Treatment with outgrowth endothelial cells protects cerebral barrier against ischemic injury |
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| Institution: | 1. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;2. Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;3. Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China;4. School of Life Sciences, Zhengzhou University, Zhengzhou, China;5. State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China;1. Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu, India;2. Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India;3. Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India;4. Department of Orthopaedics, Government Medical College and Hospital, Karur, Tamil Nadu, India;5. Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India;6. Department of Orthopaedics, Sanjay Gandhi Institute of Trauma & Orthopaedics, Bengaluru, Karnataka, India;7. Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow, Uttar Pradesh, India;8. Department of Orthopaedics, Faculty of Medicine - Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, Tamil Nadu, India;1. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany;2. Centre for Interdisciplinary Clinical Immunology, Rheumatology and Autoinflammatory Diseases, University Hospital Tuebingen, Tuebingen, Germany;1. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;2. Departments of Medicine and Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;3. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;4. Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;5. Program for Advanced Cell Therapy, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;6. Departments of Biostatistics & Medical Informatics and Statistics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;7. Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;8. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;1. Inpatients Department, Nanjing Qi-xia Xi-gang Community Health Service Centers, Nanjing, China;2. Research and Development Department, Nanjing Regenerative Medicine Engineering and Technology Research Center, Nanjing, China;1. Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Japan;2. Department of Neurology, Shiga University of Medical Science, Otsu, Japan |
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| Abstract: | Background and aimsWe have previously reported that outgrowth endothelial cells (OECs) restore cerebral endothelial cell integrity through effective homing to the injury site. This study further investigates whether treatment with OECs can restore blood–brain barrier (BBB) function in settings of ischemia-reperfusion injury both in vitro and in vivo.MethodsAn in vitro model of human BBB was established by co-culture of astrocytes, pericytes, and human brain microvascular endothelial cells (HBMECs) before exposure to oxygen-glucose deprivation alone or followed by reperfusion (OGD±R) in the absence or presence of exogenous OECs. Using a rodent model of middle cerebral artery occlusion (MCAO), we further assessed the therapeutic potential of OECs in vivo.ResultsOwing to their prominent antioxidant, proliferative, and migratory properties, alongside their inherent capacity to incorporate into brain vasculature, treatments with OECs attenuated the extent of OGD±R injury on BBB integrity and function, as ascertained by increases in transendothelial electrical resistance and decreases in paracellular flux across the barrier. Similarly, intravenous delivery of OECs also led to better barrier protection in MCAO rats as evidenced by significant decreases in ipsilateral brain edema volumes on day 3 after treatment. Mechanistic studies subsequently showed that treatment with OECs substantially reduced oxidative stress and apoptosis in HBMECs subjected to ischemic damages.ConclusionThis experimental study shows that OEC-based cell therapy restores BBB integrity in an effective manner by integrating into resident cerebral microvascular network, suppressing oxidative stress and cellular apoptosis. |
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