Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling.
Acta Neuropathol Commun
; 10(1): 120, 2022 08 19.
Article
en En
| MEDLINE
| ID: mdl-35986378
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 KIAA1549BRAF 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.
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Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Astrocitoma
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Neoplasias Encefálicas
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Células Madre Pluripotentes Inducidas
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Glioma
Límite:
Animals
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Child
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Humans
Idioma:
En
Revista:
Acta Neuropathol Commun
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos