Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma. Blood 2024 May 16;143(20):2037-2052
Date
03/01/2024Pubmed ID
38427938Pubmed Central ID
PMC11143522DOI
10.1182/blood.2023022591Scopus ID
2-s2.0-85189689054 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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.
Author List
Allison RL, Welby E, Ehlers V, Burand A, Isaeva O, Nieves Torres D, Highland J, Brandow AM, Stucky CL, Ebert ADAuthors
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinOlena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anemia, Sickle CellCapsaicin
Cell Differentiation
Female
Humans
Induced Pluripotent Stem Cells
Male
Plasma
Sensory Receptor Cells
