Abstract
Here we provide new technology for generating human peptidergic nociceptive sensory neurons in a straightforward and efficient way. The cellular source, human epidermal neural crest stem cells (hEPI-NCSC), consists of multipotent somatic stem cells that reside in the bulge of hair follicles. hEPI-NCSC and primary sensory neurons have a common origin, the embryonic neural crest. For directed differentiation, hEPI-NCSC were exposed to pertinent growth factors and small molecules in order to modulate master signalling networks involved in differentiation of neural crest cells into postmitotic peptidergic sensory neurons during embryonic development. The neuronal populations were homogenous in regard to antibody marker expression. Cells were immunoreactive for essential master regulatory genes, including NGN1/2, SOX10, and BRN3a among others, and for the pain-mediating genes substance P (SP), calcitonin gene related protein (CGRP) and the TRPV1 channel. Approximately 30% of total cells responded to capsaicin, indicating that they expressed an active TRPV1 channel. In summary, hEPI-NCSC are a biologically relevant and easily available source of somatic stem cells for generating human peptidergic nociceptive neurons without the need for genetic manipulation and cell purification. As no analgesics exist that specifically target TRPV1, a ready supply of high-quality human peptidergic nociceptive sensory neurons could open the way for new approaches, in a biologically relevant cellular context, to drug discovery and patient-specific disease modelling that is aimed at pain control, and as such is highly desirable.
Highlights
Many serious diseases, including cancer, heart disease, diabetes, AIDS and arthritis, are often associated with unmitigated pain
This publication reflects only the authors’ views and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein and StemBANCC
Because neural crest cells give rise to nociceptive peptidergic sensory neurons, the overall goal of the present study was to determine whether hEPI-NCSC could be differentiated efficiently into peptidergic nociceptive neurons that respond to capsaicin
Summary
Many serious diseases, including cancer, heart disease, diabetes, AIDS and arthritis, are often associated with unmitigated pain. Despite major advances in our understanding of the molecular mechanisms underlying pain and even though the potential drug targets identified by the pharmaceutical industry have increased dramatically, there are still only a few analgesic drug classes, primarily opioids and aspirin-like drugs, all of which have safety issues [1]. HEPI-NCSC derived nociceptive peptidergic sensory neurons from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution (MSB). This publication reflects only the authors’ views and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein and StemBANCC. The human foetal material was provided by the Joint MRC/Wellcome Trust (grant # 099175/Z/12/Z) Human Developmental Biology Resource (http://www.hdbr.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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