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FACT SHEETS

Rigorous Methods for Stem Cell-based Models of Neuropathic Pain: Information For Researchers

2026 Neuropathic Pain

Home / Resources / Fact Sheets / Rigorous Methods for Stem Cell-based Models of Neuropathic Pain: Information For Researchers

Published

6 April 2026

GLOBAL YEAR

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Rigorous Methods for Stem Cell-based Models of Neuropathic Pain: Information For Researchers

Authors

  • Pascal Röderer, PhD, Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany; Scientific Center for Neuropathic Pain Aachen SCNAACHEN, Uniklinik RWTH Aachen, Aachen, Germany.
  • Hajira Elahi, PhD, Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Patrick Dougherty, PhD, Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Angelika Lampert, MD, Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany; Scientific Center for Neuropathic Pain Aachen SCNAACHEN, Uniklinik RWTH Aachen, Aachen, Germany.
  • Franziska Denk, DPhil, Wolfson Sensory, Pain and Regeneration Centre (SPaRC), Guy’s Campus, King’s College London.
  • Margarita Calvo, PhD, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile; Anesthesiology Division, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • Neil O’Connell, PhD, Centre for Health and Wellbeing Across the Lifecourse, Department of Health Sciences, Brunel University London, London, UK.

Introduction

This fact sheet aims to bridge pain and stem cell research by summarizing key resources and recommendations for modeling neuropathic pain using human stem cell-derived in vitro mod­els. Translational limitations of traditional preclinical models of neuropathic pain have driven increased interest in developing robust human-based experimental systems. In response, induced pluripotent stem cell (iPSC)-derived sensory neurons (iSNs) have emerged as a central experimental platform with high translational potential. These models offer key advantages over many existing approaches, including scalability and the ability to model human genetic variation, enabling functional characterization and drug screening directly in human sensory neurons.

A growing body of literature now uses this technology to model a wide range of neuropathic pain conditions. This rapid expansion underscores the need for standardized methodological frame­works to ensure rigor, reproducibility, and translational relevance of experimental findings. Importantly, iPSC-based modeling of neurological disease is an established field. The extensive body of literature in this area [13,15,26] provides a strong foundation from which best practices can be adapted and applied to sensory and pain neurobiology:

Examples of neuropathic pain conditions that have been modeled using iPSC

In vitro models of genetic pain conditions have been able to reca­pitulate patient-specific phenotypes in iSNs. Models of inherited erythromelalgia due to Nav1.7 gain-of-function mutations revealed increased spontaneous activity, firing and bursting frequency, as well as a higher heat-sensitivity of patient-derived iSNs compared to controls [1,6,37]. Similar results were observed for a patient-specific model of small fiber neuropathy. Here, a pharmacological interven­tion that normalized the firing behavior of iSNs was later success­fully translated to the patient [41]. Loss-of-function mutations in Nav1.7, which cause congenital insensitivity to pain, were reported to result in the expected reduced excitability of iSNs [36].

Beyond electrophysiological outcomes and impaired neurite out­growth, neurotrophin signaling and paranodal integrity were reported in an iSN model of hereditary sensory neuropathy [9]. Similarly, dysregu­lation of axon guidance was reported in an iSN model of Fabry disease [17]. Neurotoxicity studies focusing on chemotherapy-induced periph­eral neuropathies revealed dose-dependent morphological alterations, such as reduced neurite outgrowth, retraction, and fragmentation of axons, in addition to reduced cellular viability and increased expression of neuronal injury, cellular stress, and apoptosis genes [5,20,38,50].

Beyond modeling of neuropathic pain conditions, iSNs have been employed as a tool to translate findings from animal models in a human in vitro system, e.g., modulation of PKA signaling via anthrax toxins or chemogenetic silencing of hyperactive nociceptors [45,60].

Patient recruitment and stem cell repositories

When recruiting donors for iPSC-based research projects, it is essen­tial to clarify the need for ethical approval with local authorities and to provide donors with comprehensive information to obtain their in­formed consent. Information that should be provided in the consent materials has been suggested and summarized by Orzechowski et al. [44] and should include background information on the study, po­tential use of cells in future (commercial) research, storage of patient material and cell lines, as well as how to deal with incidental medical findings. Where possible, detailed demographic, clinical, medical, diagnostic, and genetic data should be collected and linked to the generated cell lines [13]. The chosen cohort for an iPSC-based study should be tailored to the specific research question of that study and strive for an appropriately representative, diverse sample.

In addition to reprogramming iPSC lines for a new study, already reprogrammed and quality-controlled iPSC lines from control or disease backgrounds can be obtained from various cell banks, re­positories, or directly from the lab that generated and published the lines. Here is a list of global PSC banks: African iPSC Initiative, Cell­Bank Australia, Coriell, European Bank for Induced Pluripotent Stem Cells, HipSci, Indian Stem Cell Repository, National Stem Cell Bank Korea, New York Stem Cell Foundation Repository, NINDS Human Cell and Data Repository, RIKEN BRC Japan, the Human Pluripotent Stem Cell Registry, UK Stem Cell Bank, WiCell.

Reprogramming and PSC quality control

Since the discovery of epigenetic reprogramming in 2006, iPSC technology has become a robust and widely adopted platform, sup­ported by established protocols and quality control standards to en­sure reproducibility, genomic integrity, and biological relevance. As such, several key considerations should be made when generating and using iPSC lines when modeling neuropathic pain mechanisms.

The source tissue used for reprogramming should be careful­ly selected and explicitly reported, as somatic cells may carry acquired genetic or epigenetic alterations that persist following reprogramming [43]. For example, dermal fibroblasts can potentially accumulate UV-associated or age-related mutations that may be retained in derived iPSC lines [40,56]. Where feasible, peripheral blood mononuclear cells (PBMCs) offer advantages, including ease of collection and reduced environmental mutational burden. Repro­gramming should be performed, preferably using genome-non-in­tegrating approaches, such as Sendai virus, episomal plasmids, or mRNA-based methods, to minimize insertional mutagenesis. iPSC lines should be assessed for genomic stability via karyotyping or copy-number analysis, and female donor–derived lines should be evaluated for X-chromosome inactivation status, especially when relevant to genetic pain studies [10]. Given the sensitivity of pluripotent stem cells to culture conditions and to ensure experimental reliability, iPSC cultures should be regularly screened for microbial contamination (e.g., mycoplasma), and the use of chemically de­fined, xeno-free media and matrices is required to reduce batch-to-batch variability and improve reproducibility across laboratories. The International Society for Stem Cell Research (ISSCR) recently published recommended standards for the use of human stem cells in research [55], as well as recommendations for reporting practices for publishing results with human pluripotent stem cells [47].

Differentiation strategies, quality control, and cell type validation

Multiple protocols have been published during the last 15 years for the in vitro derivation of human peripheral sensory neurons from pluripotent stem cells [27]. Most of these protocols can be divided into one of three approaches:

  1. Differentiation of sensory neurons from iPSCs guided by small molecules.
  2. Differentiation of sensory neurons from iPSCs guided by overexpression of fate-specifying transcription factors.
  3. Generation of a stable intermediate neural progenitor or neu­ral crest cell population from iPSCs that can be further guided into sensory neurons or other neural crest derivatives.

Most published protocols generate a generic or mixed sensory neuron population [2,4,14,19,22,31,39]. However, some protocols report the generation of cultures enriched for nociceptive [3,7,11,46,51], mechanore­ceptive [21,42,52] or proprioceptive [12,21] sensory neurons or to sort mixed sensory neuron cultures for specific subtypes after differentiation [49].

When implementing a differentiation protocol, validating and characterizing the generated cell type is very important. Identity of iSNs should be validated by testing for the co-expression of general sensory-neuron markers (e.g., peripherin, ISLET1, BRN3A) and subtype-specific markers (e.g., TRPV1, TRKA, Nav1.7, Nav1.8) [28]. In addition, electrophysiological functionality can be assessed by patch clamp and multielectrode array recordings in combi­nation with specific pharmacological agonists or blockers [23,28]. A note of caution: stem-cell-derived in vitro models mimic human development; therefore, their state of maturation and functional­ity is a moving target that evolves during the course of culture. It has been shown that opioid receptors, while expressed early on in iSNs, initiate functional intracellular signaling only after prolonged culture times [48] and that robust membrane localization of Nav1.7 also only emerges over time in culture [32]. Therefore, when work­ing with a novel target, it is advisable to characterize its expres­sion, localization, and function in the chosen iSN model system over an extended period. Published transcriptome data of iSNs generated with existing, common protocols can be used to inform initial model selection [e.g., 33].

Statistical considerations and experimental design

As with in vivo research, translating findings from iPSC-based models to the clinic requires robust experimental design and appropriate sta­tistical approaches, and several aspects must be considered. Primary outcomes should be defined a priori, and selected assays should directly measure the biological concepts under investigation [5,58]. Importantly, multiple complementary assays are often necessary to validate findings, especially during model development. Given the di­versity of differentiation protocols used to generate sensory neurons, neuronal maturity must be carefully assessed and reported. Marker expression alone is insufficient to define functional maturity; there­fore, ion channel function and excitability should also be evaluated, preferably using patch-clamp electrophysiology and/or multielec­trode array (MEA) recordings, to ensure that developmental state does not introduce unintended variability [23]. Variability may also arise between differentiation rounds due to the multi-step nature of the process. To address this, data should be collected across multiple independent differentiations and several clones where feasible, and the differentiation batch should be considered during analysis.

Insights from other iPSC-based research fields indicate that genetic background is a major source of variability among reprogrammed iPSC lines [24,53]. This consideration is particularly important when modeling idiopathic or environmentally driven pain conditions, such as chemotherapy-induced peripheral neuropathy (CIPN). In such cases, experimental groups should include iPSC lines derived from multiple donors rather than relying on repeated measurements from a single line. Transcriptomic analyses suggest that groups often re­quire four to six independent lines, although the appropriate sample size should be determined by model-specific power analysis [13,18,29]. In the case of monogenic pain disorders, such as Nav1.7 channelop­athies, the use of isogenic controls provides an effective strategy to control for genetic background, provided that rigorous quality control is performed to exclude off-target effects of genome editing.

Beyond experimental design, accurate and consistent reporting of experimental parameters is essential for methodological rigor. Standardized reporting frameworks, such as the RIVER Recommenda­tions [57], the FAIR guidelines [59], and the ENTRUST PE framework [16] provide practical guidance for transparent documentation and are strongly encouraged to improve the reproducibility of neuropathic pain models across laboratories.

Conclusion and Outlook

This fact sheet summarizes currently available methods and con­cepts for working with stem cell-derived models of neuropathic pain and aims to bridge pain researchers to resources available within the stem cell research community.

While iSN models have been optimized during the last decade and successfully employed to elucidate pathomechanisms and patient-specific phenotypes, some limitations and challenges remain: the lack of the natural niche of sensory neurons within our culture systems, the need for prolonged maturation times, and a reduced functionality in iSNs compared to primary hDRG neurons when it comes to certain pain targets, e.g., TRPV1 and Nav1.9. Optimized culture conditions and differentiation paradigms should help overcome these obstacles. In recent years, the number of more complex culture systems increased, including co-cultures of human iSNs with primary or iPSC-derived Schwann cells or satellite glial cells [4,8,22,30,54], iPSC-derived dorsal root ganglion organoids [34,35] and assembloids of multiple neuronal organoids reconstructing the somatosensory pathway [25]. Development and application of rigor­ous methods, as well as openly reporting and sharing differentiation and culture protocols within our research community, will help to further improve our model systems and research, bringing us closer to a better understanding of peripheral neuron development, function, and pathology.

Resource

https://youtu.be/iFfjQ5k7hqo?si=5b0y2wiiWNHGoV6g Watch an 8-minute video that walks through key resources, dif­ferentiation strategies, and practical tips for working with induced pluripotent stem cell (iPSC)-derived models in the context of neuropathic pain research, presented by Pascal Röderer, PhD.

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Disclosures

ALa receives councelling fees from Grünenthal and Orion.

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