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- Title
Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling.
- Authors
Anastasaki, Corina; Chatterjee, Jit; Cobb, Olivia; Sanapala, Shilpa; Scheaffer, Suzanne M.; De Andrade Costa, Amanda; Wilson, Anna F.; Kernan, Chloe M.; Zafar, Ameera H.; Ge, Xia; Garbow, Joel R.; Rodriguez, Fausto J.; Gutmann, David H.
- 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.
- Subjects
INDUCED pluripotent stem cells; PLURIPOTENT stem cells; GLIOMAS; BRAIN tumors
- Publication
Acta Neuropathologica Communications, 2022, Vol 10, Issue 1, p1
- ISSN
2051-5960
- Publication type
Article
- DOI
10.1186/s40478-022-01428-2