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Abstract A11: Urine sample-derived cerebral organoids suitable for modeling brain development and pathogenesis

Human cerebral organoids (COs) have been leveraged in many recent studies that led to significant discoveries regarding developmental biology, disease mechanisms, and pharmacologic responses in the central nervous system. Here, we intend to establish cerebral organoids suitable for modeling brain development and pathogenesis based on somatic cells that are isolated noninvasively. The development of such organoids began with the collection of urinary epithelial cells (UECs) from human urine samples. We have obtained multiple lines of human UEC-derived induced pluripotent stem cells (hUEC-iPSCs) by cell reprogramming. COs were generated from hUEC-iPSCs using a protocol optimized by our group. To comprehensively characterize the cellular and molecular features of our COs, we examined samples at different developmental time points. The hUEC-iPSC-developed COs exhibit normal development with neurogenesis and maturation of neuronal cells forming brain layers. These COs produce neurotropic and anti-inflammatory factors that are presumably critical for neurogenesis and neural repair. Several metalloproteases that may facilitate cell migration and microenvironment rearrangement are also present. After transplantation into the mouse cerebrum, vascularization quickly develops in the implanted COs, suggesting their viability and ability to interact with the environment. To gauge cellular plasticity of hUEC-iPSC-developed COs along their development, we exposed the COs that were developed using three different protocols and initially committed to telencephalic development to culture media containing FGF2 and FGF19. Multiple markers of the developing hindbrain were highly upregulated in the COs, indicating that their cellular plasticity and potential to be reprogrammed into noncerebral neural tissue in response to optimized stimuli. Overall, our work begins to reveal the promise of generating personalized COs from cells that are isolated from urine samples. These COs present with cellular plasticity that permits a possibility of generating neural tissue of various brain regions by converting prosencephalic organoids into a mesencephalic or rhombencephalic fate. With further adaptation, this human CO platform could form a unique and personalized model for the investigation of neural development influenced by oncogenic signaling and facilitate the development of novel therapies for treating neurologic malignancy. Citation Format: Jiangnan Hu, Victor Lin, Mark Goldberg, Yu-chieh Wang. Urine sample-derived cerebral organoids suitable for modeling brain development and pathogenesis [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A11.