Human Neural Stem Cell Biodistribution and Predicted Tumor Coverage by a Diffusible Therapeutic in a Mouse Glioma Model

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Abstract

Engineered neural stem cells (NSCs) intrinsically migrating to brain tumors offer a promising mechanism for local therapeutic delivery. However, difficulties in quantitative assessments of NSC migration and in estimates of tumor coverage by diffusible therapeutics have impeded development and refinement of NSC-based therapies. To address this need, we developed techniques by which conventional serial-sectioned formalin-fixed paraffin-embedded (FFPE) brains can be analyzed in their entirety across multiple test animals. We considered a conventional human glioblastoma model: U251 glioma cells orthotopically engrafted in immunodeficient mice receiving intracerebral (i.c.) or intravenous (i.v.) administrations of NSCs expressing a diffusible enzyme to locally catalyze chemotherapeutic formation. NSC migration to tumor sites was dose-dependent, reaching 50%–60% of total administered NSCs for the i.c route and 1.5% for the i.v. route. Curiously, the most efficient NSC homing was seen with smaller NSC doses, implying existence of rate-limiting process active during administration and/or migration. Predicted tumor exposure to a diffusing therapeutic (assuming a 50 µm radius of action) could reach greater than 50% of the entire tumor volume for i.c. and 25% for i.v. administration. Within individual sections, coverage of tumor area could be as high as 100% for i.c. and 70% for i.v. routes. Greater estimated therapeutic coverage was observed for larger tumors and for larger tumor regions in individual sections. Overall, we have demonstrated a framework within which investigators may rationally evaluate NSC migration to, and integration into, brain tumors, and therefore enhance understanding of mechanisms that both promote and limit this therapeutic modality. Stem Cells Translational Medicine 2017;6:1522–1532

Neural stem cells (NSCs) intrinsically migrate to sites of brain tumors, and engineered NSCs offer a promising mechanism for local delivery of therapeutic agents. In this article we present, for formalin-fixed paraffin-embedded (FFPE) xenograft-bearing mouse brain tissue sections, quantitative assessments of NSC migration efficiency and local distribution at tumor sites (in B and D, red marks NSCs and dark green marks glioblastoma cells), as well as tumor coverage estimated for the secreted therapeutics delivered by these NSCs (in D, light green indicates 25 or 50 μm radii of action). This study provides an analytical paradigm facilitating optimization of this and other cell-based therapies.

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