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
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-023-00471-y |
| _version_ | 1797636717718536192 |
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| author | Undine Haferkamp Carla Hartmann Chaudhry Luqman Abid Andreas Brachner Alevtina Höchner Anna Gerhartl Bernadette Harwardt Selin Leckzik Jennifer Leu Marco Metzger Marina Nastainczyk-Wulf Winfried Neuhaus Sabrina Oerter Ole Pless Dan Rujescu Matthias Jung Antje Appelt-Menzel |
| author_facet | Undine Haferkamp Carla Hartmann Chaudhry Luqman Abid Andreas Brachner Alevtina Höchner Anna Gerhartl Bernadette Harwardt Selin Leckzik Jennifer Leu Marco Metzger Marina Nastainczyk-Wulf Winfried Neuhaus Sabrina Oerter Ole Pless Dan Rujescu Matthias Jung Antje Appelt-Menzel |
| author_sort | Undine Haferkamp |
| collection | DOAJ |
| description | Abstract 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. Graphical abstract . |
| first_indexed | 2024-03-11T12:39:08Z |
| format | Article |
| id | doaj.art-e79d3dddebfc4e0ba9d9d75350e53843 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-03-11T12:39:08Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-e79d3dddebfc4e0ba9d9d75350e538432023-11-05T12:27:08ZengBMCFluids and Barriers of the CNS2045-81182023-10-0120112010.1186/s12987-023-00471-yHuman isogenic cells of the neurovascular unit exert transcriptomic cell type-specific effects on a blood-brain barrier in vitro model of late-onset Alzheimer diseaseUndine Haferkamp0Carla Hartmann1Chaudhry Luqman Abid2Andreas Brachner3Alevtina Höchner4Anna Gerhartl5Bernadette Harwardt6Selin Leckzik7Jennifer Leu8Marco Metzger9Marina Nastainczyk-Wulf10Winfried Neuhaus11Sabrina Oerter12Ole Pless13Dan Rujescu14Matthias Jung15Antje Appelt-Menzel16Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPortInstitute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-WittenbergInstitute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-WittenbergCenter Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbHFraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT)Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbHInstitute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-WittenbergInstitute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-WittenbergFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPortFraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT)Institute of Legal Medicine, University HospitalCenter Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbHFraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT)Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPortDepartment of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of ViennaInstitute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-WittenbergFraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT)Abstract 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. Graphical abstract .https://doi.org/10.1186/s12987-023-00471-yApolipoprotein EHuman induced pluripotent cellsBlood-brain barrierNeurovascular unitAlzheimer diseaseLate-onset Alzheimer disease |
| spellingShingle | Undine Haferkamp Carla Hartmann Chaudhry Luqman Abid Andreas Brachner Alevtina Höchner Anna Gerhartl Bernadette Harwardt Selin Leckzik Jennifer Leu Marco Metzger Marina Nastainczyk-Wulf Winfried Neuhaus Sabrina Oerter Ole Pless Dan Rujescu Matthias Jung Antje Appelt-Menzel 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 Fluids and Barriers of the CNS Apolipoprotein E Human induced pluripotent cells Blood-brain barrier Neurovascular unit Alzheimer disease Late-onset Alzheimer disease |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Apolipoprotein E Human induced pluripotent cells Blood-brain barrier Neurovascular unit Alzheimer disease Late-onset Alzheimer disease |
| url | https://doi.org/10.1186/s12987-023-00471-y |
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