Human iPSC-Derived Dorsal Root Ganglion Organoid Modeling of Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting 30-40% of patients treated with neurotoxic chemotherapy. Sensory symptoms arise from injury to dorsal root ganglion (DRG) neurons and their axons; yet, the underlying mechanisms remain incompletely understood. While human induced pluripotent stem cell (iPSC)-derived sensory neuron (iSN) monolayers have provided mechanistic insight, they lack the three-dimensional architecture and cellular heterogeneity of native DRG tissue. Here, we generated human iPSC-derived DRG organoids (iDRGOs) containing mixed neuronal and peripheral glial populations and established a quantitative neurite outgrowth assay to model chemotherapy-induced neurotoxicity in a 3D context. iDRGOs from three healthy donors were exposed to bortezomib, vincristine, or paclitaxel. All three drugs caused dose-dependent neurite outgrowth impairment without significant short-term changes in organoid size, consistent with early axonal injury. Vincristine reduced MAP2 levels when normalized to total protein, whereas bortezomib and paclitaxel showed divergent microtubule-associated responses compared to monolayer cultures. The developmental stage significantly influenced the baseline neurite outgrowth, highlighting the need for age standardization. These results establish iDRGOs as a physiologically relevant human platform that complements monolayer models for mechanistic studies and therapeutic screening in CIPN.