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A highly efficient method to differentiate CGRP-expressing peptidergic nociceptors from human induced pluripotent stem cells.

Overview

Authors: Galbha Duggal1,2, Xinyu Li1, Philippa Pettingill1, Tatjana Lalic1, Shailesh Kumar Gupta3, Christine Flodgaard Høgsbro4, Viola Volpato5, Caleb Webber5, Rory Bowden6, Despoina Charou1, Kanisa Arunasalam1, Marcello Maresca7, Ryan Hicks8, Satyan Chintawar1,2, M. Zameel Cader1,2
  1. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  2. Oxford StemTech, The Oxford Science Park, Oxford, UK
  3. Global Portfolio & Project Management, Oncology R&D, Cambridge, UK
  4. Department of Neurology, Faculty of Health and Medical Sciences, Danish Headache Center, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark
  5. UK Dementia Research Institute, Department of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK
  6. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  7. Discovery Biology, Discovery Sciences IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
  8. Bioanalytical and Biomarker Labs, Thermofisher Scientific, Gothenburg, Sweden
Institutions: University of Oxford (United Kingdom); University of Copenhagen (Denmark); Glostrup Hospital (Denmark); UK Dementia Research Institute (United Kingdom); Cardiff University (United Kingdom); Centre for Human Genetics (United Kingdom); AstraZeneca (Sweden) (Sweden); Thermo Fisher Scientific (Sweden) (Sweden)
Journal: Stem cell reports, volume 21, issue 7, article 102971
Dates: received 24 January 2025; accepted 21 May 2026; published online 25 June 2026; in print July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.stemcr.2026.102971 · PMID 42349425 · PMCID PMC13385448 · OpenAlex W4410075745
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: human (organism), pain (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Preprocessing, Evoked potentials, Single-unit activity, calcium imaging
Keywords: iPSC, nociceptor, pain, sensory neurons, CGRP, peptidergic, trigeminal, migraine, human, inflammation
MeSH: Calcitonin Gene-Related Peptide*, Cell Differentiation*, Induced Pluripotent Stem Cells*, Nociceptors*, Humans, Sumatriptan, TRPV Cation Channels (* major topic)
Topic: Pain Mechanisms and Treatments (Physiology, Medicine), according to OpenAlex
Citations: not cited yet (Europe PMC); 79 references in the paper
Research resources: Rabbit anti-TRKA RRID:AB_10658910, Rabbit anti-NEUN RRID:AB_10807945, Rabbit anti-BRN3A RRID:AB_1640222, Mouse anti-CGRP RRID:AB_1658411, Goat anti-PERIPHERIN RRID:AB_2171328, Mouse anti-TUJ1 RRID:AB_2313773, Rabbit anti-TRPV1 RRID:AB_2313819, Rabbit anti-RET RRID:AB_2341013, Rabbit anti-PAX6 RRID:AB_2565003, Rabbit anti-SYNAPTOPHYSIN RRID:AB_301417, Chicken anti-GFAP RRID:AB_304558, Rabbit anti-CASPASE3 RRID:AB_443014, Goat anti-SIX1 RRID:AB_641021, Rabbit anti-cMET RRID:AB_880695, Rabbit anti-ISLET-1 RRID:AB_881306

Abstract

Pain disorders such as neuropathic pain and headache remain areas of considerable unmet need and considered high risk by pharma. Human-induced pluripotent stem cells (iPSC)-derived sensory neurons have already been used to accelerate translational research but the current differentiation protocols produce non-peptidergic nociceptors. We demonstrate for the first time the robust differentiation of hiPSC into peptidergic nociceptor lineage with high yield. These nociceptors express CGRP and TRPV1 and show functional maturity including the expression of TTX-resistant currents and responding to TRPV1 and TRPA1 agonists. Importantly, they were able to release CGRP basally and upon stimulation by inflammatory soup, which was inhibited upon the application of the 5-HT1B/1D/1F agonist, sumatriptan, a migraine prophylactic drug. We report the successful generation of a novel in vitro functional peptidergic nociceptor model which will allow investigation of disease mechanisms in pain and translational phenotypic drug screening for new effective pain therapies.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

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Data

No dataset and no data link were found in the paper.

Data and code availability

Single-cell RNA-seq data have been deposited at GEO at GEO: GSE331403 and are publicly available as of the date of publication. All data reported in this paper will be shared by the lead contact upon request. This paper does not report original code.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Galbha Duggal (0000-0001-5969-0825); M. Zameel Cader (0000-0002-6952-406X); removed Galbha Duggal; M. Zameel Cader

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 10 keywords, 7 MeSH terms, 5 funders, 77 references, 15 RRIDs.

Cite

This paper

Duggal, G., Li, X., Pettingill, P., Lalic, T., Gupta, S. K., Høgsbro, C. F., Volpato, V., Webber, C., Bowden, R., Charou, D., Arunasalam, K., Maresca, M., Hicks, R., Chintawar, S., & Cader, M. Z. (2026). A highly efficient method to differentiate CGRP-expressing peptidergic nociceptors from human induced pluripotent stem cells. Stem cell reports, 21(7), 102971. https://doi.org/10.1016/j.stemcr.2026.102971

BibTeX

@article{duggal2026highly,
author = {Duggal, Galbha and Li, Xinyu and Pettingill, Philippa and Lalic, Tatjana and Gupta, Shailesh Kumar and Høgsbro, Christine Flodgaard and Volpato, Viola and Webber, Caleb and Bowden, Rory and Charou, Despoina and Arunasalam, Kanisa and Maresca, Marcello and Hicks, Ryan and Chintawar, Satyan and Cader, M. Zameel},
title = {{A highly efficient method to differentiate CGRP-expressing peptidergic nociceptors from human induced pluripotent stem cells}},
journal = {Stem cell reports},
year = {2026},
month = jun,
volume = {21},
number = {7},
pages = {102971},
publisher = {Elsevier},
issn = {2213-6711},
doi = {10.1016/j.stemcr.2026.102971},
url = {https://doi.org/10.1016/j.stemcr.2026.102971},
pmid = {42349425},
pmcid = {PMC13385448}
}

RIS

TY - JOUR
AU - Duggal, Galbha
AU - Li, Xinyu
AU - Pettingill, Philippa
AU - Lalic, Tatjana
AU - Gupta, Shailesh Kumar
AU - Høgsbro, Christine Flodgaard
AU - Volpato, Viola
AU - Webber, Caleb
AU - Bowden, Rory
AU - Charou, Despoina
AU - Arunasalam, Kanisa
AU - Maresca, Marcello
AU - Hicks, Ryan
AU - Chintawar, Satyan
AU - Cader, M. Zameel
TI - A highly efficient method to differentiate CGRP-expressing peptidergic nociceptors from human induced pluripotent stem cells
T2 - Stem cell reports
J2 - Stem Cell Reports
PY - 2026
DA - 2026/06/25
VL - 21
IS - 7
SP - 102971
SN - 2213-6711
PB - Elsevier
DO - 10.1016/j.stemcr.2026.102971
UR - https://doi.org/10.1016/j.stemcr.2026.102971
LA - en
ER -

CSL-JSON

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