Establishment of a human pluripotent stem cell-derived sensory neuron model for diabetic peripheral neuropathy and pharmacological evaluation
Abstract
Abstract Objectives Diabetic peripheral neuropathy (DPN) lacks effective disease-modifying therapies due to the shortage of standardized, human-relevant in vitro models. This study aimed to establish a human pluripotent stem cell (hPSC)-derived sensory neuron platform to model DPN pathogenesis and evaluate potential neuroprotective agents. Methods Human PSCs were directed into pure, mature sensory neurons (BRN3A + /ISL1 + /Peripherin + /HB9 − ). A combinatorial DPN injury model was constructed using high glucose (HG, 45 mM) pre-treatment followed by acute hydrogen peroxide (H 2 O 2 )-induced oxidative stress, incorporating mannitol osmotic controls. The protective effects of N-acetylcysteine (NAC), minocycline, and metformin were evaluated via intracellular ROS levels, mitochondrial membrane potential, cellular viability, and 21-day neurite network integrity. Results High glucose specifically reduced neuronal viability via metabolic toxicity rather than hyperosmolarity. Pharmacological pre-treatments with NAC, minocycline, or metformin significantly suppressed HG/H 2 O 2 -induced ROS overproduction, prevented mitochondrial membrane potential collapse, and enhanced cellular viability. Crucially, long-term morphological analysis over 21 days demonstrated that early drug intervention effectively rescued neurite fragmentation and attenuated progressive axonal degeneration. Discussion This hPSC-derived sensory neuron platform faithfully recapitulates key metabolic and long-term…
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