PMID- 33213497 OWN - NLM STAT- MEDLINE DCOM- 20211011 LR - 20231104 IS - 1750-1326 (Electronic) IS - 1750-1326 (Linking) VI - 15 IP - 1 DP - 2020 Nov 19 TI - An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases. PG - 70 LID - 10.1186/s13024-020-00418-z [doi] LID - 70 AB - INTRODUCTION: The neurovascular unit (NVU) - the interaction between the neurons and the cerebrovasculature - is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU. METHOD: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. RESULTS: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer's disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model. CONCLUSION: This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses. FAU - Robert, Jerome AU - Robert J AUID- ORCID: 0000-0002-2847-9362 AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. jerome.robert@usz.ch. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. jerome.robert@usz.ch. AD - Institute of Clinical Chemistry, University hospital Zurich, 8000 Zurich, Wagistrasse 14, CH-8952, Schlieren, Switzerland. jerome.robert@usz.ch. FAU - Weilinger, Nicholas L AU - Weilinger NL AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Cao, Li-Ping AU - Cao LP AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Centre for Applied Neurogenetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Cataldi, Stefano AU - Cataldi S AD - Centre for Applied Neurogenetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Button, Emily B AU - Button EB AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Stukas, Sophie AU - Stukas S AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Martin, Emma M AU - Martin EM AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Seibler, Philip AU - Seibler P AD - Institute of Neurogenetics, University of Luebeck, 23562, Luebeck, Germany. FAU - Gilmour, Megan AU - Gilmour M AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Caffrey, Tara M AU - Caffrey TM AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Rowe, Elyn M AU - Rowe EM AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Fan, Jianjia AU - Fan J AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - MacVicar, Brian AU - MacVicar B AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. FAU - Farrer, Matthew J AU - Farrer MJ AD - Centre for Applied Neurogenetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. AD - Laboratory for Neurogenetics & Neuroscience, McKnight and Fixel Institutes, University of Florida, Gainesville, 32610, USA. FAU - Wellington, Cheryl L AU - Wellington CL AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. cheryl.wellington@ubc.ca. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada. cheryl.wellington@ubc.ca. AD - School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. cheryl.wellington@ubc.ca. AD - International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, V5Z 1M9, Canada. cheryl.wellington@ubc.ca. LA - eng GR - FDN148397/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201119 PL - England TA - Mol Neurodegener JT - Molecular neurodegeneration JID - 101266600 SB - IM MH - Alzheimer Disease/metabolism MH - Arteries/*metabolism/physiopathology MH - Astrocytes/*metabolism MH - Blood-Brain Barrier/metabolism MH - Coculture Techniques MH - Endothelial Cells/*metabolism MH - Humans MH - Induced Pluripotent Stem Cells/cytology MH - Neurodegenerative Diseases/*metabolism/pathology MH - Neurons/metabolism PMC - PMC7678181 COIS- The authors declare no competing interests. EDAT- 2020/11/21 06:00 MHDA- 2021/10/12 06:00 PMCR- 2020/11/19 CRDT- 2020/11/20 05:29 PHST- 2020/06/08 00:00 [received] PHST- 2020/11/03 00:00 [accepted] PHST- 2020/11/20 05:29 [entrez] PHST- 2020/11/21 06:00 [pubmed] PHST- 2021/10/12 06:00 [medline] PHST- 2020/11/19 00:00 [pmc-release] AID - 10.1186/s13024-020-00418-z [pii] AID - 418 [pii] AID - 10.1186/s13024-020-00418-z [doi] PST - epublish SO - Mol Neurodegener. 2020 Nov 19;15(1):70. doi: 10.1186/s13024-020-00418-z.