPN via siRNA suppressed Aβ-induced neuronal cell death in cell culture. Notably, compared with PBS, hNTSC transplantation significantly enhanced performance on the Morris water maze, with reduced levels of OPN after transplantation in a mouse model of AD. These findings reveal that hBO models are useful to evaluate the therapeutic effect and mechanism of stem cells for application in treating AD.
