PMID- 37907966 OWN - NLM STAT- MEDLINE DCOM- 20231102 LR - 20231103 IS - 2045-8118 (Electronic) IS - 2045-8118 (Linking) VI - 20 IP - 1 DP - 2023 Oct 31 TI - Human isogenic cells of the neurovascular unit exert transcriptomic cell type-specific effects on a blood-brain barrier in vitro model of late-onset Alzheimer disease. PG - 78 LID - 10.1186/s12987-023-00471-y [doi] LID - 78 AB - BACKGROUND: The function of the blood-brain barrier (BBB) is impaired in late-onset Alzheimer disease (LOAD), but the associated molecular mechanisms, particularly with respect to the high-risk APOE4/4 genotype, are not well understood. For this purpose, we developed a multicellular isogenic model of the neurovascular unit (NVU) based on human induced pluripotent stem cells. METHODS: The human NVU was modeled in vitro using isogenic co-cultures of astrocytes, brain capillary endothelial-like cells (BCECs), microglia-like cells, neural stem cells (NSCs), and pericytes. Physiological and pathophysiological properties were investigated as well as the influence of each single cell type on the characteristics and function of BCECs. The barriers established by BCECs were analyzed for specific gene transcription using high-throughput quantitative PCR. RESULTS: Co-cultures were found to tighten the barrier of BCECs and alter its transcriptomic profile under both healthy and disease conditions. In vitro differentiation of brain cell types that constitute the NVU was not affected by the LOAD background. The supportive effect of NSCs on the barrier established by BCECs was diminished under LOAD conditions. Transcriptomes of LOAD BCECs were modulated by different brain cell types. NSCs were found to have the strongest effect on BCEC gene regulation and maintenance of the BBB. Co-cultures showed cell type-specific functional contributions to BBB integrity under healthy and LOAD conditions. CONCLUSIONS: Cell type-dependent transcriptional effects on LOAD BCECs were identified. Our study suggests that different brain cell types of the NVU have unique roles in maintaining barrier integrity that vary under healthy and LOAD conditions. . CI - (c) 2023. The Author(s). FAU - Haferkamp, Undine AU - Haferkamp U AD - Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525, Hamburg, Germany. FAU - Hartmann, Carla AU - Hartmann C AD - Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany. FAU - Abid, Chaudhry Luqman AU - Abid CL AD - Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany. FAU - Brachner, Andreas AU - Brachner A AD - Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, Vienna, 1210, Austria. FAU - Hochner, Alevtina AU - Hochner A AD - Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Wurzburg, Germany. FAU - Gerhartl, Anna AU - Gerhartl A AD - Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, Vienna, 1210, Austria. FAU - Harwardt, Bernadette AU - Harwardt B AD - Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany. FAU - Leckzik, Selin AU - Leckzik S AD - Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany. FAU - Leu, Jennifer AU - Leu J AD - Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525, Hamburg, Germany. FAU - Metzger, Marco AU - Metzger M AD - Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Wurzburg, Germany. AD - Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Wurzburg, 97070, Wurzburg, Germany. FAU - Nastainczyk-Wulf, Marina AU - Nastainczyk-Wulf M AD - Institute of Legal Medicine, University Hospital, 06112, Halle (Saale), Germany. FAU - Neuhaus, Winfried AU - Neuhaus W AD - Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, Vienna, 1210, Austria. AD - Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems, 3500, Austria. FAU - Oerter, Sabrina AU - Oerter S AD - Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Wurzburg, Germany. AD - Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Wurzburg, 97070, Wurzburg, Germany. FAU - Pless, Ole AU - Pless O AD - Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525, Hamburg, Germany. FAU - Rujescu, Dan AU - Rujescu D AD - Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna, 1090, Austria. FAU - Jung, Matthias AU - Jung M AD - Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany. matthias.jung@uk-halle.de. FAU - Appelt-Menzel, Antje AU - Appelt-Menzel A AD - Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Wurzburg, Germany. antje.appelt-menzel@uni-wuerzburg.de. AD - Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Wurzburg, 97070, Wurzburg, Germany. antje.appelt-menzel@uni-wuerzburg.de. LA - eng PT - Journal Article DEP - 20231031 PL - England TA - Fluids Barriers CNS JT - Fluids and barriers of the CNS JID - 101553157 SB - IM MH - Humans MH - Blood-Brain Barrier/metabolism MH - Transcriptome MH - *Alzheimer Disease/metabolism MH - *Induced Pluripotent Stem Cells/physiology MH - Brain MH - Astrocytes/metabolism PMC - PMC10617216 OTO - NOTNLM OT - Alzheimer disease OT - Apolipoprotein E OT - Blood-brain barrier OT - Human induced pluripotent cells OT - Late-onset Alzheimer disease OT - Neurovascular unit COIS- The authors declare no competing interests. EDAT- 2023/11/01 06:43 MHDA- 2023/11/02 12:45 PMCR- 2023/10/31 CRDT- 2023/11/01 01:07 PHST- 2023/07/12 00:00 [received] PHST- 2023/10/01 00:00 [accepted] PHST- 2023/11/02 12:45 [medline] PHST- 2023/11/01 06:43 [pubmed] PHST- 2023/11/01 01:07 [entrez] PHST- 2023/10/31 00:00 [pmc-release] AID - 10.1186/s12987-023-00471-y [pii] AID - 471 [pii] AID - 10.1186/s12987-023-00471-y [doi] PST - epublish SO - Fluids Barriers CNS. 2023 Oct 31;20(1):78. doi: 10.1186/s12987-023-00471-y.