Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number120
JournalActa Neuropathologica Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • BRAF
  • Human induced pluripotent stem cells
  • Low-grade glioma
  • NF1
  • Pediatric brain tumor
  • Pilocytic astrocytoma

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