Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling
Abstract A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs)...
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| Format: | Article |
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BMC
2022-08-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01428-2 |
| _version_ | 1818497988046094336 |
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| author | Corina Anastasaki Jit Chatterjee Olivia Cobb Shilpa Sanapala Suzanne M. Scheaffer Amanda De Andrade Costa Anna F. Wilson Chloe M. Kernan Ameera H. Zafar Xia Ge Joel R. Garbow Fausto J. Rodriguez David H. Gutmann |
| author_facet | Corina Anastasaki Jit Chatterjee Olivia Cobb Shilpa Sanapala Suzanne M. Scheaffer Amanda De Andrade Costa Anna F. Wilson Chloe M. Kernan Ameera H. Zafar Xia Ge Joel R. Garbow Fausto J. Rodriguez David H. Gutmann |
| author_sort | Corina Anastasaki |
| collection | DOAJ |
| description | Abstract A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs) harboring the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Herein, we identified that hiPSC-derived neuroglial progenitor populations (neural progenitors, glial restricted progenitors and oligodendrocyte progenitors), but not terminally differentiated astrocytes, give rise to tumors retaining LGG histologic features for at least 6 months in vivo. Additionally, we demonstrated that hiPSC-LGG xenograft formation requires the absence of CD4 T cell-mediated induction of astrocytic Cxcl10 expression. Genetic Cxcl10 ablation is both necessary and sufficient for human LGG xenograft development, which additionally enables the successful long-term growth of patient-derived pediatric LGGs in vivo. Lastly, MEK inhibitor (PD0325901) treatment increased hiPSC-LGG cell apoptosis and reduced proliferation both in vitro and in vivo. Collectively, this study establishes a tractable experimental humanized platform to elucidate the pathogenesis of and potential therapeutic opportunities for childhood brain tumors. |
| first_indexed | 2024-12-10T18:52:15Z |
| format | Article |
| id | doaj.art-0bce5b7aff7c4c1bb0ec1923cf2a939e |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-10T18:52:15Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-0bce5b7aff7c4c1bb0ec1923cf2a939e2022-12-22T01:37:16ZengBMCActa Neuropathologica Communications2051-59602022-08-0110111910.1186/s40478-022-01428-2Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modelingCorina Anastasaki0Jit Chatterjee1Olivia Cobb2Shilpa Sanapala3Suzanne M. Scheaffer4Amanda De Andrade Costa5Anna F. Wilson6Chloe M. Kernan7Ameera H. Zafar8Xia Ge9Joel R. Garbow10Fausto J. Rodriguez11David H. Gutmann12Department of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Radiology, Washington University School of MedicineDepartment of Radiology, Washington University School of MedicineDepartment of Pathology, David Geffen School of Medicine at UCLADepartment of Neurology, Washington University School of MedicineAbstract A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs) harboring the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Herein, we identified that hiPSC-derived neuroglial progenitor populations (neural progenitors, glial restricted progenitors and oligodendrocyte progenitors), but not terminally differentiated astrocytes, give rise to tumors retaining LGG histologic features for at least 6 months in vivo. Additionally, we demonstrated that hiPSC-LGG xenograft formation requires the absence of CD4 T cell-mediated induction of astrocytic Cxcl10 expression. Genetic Cxcl10 ablation is both necessary and sufficient for human LGG xenograft development, which additionally enables the successful long-term growth of patient-derived pediatric LGGs in vivo. Lastly, MEK inhibitor (PD0325901) treatment increased hiPSC-LGG cell apoptosis and reduced proliferation both in vitro and in vivo. Collectively, this study establishes a tractable experimental humanized platform to elucidate the pathogenesis of and potential therapeutic opportunities for childhood brain tumors.https://doi.org/10.1186/s40478-022-01428-2Low-grade gliomaPediatric brain tumorPilocytic astrocytomaNF1BRAFHuman induced pluripotent stem cells |
| spellingShingle | Corina Anastasaki Jit Chatterjee Olivia Cobb Shilpa Sanapala Suzanne M. Scheaffer Amanda De Andrade Costa Anna F. Wilson Chloe M. Kernan Ameera H. Zafar Xia Ge Joel R. Garbow Fausto J. Rodriguez David H. Gutmann Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling Acta Neuropathologica Communications Low-grade glioma Pediatric brain tumor Pilocytic astrocytoma NF1 BRAF Human induced pluripotent stem cells |
| title | Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling |
| title_full | Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling |
| title_fullStr | Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling |
| title_full_unstemmed | Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling |
| title_short | Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling |
| title_sort | human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low grade glioma modeling |
| topic | Low-grade glioma Pediatric brain tumor Pilocytic astrocytoma NF1 BRAF Human induced pluripotent stem cells |
| url | https://doi.org/10.1186/s40478-022-01428-2 |
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