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