TY - JOUR
T1 - Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling
AU - Anastasaki, Corina
AU - Chatterjee, Jit
AU - Cobb, Olivia
AU - Sanapala, Shilpa
AU - Scheaffer, Suzanne M.
AU - De Andrade Costa, Amanda
AU - Wilson, Anna F.
AU - Kernan, Chloe M.
AU - Zafar, Ameera H.
AU - Ge, Xia
AU - Garbow, Joel R.
AU - Rodriguez, Fausto J.
AU - Gutmann, David H.
N1 - Funding Information:
This work was supported by a National Cancer Institute R50 Research Specialist Award (1-R50-CA233164-01 to C.A.), pre-pilot funding for small-animal MRI from the Siteman Cancer Center (to C.A.), grants from the Pediatric Brain Tumor Foundation (P20-00873 to D.H.G.) and Ian’s Friends Foundation (to D.H.G.), and a Research Program Award from the National Institutes of Neurological Disorders and Stroke (1-R35-NS07211-01 to D.H.G.). The GEiC Center at WUSM engineered the hiPSCs and is subsidized by NCI Cancer Center Support Grant P30-CA091842. The Washington University Ophthalmology Core facility is funded by National Eye Institute Grant P30EY002687.
Funding Information:
This work was supported by a National Cancer Institute R50 Research Specialist Award (1-R50-CA233164-01 to C.A.), pre-pilot funding for small-animal MRI from the Siteman Cancer Center (to C.A.), grants from the Pediatric Brain Tumor Foundation (P20-00873 to D.H.G.) and Ian’s Friends Foundation (to D.H.G.), and a Research Program Award from the National Institutes of Neurological Disorders and Stroke (1-R35-NS07211-01 to D.H.G.). The GEiC Center at WUSM engineered the hiPSCs and is subsidized by NCI Cancer Center Support Grant P30-CA091842. The Washington University Ophthalmology Core facility is funded by National Eye Institute Grant P30EY002687.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - BRAF
KW - Human induced pluripotent stem cells
KW - Low-grade glioma
KW - NF1
KW - Pediatric brain tumor
KW - Pilocytic astrocytoma
UR - http://www.scopus.com/inward/record.url?scp=85136714229&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136714229&partnerID=8YFLogxK
U2 - 10.1186/s40478-022-01428-2
DO - 10.1186/s40478-022-01428-2
M3 - Article
C2 - 35986378
AN - SCOPUS:85136714229
SN - 2051-5960
VL - 10
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 120
ER -