Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes
For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervou...
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MDPI AG
2021-07-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/7/1705 |
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| author | Nikita Arnst Pedro Belio-Mairal Laura García-González Laurie Arnaud Louise Greetham Emmanuel Nivet Santiago Rivera Alexander Dityatev |
| author_facet | Nikita Arnst Pedro Belio-Mairal Laura García-González Laurie Arnaud Louise Greetham Emmanuel Nivet Santiago Rivera Alexander Dityatev |
| author_sort | Nikita Arnst |
| collection | DOAJ |
| description | For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer’s disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target. However, a more comprehensive analysis of the role of MT5-MMP is necessary to evaluate how its targeting affects neurons and glia in pathological and physiological situations. In this study, leveraging on CRISPR-Cas9 genome editing strategy, we established cultures of human-induced pluripotent stem cells (hiPSC)-derived neurons and astrocytes to investigate the impact of MT5-MMP deficiency on their phenotypes. We found that MT5-MMP-deficient neurons exhibited an increased number of primary and secondary neurites, as compared to isogenic hiPSC-derived neurons. Moreover, MT5-MMP-deficient astrocytes displayed higher surface area and volume compared to control astrocytes. The MT5-MMP-deficient astrocytes also exhibited decreased GLAST and S100β expression. These findings provide novel insights into the physiological role of MT5-MMP in human neurons and astrocytes, suggesting that therapeutic strategies targeting MT5-MMP should be controlled for potential side effects on astrocytic physiology and neuronal morphology. |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T09:43:34Z |
| publishDate | 2021-07-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-e6935342236f47a8bb77f73f0eda0edc2023-11-22T03:28:43ZengMDPI AGCells2073-44092021-07-01107170510.3390/cells10071705Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived AstrocytesNikita Arnst0Pedro Belio-Mairal1Laura García-González2Laurie Arnaud3Louise Greetham4Emmanuel Nivet5Santiago Rivera6Alexander Dityatev7Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, GermanyMolecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, GermanyInst Neurophysiopathol, CNRS, INP, Aix Marseille Université, 13385 Marseille, FranceInst Neurophysiopathol, CNRS, INP, Aix Marseille Université, 13385 Marseille, FranceInst Neurophysiopathol, CNRS, INP, Aix Marseille Université, 13385 Marseille, FranceInst Neurophysiopathol, CNRS, INP, Aix Marseille Université, 13385 Marseille, FranceInst Neurophysiopathol, CNRS, INP, Aix Marseille Université, 13385 Marseille, FranceMolecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, GermanyFor some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer’s disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target. However, a more comprehensive analysis of the role of MT5-MMP is necessary to evaluate how its targeting affects neurons and glia in pathological and physiological situations. In this study, leveraging on CRISPR-Cas9 genome editing strategy, we established cultures of human-induced pluripotent stem cells (hiPSC)-derived neurons and astrocytes to investigate the impact of MT5-MMP deficiency on their phenotypes. We found that MT5-MMP-deficient neurons exhibited an increased number of primary and secondary neurites, as compared to isogenic hiPSC-derived neurons. Moreover, MT5-MMP-deficient astrocytes displayed higher surface area and volume compared to control astrocytes. The MT5-MMP-deficient astrocytes also exhibited decreased GLAST and S100β expression. These findings provide novel insights into the physiological role of MT5-MMP in human neurons and astrocytes, suggesting that therapeutic strategies targeting MT5-MMP should be controlled for potential side effects on astrocytic physiology and neuronal morphology.https://www.mdpi.com/2073-4409/10/7/1705Alzheimer’s diseasehuman-induced pluripotent stem cellsdisease modelingneuronal differentiationhiPSC-derived astrocytesmetalloproteinase |
| spellingShingle | Nikita Arnst Pedro Belio-Mairal Laura García-González Laurie Arnaud Louise Greetham Emmanuel Nivet Santiago Rivera Alexander Dityatev Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes Cells Alzheimer’s disease human-induced pluripotent stem cells disease modeling neuronal differentiation hiPSC-derived astrocytes metalloproteinase |
| title | Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes |
| title_full | Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes |
| title_fullStr | Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes |
| title_full_unstemmed | Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes |
| title_short | Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes |
| title_sort | deficiency in mt5 mmp supports branching of human ipscs derived neurons and reduces expression of glast s100 in ipscs derived astrocytes |
| topic | Alzheimer’s disease human-induced pluripotent stem cells disease modeling neuronal differentiation hiPSC-derived astrocytes metalloproteinase |
| url | https://www.mdpi.com/2073-4409/10/7/1705 |
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