A humanized focus on sickle cell pain

In this issue of Blood, Allison et al derive sensory neurons from pluripotent stem cells (iPSCs) induced from patients with sickle cell disease (SCD) and determine that SCD iPSC neurons exhibit multiple indicators of hyperexcitability relative to healthy control iPSC neurons.¹ This study is an important step forward as it is the first to use patient-derived nervous system tissue for the study of fundamental sickle cell pain mechanisms.

Preclinical pain research has yielded few translational successes over the past several decades, perhaps because of overreliance on rodent models.^2,3 Many groups, including our own, now routinely incorporate, or exclusively study, novel pain targets in human tissue to increase target translatability. Particular focus has been placed on targets in dorsal root ganglia afferents, the first neurons through which internal and external sensory information is transduced and transmitted to the central nervous system. Over the past decade, accessibility of healthy human nervous system tissue for these types of studies has dramatically increased through academic partnerships with organ donor procurement organizations. However, tissue from select patient groups, including those with SCD, will likely never be attainable through these avenues. Knowing this, the authors of this article instead chose to derive sensory neurons from patient and healthy control iPSCs using well-defined methods.⁴ 

The results reported by Allison and colleagues are the best attempt, to date, to bridge the gap between sickle cell pain mechanisms originally characterized in transgenic mouse models and the pain mechanisms that are actually at play in patients. Notable similarities between patient iPSC sensory neurons and SCD mouse sensory neurons include hyperexcitability as measured by increasing action potential firing upon sustained depolarization and endothelin-1-induced sensitization.⁵ Exposure to plasma that was collected from patients during an acute pain event further sensitized patient iPSC sensory neurons; although not examined in this study, exposure to pain-associated plasma may also induce direct activity in patient iPSC sensory neurons like that observed in SCD mouse afferents during hypoxia-reoxygenation.⁶ In the current set of experiments, the authors did not identify a specific target that, when blocked, could prevent plasma-associated neuron sensitization. This should be the focus of future investigation, given the potential therapeutic relevance of that outcome.

Notable differences were also observed between patient iPSC and SCD mouse sensory neurons. For example, no spontaneous activity was reported in patient iPSC neurons; this has been reported in SCD mouse dorsal root ganglia neurons by more than 1 preclinical laboratory.^5,7 Capsaicin sensitization, both in naive cells and following CCL2 incubation, was also notably absent from patient iPSC sensory neurons, despite being reported in SCD mouse sensory neurons.⁸ These results, and future studies that reveal similar discrepancies between rodent and human, may suggest deprioritization of targets originally characterized in SCD mouse models. However, combined use of both live SCD mice and patient-derived iPSC sensory neurons may be the most successful path forward given that the latter are not, in fact, a perfect copy of patient dorsal root ganglia neurons. Patient iPSC neurons lack many of the functional connections that exist in vivo; the cells themselves are notably smaller than real human dorsal root ganglia neurons and, despite numerous similarities, still have quite different transcriptomes⁹; and perhaps most notably, iPSC-derived neurons are exposed to circulating factors for significantly less time than dorsal root ganglia neurons from both transgenic mice and patients. Altogether, this study is a landmark for the field because it moves our understanding of sickle cell pain mechanisms forward and because it shows a path for how mouse models, human iPSC sensory neurons, and human neurons from organ donors can be used in combination to zero in on pain mechanisms in SCD that will have the biggest potential impact on pain outcomes in patients in need.

Conflict-of-interest disclosure: K.E.S. and T.J.P. declare no competing financial interests.