In vitro programming and pseudounipolarization of human iPSC-derived sensory neurons

Röderer, P.; Costa, A. C.; Lürkens, M.; Roll, F. M.; Buck, F.; Heidrich, L.; Aicher, J.; Neureiter, A.; Mossad, O.; Trucks-Jansen, H.; Le Cann, K.; Kalia, A. K.; Balaji, R.; Arndt, V.; Zellner, A.; Mecdad, Y.; Bajaj, T.; Stüger, M.; Schwarz, M. K.; Nitzsche, A.; Gassen, N. C.; Haag, N.; Schröter, M.; Lampert, A.; Sousa, M. M.; Brüstle, O.

doi:10.64898/2026.09.18.747563

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bioRxiv · 10.64898/2026.09.18.747563

In vitro programming and pseudounipolarization of human iPSC-derived sensory neurons

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Abstract

Ectopic expression of NGN1, BRN3A and ISLET1 (NBI) from a safe harbor locus in induced pluripotent stem cells (iPSCs) yielded robust differentiation into functional sensory neurons (iNBI-SNs) within seven days. Single nucleus transcriptomics identified peripheral sensory neuron profiles of nociceptors and mechanoreceptors. Electrophysiological studies showed that more than 98 % of iNBI-SNs display TTX-resistant sodium currents and that they establish functional connections to excitatory CNS neurons. iNBI-SNs derived from patients with inherited erythromelalgia, a pain disorder associated with gain-of-function mutations in the Nav1.7 sodium channel showed pathologically increased firing rates which could be partially rescued with a Nav1.7 inhibitor. Notably, iNBI-SNs acquire a characteristic pseudounipolar morphology upon co-culture with embryonic rodent DRG cells. Taken together, NBI-based forward programming of iPSCs represents a robust approach for the generation of human sensory neurons suitable for developmental, disease- and therapy-related studies.

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Röderer, P., Costa, A. C., Lürkens, M., Roll, F. M., Buck, F., Heidrich, L., Aicher, J., Neureiter, A., Mossad, O., Trucks-Jansen, H., Le Cann, K., Kalia, A. K., Balaji, R., Arndt, V., Zellner, A., Mecdad, Y., Bajaj, T., Stüger, M., Schwarz, M. K., Nitzsche, A., Gassen, N. C., Haag, N., Schröter, M., Lampert, A., Sousa, M. M., Brüstle, O.. 2026-09-21. In vitro programming and pseudounipolarization of human iPSC-derived sensory neurons. https://doi.org/10.64898/2026.09.18.747563

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