Urine sample-derived cerebral organoids suitable for studying neurodevelopment and neuroregeneration

Purpose: Human cerebral organoids (COs) have yielded significant discoveries regarding developmental biology, disease mechanisms and pharmacological responses in the central nervous system. Here, we intend to establish cerebral organoids suitable for modeling brain development and neuroregeneration based on somatic cells that are isolated noninvasively. Methods: The development of such organoids began with the collection of urinary epithelial cells (UECs) from human urine samples, followed by reprograming them into induced pluripotent stem cells (hUEC-iPSCs), which were further used for the generation of COs. To comprehensively characterize the cellular and molecular features of our COs, we examined samples at different developmental time points in vitro. To check their survival ability and the neuroregenerative potential, the COs were implanted into immunodeficient mouse brains and further examined. Results: 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. Conclusions: Our work begins to reveal the promise of generating personalized COs from cells that are isolated from urine samples. With further adaptation, this human CO platform could form a unique and personalized model for the investigation of neural development and facilitate the innovation of novel therapies for treating neurological diseases.