| First Author | Anastasaki C | Year | 2022 |
| Journal | Acta Neuropathol Commun | Volume | 10 |
| Issue | 1 | Pages | 120 |
| PubMed ID | 35986378 | Mgi Jnum | J:337179 |
| Mgi Id | MGI:7331695 | Doi | 10.1186/s40478-022-01428-2 |
| Citation | Anastasaki C, et al. (2022) Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling. Acta Neuropathol Commun 10(1):120 |
| abstractText | 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. |
