Establishment of a human pluripotent stem cell-derived sensory neuron platform for studying diabetes-associated metabolic and oxidative stress-induced neuronal injury.

Authors

Jialin Zhu, Yanfeng Zhang, Jiaqi Zhang, Zhaobo Nie

Published in

Journal of neuroscience methods. Pages 110919. Oct 02, 2026. Epub Oct 02, 2026.

Abstract

Diabetic peripheral neuropathy (DPN) lacks effective disease-modifying therapies, partly due to the limited availability of standardized human-relevant in vitro models. Human pluripotent stem cell (hPSC)-derived sensory neurons provide a potential platform for investigating human neuronal vulnerability under diabetes-associated stress conditions and evaluating neuroprotective strategies.
In this study, we established an hPSC-derived sensory neuron-enriched platform to model diabetes-associated neuronal stress. Human PSCs were differentiated into sensory neuron-enriched cultures characterized by sensory neuronal markers BRN3A (POU4F1), ISL1, and Peripherin (PRPH), as well as nociceptive-associated markers including TRPV1 and Nav1.7 (SCN9A). A sequential metabolic-oxidative stress paradigm was developed using high glucose (HG, 45mM) pretreatment followed by hydrogen peroxide (H₂O₂)-induced oxidative challenge, with mannitol osmotic controls incorporated.
High glucose exposure reduced cellular viability, whereas osmotic control conditions produced minimal effects. Combined HG/H₂O₂ exposure induced greater cellular injury and oxidative alterations than individual stress conditions. Pharmacological intervention with N-acetylcysteine (NAC), minocycline, or metformin partially restored cellular viability, reduced oxidative signals, and improved mitochondrial membrane potential-associated changes. Long-term morphological analysis demonstrated that early intervention preserved neurite network integrity and attenuated persistent reductions in neurite length following metabolic-oxidative stress.
Compared with conventional in vitro models based primarily on non-human systems or high glucose exposure alone, this hPSC-derived sensory neuron platform provides a human-relevant approach that incorporates sequential metabolic and oxidative challenges and enables evaluation of both acute cellular responses and long-term neuronal structural alterations.
This study establishes a human sensory neuron-based experimental system for investigating diabetes-associated neuronal vulnerability and evaluating potential neuroprotective compounds. The platform provides a complementary tool for studying metabolic-oxidative mechanisms underlying sensory neuronal injury associated with DPN.

PMID:
42826868
Bibliographic data and abstract were imported from PubMed on 03 Oct 2026.

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