Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma

• Published in: Blood Vol. 143; no. 20; pp. 2037 - 2052
• Main Authors: Allison, Reilly L., Welby, Emily, Ehlers, Vanessa, Burand, Anthony, Isaeva, Olena, Nieves Torres, Damaris, Highland, Janelle, Brandow, Amanda M., Stucky, Cheryl L., Ebert, Allison D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2024
• Subjects: Anemia, Sickle Cell - blood; Anemia, Sickle Cell - pathology; Capsaicin - pharmacology; Cell Differentiation; Female; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Male; Plasma - metabolism; Sensory Receptor Cells - metabolism; Sensory Receptor Cells - pathology; Sensory Receptor Cells - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2023022591

•SCD stem cell–derived sensory neurons (iSNs) exhibit pronounced sensitization to electrical stimulation.•SCD plasma sensitizes SCD iSNs to transient receptor potential cation channel subfamily V member 1 stimulation by capsaicin. [Display omitted] Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from patients with SCD. Here, we used induced pluripotent stem cells (iPSCs), derived from patients with SCD, differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Furthermore, we find that plasma taken from patients with SCD during acute pain associated with a vaso-occlusive event increases the calcium responses to the nociceptive stimulus capsaicin in SCD iSNs compared with those treated with paired plasma from patients with SCD at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of plasma from patients with SCD, which sensitizes SCD iSNs to subthreshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology. Both acute and chronic pain crises are major challenges for patients with sickle cell disease (SCD) and their pathophysiological basis remains uncertain. Allison et al derived sensory neurons from induced pluripotent stem cells (iPSCs) from patients with SCD and determined that SCD iPSC neurons exhibit multiple indicators of hyperexcitability relative to healthy control iPSC neurons. This work establishes a human-specific model of SCD sensory neurons and suggests that both intrinsic and extrinsic blood-derived factors may underly SCD pain.